Autoimmune News

Suffering human are a "scarce social resource" that must not be jeopardized by allowing clinical trial access to all

2010-06-05T19:14:00.000-07:00

I found an opinion piece by a couple of prominent bio"ethicists" telling why cures for the suffering and dying must be delayed. The sick and dying cannot have access to cures that rats and mice can get now. It is important really to let us suffer. Yes, very, very important. See if researchers who found cures for our diseases in lab animals were allowed to use them immediately on the sick who are begging for them, well then there might not be enough volunteers for the 'careful' clinical trials that make armies of clinical trial workers fortunes.

I stopped counting at 22 lab animal out and out cures or treatment as good as cures for autoimmune disease like my son is crippled with and have so limited my life as well. Yes 22 things a mouse can have that you I and my son cannot because those clinical trials need 'fresh meat' for their trials.

It would be different if the multi-billion dollar clinical trial industry allowed every patient in that asked to be in. But the dirty little secret of the clinical trial billion dollar industry is that they exclude tens of thousands of critically ill patients who have the illnesses they are testing for but who do not have the right inclusionary or exclusionary criteria (too young, too old, too long with the disease, too short a time with the disease, not every one of the symptoms, or having an additional disease as well as the tested disease, which is all too common for autoimmune patients, or you live too far away, or, or, or, etc.).

I know because my son has happened twice been rejected for clinical trials. Even though he had the right condition and we lived close by the testing center, and he was the right age, he did not have a lesion quite large enough for the study. There were dozens of other trials I did not even apply to because the inclusionary/exclusionary criteria were so specific, so tightly written that he had no chance.

But when the medication is approved by the FDA, everyone has access not just the ones who have those narrow inclusionary and exclusionary criteria. So why not test everyone?

Our bio"ethics" friends do not see the tens of thousands turned away. Nor do they care about their suffering and deaths. They see it as "ethical" to let the suffering continue because, hey, we have to have thousands of human lab rats so that the clinical trial folks can pick a few dozen lucky ones to get a chance at the new meds or treatment.

For thousands of years civilizations and cultures found treatments and cures for illnesses the old fashion way trial and error. Some folks died. True. But many more were saved when the right treatment and dosage was established. I would be proud to volunteer and if need be die, just for the chance that my son could get a cure a day earlier. Why should he live in misery when there are so many ways that might allow his immune system to function normally?

What does society gain by spending one billion dollars and ten years on each and every new medication that comes out? Nothing. The only ones who gain are the folks who work in the multi billion dollar clinical trial industry.

Every one else loses.

The patients lose a chance at years of healthy lives or living at all. Big Pharma loses billions on the trials which means obscenely high costs for new meds.

The last bill for my son's seven vials of Remicade was 7K!!! He has an infusion every six weeks. My retirement age wife must keep working, so we have insurance which pays ever lesser amounts--now about 3/4ths of the cost which is pretty much my entire disability retirement. Could the meds be cheaper if clinical trial costs were less? Of course!

No one gains anything from the current immoral system except those employed in the clinical trial industry.

In ten minutes you and I could put together a much faster and more ethical system that would still be safer than the age old trial and error method of the curanderos, witch doctors, and forest herbalists.

Simply designate an institution as the National Testing Center. Free the Center of all FDA slowdowns and all risk of lawsuits or liability. Only patients who signed extensive informed waivers allowed in. The place funded half by government, half by Big Pharma. The rights to profits from the cures divided into three. One part to the government, one part to the person(s) whose idea it was, one part to Big Pharma based on the percentage they contribute to the National Testing Center. All patients who volunteer, every one of them, allowed to participate in trials.

The only goal of the National Testing Center is a cure as fast as possible. No other agenda. Only cures. Safety is not as important as cures. Money is not as important as cures. Delays for playing double blind games not allowed (of course we must have some good tests to keep track of disease progression--perhaps T reg competence?) Nothing gets in the way of cures as fast as possible.

At this Center everything is tried. All the cures for the mice. Every idea tested. Also all patients encouraged to keep an open access online journal of what is happening to him/her--treatment symptoms, problems, discomforts, successes. Anyone, especially potential patients, allowed to read what is written on the on line blogs. Those who died have their name memorialized on a Wall of Heroes that is the first thing seen when entering. Everyone would understand the risks. But we would also understand the incredible heroism of those who were freely willing to die to find that ultimate cure.

There would have to be an adjudication court to decide what percentage of profits the various "idea folks" contributed to the cures, yet even here there are easy solutions and models to choose from.

So why don't we do this simple quick thing to end suffering and death? Incidentally it would likely make the United States the center for cures for the world. It would bring unprecedented wealth to our country. No more Great Recession, no more trillions in debt to the Chinese. Who could be against this idea of fast cures now?

The Clinical Trial billion dollar industry! And the "cover your ass" bureaucrats at the FDA who are terrified to say yes to anything novel or new. No one else. Well except for the two bio "ethicists", Jonathan Kimmelman and Alex John London, writing in the article in blue below.

Please note: I have added bold face to written lines in their opinion piece that I find most ethically challenged. Did you know for instance, that your sick and pained body is a "scare social resource" that must be preserved in pain for the benefit of the clinical trial industry? Or that "providing dying patients access" is not a "true measure of a clinical trials worth"? Translation providing access for the sick and dying makes money for no one under the current byzantine clinical trial system.

http://www.scienceprogress.org/2010/06/clinical-trials-and-the-common-good/

BIOETHICS
Clinical Trials and the Common Good
Testing Innovative Therapies Is More than a Private Affair

By Jonathan Kimmelman and Alex John London | Tuesday, June 1st, 2010

It’s a drama that plays out again and again wherever cutting-edge science meets mortal disease. First, researchers test a therapy that works miracles in animals. Expectant patients flock to those researchers. But then regulatory authorities and ethics committees prevent the researchers from offering the new therapy because of concerns about safety or the science behind the animal study.

Some critics view this as a perversion of medical ethics. What happens between dying patients and their physicians, according to these critics, belongs to them and them alone. They further argue that oversight and ethics are now impeding medical progress. We think these critics are wrong on both counts.

Clinical research is not a private act. It is, instead, a public activity. For one, it is aimed primarily at producing a public good: the knowledge communities require to address their unmet health needs. For another, clinical trials are much larger than private transactions between consenting patients and researchers. The development of new therapies is, in the end, a group endeavor: taxpayers support basic research, companies fund trials, academic medical centers provide the space and equipment, and scientists conduct the research. The true measure of a clinical trial’s worth is not whether it provides dying patients access to unproven medications, but rather, whether it produces a bountiful yield of knowledge that empowers future healthcare providers.

Trials of novel interventions often occur at the vanguard of science, and each stage in the process of translating basic research into clinically useful interventions depends critically on the quality of the information generated at prior stages. As a result, physicians and patients will often have a difficult time distinguishing strong studies from weaker ones. Physicians and patient-volunteers thus lack the ability to reward producers of strong studies by joining their trials and avoiding studies of lesser scientific quality. Oversight structures are necessary to ensure that studies are rigorously designed and that they will pass on valuable knowledge to the next link in the chain of discovery. They also help to ensure that participants, physicians, researchers, and investors can pursue their individual interests without compromising the social mission of the research enterprise.

Clinical trials that are unsafe, or that have a poor scientific justification, pose several threats to the kinds of cooperation needed to transform hard-won advances in basic science into improved care at the bedside. A string of disappointing clinical trials can lead sponsors and scientists to prematurely withdraw support from an otherwise promising area. Unexpected and/or mismanaged safety issues can sully the standing of an entire field and interrupt recruitment of talented researchers and investment from academic research centers.

Poorly justified or unsafe clinical trials also threaten a misallocation of scarce social resources. Patient-volunteers, for instance, are in short supply for many types of research, and fewer than 60 percent of National Cancer Institute-funded clinical trials are able to recruit enough volunteers to complete the study. It is a legitimate ethical concern if scientifically unsound studies draw volunteers away from studies that have greater merit. Another way that trials place demands on scarce resources is through personnel: trials require highly specialized medical expertise. Medical scientists who commit their expertise to weak trials are less able to contribute to other, more worthy research endeavors.

Unfortunately, medical research has a long way to go in terms of strengthening the scientific justification for testing novel therapies like stem cells, vaccines, or approaches involving gene transfer. Animal studies are often poorly designed, executed, and reported. In some cases, interventions are introduced into humans in ways that deviate from what was tested in animals. One recent study showed that preclinical researchers often do not publish all their animal studies, leading to significant overestimates of a drug’s effectiveness. It is not at all clear that oversight bodies and ethics committees, which focus on the willingness of researchers and patient-volunteers to undertake a study, do an adequate job promoting the scientific quality of clinical studies.

Policy proposals that would seek to loosen scientific standards so that patients can more easily access unproven therapies miss the point of research. To preserve the power of clinical research as an engine for scientific advancement, we must recognize that successful scientific innovation requires the sustained cooperation of myriad stakeholders and that the knowledge that results from this extended collaboration represents an important social good.

Jonathan Kimmelman is Associate Professor, Biomedical Ethics Unit and Department of Social Studies and Medicine at McGill University. Alex John London is Associate Professor of Philosophy and Director of the Center for the Advancement of Applied Ethics and Political Philosophy at Carnegie Mellon University

New evidence that incompetent T regs are a root cause of asthma perhaps allergy and autoimmune as well

2010-05-18T21:34:00.000-07:00

We know from previous research that the T reg or"good guy" cells in folks with autoimmune disease seemed to be 'incompetent'. They appeared to not be able to turn off the inappropriate autoimmune reaction started by the auto reactive antibodies ( think tiny chemical guided missiles) produced by 'rogue" B cells and continued and increased by the 'bad guy' T effector cells. The autoantibodies label our cells as needing to be attacked and the T effectors enthusiastically follow their directions.

We think we know that T regs in folks with normally functioning immune systems seem able to tamp down the autoimmune reactions before they start.

Apparently those of us suffering from one of the 80 or so named autoimmune disease could use properly functioning T regs. Perhaps the T regs working as they should would be enough to stop disease progression. No one is quite sure, but it is beginning to appear more and more like that may be true.

Now we have evidence that malfunctioning T regs may be at the heart of asthma as well. It seems that folks with asthma have lots of extra T regs in their lungs. Far more than in the lungs of folks without asthma. This is what we would expect if the job of T regs was to settle down over active immune responses like inflammation in the lungs.

You see the T regs of those of us with asthma still answer the call to stop the autoimmune inflammatory damage but when they get to the correct site in the body, they are incompetent. They cannot do their job. Hence more and more T regs are called in by the out of control inflammatory signals being given off by the damaged tissue. Sadly no matter how many T regs arrive, they cannot do anything to help.

If a way could be found to fix our T regs with some form of the multiple ways we know to change gene expression than we might get competent correctly functioning T regs. Please God from my hand to your ear. Then at least some if not all asthma, allergy, eczema, and autoimmune disease might be able to be stopped.

That day is still a long way off. But heroic lab scientist keep chipping away at what we do not know so that one day we will know enough so no one has to suffer from these horrors again.

Below is an abstract of a study done by fine folks at the University of Manchester which found the extra T regs in the lungs of asthma patients thus linking a possible cause of asthma with a probable cause of other autoimmune disease. Note when they mention 'effector lymphocyte activity' they are talking about our old nemesis, the 'bad guy' cells, T effectors. T effs attack our tissues in autoimmune disease.

One might infer that some kind of plasmapheresis or shifting/sorting of our blood cells to eliminate T effectors would stop disease, but sadly the T effs may be just a different side of the same coin that is T regs. Eliminate T effectors and then our incompetent T regs would convert into competent T effectors. Some studies appear to show that T effs change into T regs and vice versa.

The likely problem that we, the afflicted, have with our immune system, then, is that our T regs somehow do not function correctly to stop inflammation in the T reg configuration, but when they are in the T effector configuration they can function to cause inflammation, tissue damage and the killing of pathogens.

Probably if the T effectors configuration did not function correctly we would have died of infection long ago. So instead of hating them for the pain they cause, we should be glad that they can function to stop disease. They just are like unruly guard dogs that attack everything friend and foe alike. Hopefully someday we will have a method to train them to behave.

Here is the abstract:

Chest. 2010 May 7. [Epub ahead of print]
Increased airway T regulatory cells in asthmatic subjects.
Smyth LJ, Eustace A, Kolsum U, Blaikely J, Singh D.
University of Manchester, NIHR Translational Research Facility, Manchester Academic Health Science Centre, University Hospital Of South Manchester Foundation Trust, Southmoor Road, Manchester, UK. M23 9LT.

Abstract
BACKGROUND: Tregulatory cells (Tregs) may play a role in suppression of effector lymphocyte activity in asthma. We hypothesized that Treg numbers would be increased in patients with more severe asthma. We also investigated the regulatory function of CD4 cells by expression of CTLA4, and the number of these cells that are intra-epithelial lymphocytes expressing CD103.

OBJECTIVES: The primary aim was to investigate Treg numbers in the BAL of patients with moderate to severe asthma compared to mild asthma and healthy controls. The secondary aim was to investigate BAL CD4+CTLA4 and CD4+CD103 expression in these groups.

METHODS: Airway lymphocytes obtained by bronchoscopy from healthy controls (6), patients with mild (15) and moderate to severe asthma (13) were characterised by multi-parameter flow cytometric analysis using 3 methods to determine the numbers of CD4+ Treg cells: CD4+CD25(bright), CD4+CD25+CD127-, CD4+FoxP3+.

RESULTS: %CD4+FoxP3+ Tregs were increased in BAL of patients with moderate to severe asthma (median 4.8%) compared to both mild asthma patients (median 2.5%, p=0.03) and healthy subjects (median 0.95, p=0.003). Similar findings were observed for CD4+CD25+CD127- Treg numbers, but not CD4CD25(bright). CD4+ CTLA4 and CD103 expression were raised in moderate to severe asthma patients compared to mild asthma and healthy controls.

CONCLUSIONS: The number of cells displaying regulatory capacity, either through FoxP3 expression or CTLA4 expression, are increased in moderate to severe asthma. CD4+CD103+ intra-epithelial lymphocytes can be retained at tissue sites of inflammation; our findings indicate a role for these cells in asthma pathophysiology.

PMID: 20453071 [PubMed - as supplied by publisher]

Keep on Cleaning Surfaces and Washing hands, MRSA Rates are up Ten Fold

2010-05-17T13:43:00.000-07:00

Dangerous skin and surface transferred bacteria (MRSA being only one) continue to increase in prevalence (and much worse virulence) throughout the United States. With no new antibiotics on the horizon and the ones we now use having little or no effect the only measure to limit these resistant bacteria is ever more cleaning and hand washing.

Ten percent bleach solutions are the best for killing these bacteria on surfaces. Alcohol also is capable of killing many of these bacteria, but is not as comprehensive as bleach solutions. Ultra violet light (as in sunlight) also kills them. Soap and water does very little but spread them around on the contaminated surfaces.

Any surface touched by any human can harbor these bacteria. The bacteria can still be cultured from completely dry surfaces for weeks after being initially contaminated. Bare wood is the safest surface material as they seem to die rather quickly on wood. Plastic is the absolute worse. An eight week test with various materials including plastic, metal, wood and cloth found that there was no diminishment in infectivity on plastic over the eight week period. Dry cloth as in sheets, towels and pillow cases was also surprising capable of causing infections for weeks. It had been thought that bacteria died on linens and towels rather quickly. But in this test using MRSA they did not. Why they survive so long on cloth, is unknown. With plastic there seems to be a good reason for their extremely long survival. Apparently even smooth feeling plastic contains millions of tiny depressions in the surface that are perfect incubators for bacteria.

Door handles, computer key boards, desk tops, text book covers are all key areas that may contain these newly evolved antibiotic resistant bacteria.

Good luck out there. Keep cleaning commonly touched areas in the classroom and keep washing your hands regularly. (Even though soap and water mostly move the bacteria around on surfaces, they are effective on the hands as the soap lifts the bacteria and running water carries them off the hands to the drain.)

A good way to know if you have washed long enough is to repeat the ABC song in your head as you wash. Wash all surfaces on your hands especially the finger tips. Scrub hard you are using friction and lubrication to break the connection of the bacteria to your skin cells. Once the connections are broken and loosen by soap and friction, away go the bacteria. It seems that bacteria have millions of tiny villi on their surfaces that act a lot like Velcro, but soap loosens their hold on human skin cells. When you finish the ABC song you have probably washed sufficiently.

The number of children hospitalized with dangerous drug-resistant staph infections surged tenfold in recent years, a study has found.

Disease incidence increased from two cases to 21 cases per 1,000 hospital admissions from 1999 to 2008. Most infections were caught in the community, not in the hospital.

The study, which was published Monday in the journal Pediatrics, involved methicillin-resistant staph infections, called MRSA. These used to occur mostly in hospitals and nursing homes, but they are increasingly showing up in other settings among children and adults. Recent evidence suggests hospital-acquired MRSA cases may be declining while community-acquired cases are becoming more common.

The results are "a good example of how something that is not unexpected remains alarming," said Dr. Buddy Creech, an infectious disease specialist at Vanderbilt University who was not involved in the study.

The study involved 25 children's hospitals; the tenfold increase in hospitalizations probably occurred nationwide, said Dr. Jason Newland, the lead author and an infectious disease physician at Children's Mercy Hospitals and Clinics in Kansas City, Mo., and the University of Missouri-Kansas City.

Almost 30,000 children were hospitalized with MRSA infections at the hospitals studied during the 10-year period. Most had skin or muscle infections, and 374 of them died. Although NewlandMRSA caused those deaths, it can be deadly and is blamed for more than 18,000 deaths in children and adults nationwide each year.

The study didn't examine whether deaths or the severity of infections increased.

http://www.latimes.com/news/nationworld/nation/la-na-staph-20100517,0,5579892.story

Genentech offers real hope for ending allergy and asthma

2010-05-15T18:27:00.000-07:00

I believe we have real hope for an effective long term way to turn off inappropriate allergy and asthma symptoms. Genentech which is among the largest biotech companies in the world if not the largest has announced they have discovered a way to not only differentiate the bad guy B cells that cause our allergic reactions but to selectively block the function of only these B cells leaving the rest of the B cell population intact. Since B cells make the antibodies that protect us from virus and bacterial attack (and possible death without them), it is HUGE news to have found a way to have selectively turned off just the "bad guy" B cells responsible for the "evil" IgE that makes so many of our lives so miserable.

Genentech is also a deep pocket company so it should be able to finance the extremely expensive, tortuously long and Byzantinely complex Food and Drug Administration required clinical trial ordeal. (FDA rhymes with delay.) Many potential cures for autoimmune and allergic diseases have been lost to patients by the "valley of death" caused by these immoral barricades the FDA puts between laboratory discovered potential cures and patients. Some of these delays seem to have to do with politics of Big Pharma and their real goal of profits, profits, profits. Delays that increase profits for Big Pharma are good delays. Since FDA derives significant funding from Big Pharma whatever Big Pharma wants, Big Pharma gets. But Genentech is a member of Big Pharma. As such their treatment might actually get through. Let's hope so.

Of course we have all been disappointed by past promises for good allergy treatments, Xolair comes to mind. I hope that Genentech is being truthful with their announcement in the prestigious Journal of Clinical Investigations. Some companies seem to over hype announcements like this--say for instance Osiris' Prochymal. So who knows? But I do believe there is real hope that our children may have truly effective treatments for allergies and asthma. Base on the article below, this Genentech breakthrough appears to be one likely candidate.

If this works for allergy and asthma, similar selective monoclonals might work for autoimmune disease as well. If we could only turn off the "bad" B cells that are making the auto antibodies which keep the autoimmune disease pot boiling, then the symptoms of the autoimmune disease would end. Go new science discoveries!

-----------------------------

Eliminating the Source of Asthma Causing Immune Molecules

ScienceDaily (May 11, 2010) — Asthma and other allergic diseases are caused by inappropriate immune responses. Soluble IgE molecules, produced by immune cells known as B cells, are key immune mediators of these diseases. Therapeutic targeting of IgE in the blood can neutralize its effects and is an effective treatment for moderate-to-severe allergic asthma. However, this approach does not halt IgE production and patients need to be treated repeatedly.

But now, a team of researchers, at Genentech Inc., South San Francisco, has developed a way to specifically eliminate IgE-producing B cells, providing a potential new long-lasting therapeutic approach to treating asthma and other allergic diseases.

IgE-producing B cells express on their surface an IgE molecule that is slightly different to the IgE molecules that they secrete. The team, led by Lawren Wu, generated a therapeutic molecule known as a monoclonal antibody that targets the portion of human IgE that is contained in IgE molecules on the surface of B cells but not in IgE molecules in the blood. When mice expressing human IgE were treated with this monoclonal antibody, their levels of IgE in the blood decreased substantially as did their numbers of IgE-producing B cells.

As the monoclonal antibody provided mice with protection in a model of allergic asthma, the authors suggest that targeting IgE-producing B cells using monoclonal antibodies similar to those described in this study might be of benefit to individuals with asthma and other allergic diseases.

The research appears in the Journal of Clinical Investigation.

http://www.sciencedaily.com/releases/2010/05/100510174620.htm

More Autoimmune hope, Re-vitalizing T-Regs

2010-03-26T21:19:00.000-07:00

There was more solid hope in the medical news today for a universal cure for autoimmune. Of course the cure currently is for mice, not people. But the principle of getting the "good guy" cells, the T-regulatory cells, to wake up and work correctly could stop autoimmune in its tracks. T regs turn off the "bad guy" cells, the T effector's attack mode thus turning off the autoimmune rampage of those "bad guy" cells.

If this trick works in humans, it could end most kinds of autoimmune diseases and most allergy and asthma as well.

Of course if the T-regs function is turned up too high and they work too well, then contagious disease or immune system suppressed viruses might become a dangerous problem (Think of the fatal PML virus be re-awakened in some Orencia and Rituxan patients).

The article mentions this technique for Rheumatoid Arthritis but it should work for a subset of patients with virtually any autoimmune diseases with the possible exception of lupus (SLE).

Here is the article:

http://www.physorg.com/news188746767.html
Finding a potential new target for treating rheumatoid arthritis
March 25, 2010
By enhancing the activity of immune cells that protect against runaway inflammation, researchers at NYU Langone Medical Center may have found a novel therapy for rheumatoid arthritis and other autoimmune diseases. In a new study published in the March 25, 2010 online edition of Science, the researchers reveal how treating these immune cells with an investigational drug wards off inflammation by holding a particular enzyme at bay.

"This is an unusual mechanism that could provide a potential therapeutic approach for the treatment of autoimmune diseases like rheumatoid arthritis or inflammatory diseases like Crohn's disease," says Michael Dustin, PhD, the Irene Diamond Professor of Immunology and professor of pathology at NYU Langone Medical Center.
The new study was spearheaded by Alexandra Zanin-Zhorov, PhD, a post-doctoral fellow in Dr. Dustin's lab, in collaboration with Juan Lafaille, PhD, associate professor of pathology and medicine, and Steven Abramson, MD, professor of medicine and pathology and director of the Division of Rheumatology. The research was supported in large part by a five-year grant from the National Institutes of Health Roadmap for Medical Research funding initiative, under its Nanomedicine Development Center Program.

Joint-destroying rheumatoid arthritis is generally considered an autoimmune disorder spurred on by the hyperactivity of conventional T cells that fight off infections, cancer, and other diseases. Within the past few years, researchers at NYU and other institutions have learned that other immune system components known as regulatory T cells counterbalance the tendency of conventional T cells to become overactive, thus holding inflammation in check.

These regulatory T cells exert their influence by communicating with other parts of the immune system. Through molecular detective work and powerful microscopy, the new study's collaborators found that an enzyme known as protein kinase C theta is only partly activated in regulatory T cells. When the regulatory cells are most active, in fact, most of the interfering enzyme is physically kept far away from the area important for cell-cell communication. "It's a very unique distribution," Dr. Dustin says. "In conventional T cells this enzyme is normally moved to the area where the cells are making contact. But in regulatory T cells, the enzyme is as far away as it can get from where the cells are communicating."

Based on that observation, the researchers began testing inhibitors of this kinase enzyme, including a molecule known as Compound 20 that had been in development by pharmaceutical company Boehringer Ingelheim. Surprisingly, the compound boosted the normal activity of regulatory T cells by about five-fold. The researchers found that specifically blocking the activity of the kinase enzyme augmented the natural tendency of the regulatory T cell to keep it out of the communication channels. Thus, the compound enhanced the regulatory cells' anti-inflammation activity.

The Yin and Yang of T cells in Rheumatoid Arthritis

In rheumatoid arthritis, either an abnormal surge by infection-fighting T cells or a dip in the activity of inflammatory-fighting T cells—or perhaps both—could cause the immune system to attack our own joints instead. "Therefore, if you have an abnormal and suppressed regulatory T cell function, you have enhanced potential for autoimmunity," says Dr. Abramson.

The researchers bolstered previous evidence for such a link by examining the blood of 25 patients with varying degrees of rheumatoid arthritis. "In essence, what we were able to show is that if you look at this regulatory T cell population in rheumatoid arthritis patients, it is abnormally low in function, and the sicker the patients are, the more depressed that cell function is," says Dr. Abramson.

The defective regulatory cells from these patients were revived in tissue cultures with this enzyme inhibitor, the study showed. "We could get them back to almost a normal level of activity, like what you'd see in a healthy individual," says Dr. Dustin.

The researchers also tested the Compound 20 inhibitor in a mouse version of Crohn's disease, which is characterized by intestinal inflammation. When the researchers treated the regulatory T cells with the enzyme inhibitor and then injected them into the mice, their anti-inflammation activity rose so much that they essentially protected the mice from the disease, even though the cells were outnumbered four to one by their pro-inflammatory counterparts.

"The theory is that if you could restore normal regulatory T cell function, then you could restore their ability to suppress the inflammation process, and prevent this abnormal destruction of your joints," Dr. Abramson says.
Provided by New York University School of Medicine

Compugen provides new hope for a universal autoimmune treatment

2010-02-09T01:45:00.000-08:00

Compugen discovery of a molecule that can turn off the misbehaving autoimmune part of our immune response while leaving intact the part that fights bacterial and viral disease could be game changer in the field of autoimmune treatments.

The results are in preclinical trials, in the mouse model of multiple sclerosis. We cannot get our hopes up too high. However just the fact that researchers are still generating new and innovative ideas especially one that could be helpful for so many autoimmune diseases does let one contemplate a future without the horror of autoimmune.

Read more here:
http://www.genengnews.com/news/bnitem.aspx?name=74501514

Hookworms fail to cure asthma. Our hopes dashed.

2010-01-12T13:54:00.000-08:00

I hate to report this news. One of the greatest hopes for a 'miracle cure' of asthma, allergy and possibly autoimmune disease has failed in a scientifically controlled clinical trial at the University of Nottingham in England.

As many of you know the group of researchers at Nottingham was the only research group in the world willing to clinically test HUMAN parasitic worms as a way to control or even cure asthma.

The idea of parasitic worms as therapy for our certain autoimmune and allergic diseases was first pioneered by Joel Weinstock then of the University of Iowa.

Weinstock used pig whipworms which could not survive in humans more than a few weeks. He claimed to have success in treating irritable bowel and colitis disorders with these pig parasitic worms. However, the worms being in the wrong host died in a few weeks and whatever benefit they gave to infected patients did not last. Weinstock could not get permission to use human worm parasites.

In the United States, Food and Drug Administration approval is needed for any clinical trial and the FDA insisted on parasites that could not survive in humans and possibly be retransmitted to others.

I like many of you was very disappointed that the US FDA refused requests for trials with human parasites or even with more trials with pig whip worms. We felt that the effects of parasites on calming a hosts immune system held great hope for our diseases. We especially felt that a HUMAN parasite would be much more likely to secret closer analogs to IL-10 and other human immune molecules that reduced inflammation and calmed our over active immune systems. We still held on to our hope that allergy, asthma and autoimmune disease could be helped by these parasites.

In stepped the courageous researchers at the Statens Serum Institut in Copenhagen Denmark who scientifically tested pig whipworms eggs (TSO's--Trichuris suis ovum) for efficacy in treating allergy. In October of last year, our Copenhagen friends released the disappointing results. The pig whipworms failed to help allergy. Perhaps there is still some slight hope that the pig whipworms might help various autoimmune digestive disorders like IBS, IBD, colitis and Crohn's. However their failure to help allergies seems to have thrown cold water even on this dimming hope.

http://autoimmunenews.blogspot.com/2009/12/tso-helmith-therapy-fails-to-stop.html

Even after the Danish disappointment, there was still hope for sufferers of allergy, asthma, and autoimmune disease looking for a cure. Perhaps a very different kind of intestinal parasite might help--the hook worms.

Hookworms are in a completely different group of worms--the flat worm family (trematodes) as opposed to the round worm family (nematodes) that the whipworms are in. Perhaps this different family of parasites would work better than the whipworms especially if a HUMAN parasite was used.

Brave researchers at the University of Nottingham decided to give human hookworms a scientifically controlled clinical trial. We held out hope that these researchers would succeed in finally achieving clinical success. Our friends at Nottingham had somehow gained permission to conduct a real scientific trial of actual human parasite. Quick and easy cures with worm parasites still seemed possible.

Sadly our hopes are dashed again. The trial at the University of Nottingham failed to show a clinically significant difference between the group getting the human hookworms and the group who got sham shots of histamines as a control.

The hookworm larva do not enter the body through the mouth as do whipworms. They burrow through the skin which causes a mild rash and some itching. So the control group had to be given something that would duplicate this rash--histamine.

For a clinical trial to be valid neither the doctor nor the patients should know which group of patients received the 'treatment' and which group of patients did not (This process is called doing a "double blind, randomized" procedure.). Those who do not receive treatment must have similar symptoms initially as those that do, hence the histamine.

Sadly the truly infected hook worm group did not show any significantly better asthma control than the sham hook worm infected histamine group. What a huge disappointment!

Read more here:

http://www.docguide.com/news/content.nsf/PaperFrameSet?OpenForm&newsid=852576140048867A85257698004257D3&topabstract=1&u=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=20030661

I have put in bold face type the most significant sentences in the summary below of the University of Nottingham hookworm results for asthma patients:

Clin Exp Allergy. 2009 Dec 16. [Epub ahead of print]
Experimental hookworm infection: a randomized placebo-controlled trial in asthma.
Feary JR, Venn AJ, Mortimer K, Brown AP, Hooi D, Falcone FH, Pritchard DI, Britton JR.

Division of Epidemiology and Public Health, University of Nottingham, Nottingham, UK.
Summary Background Epidemiological studies suggest that hookworm infection protects against asthma, and therefore that hookworm infection may have a direct or an indirect therapeutic potential in this disease. We now report the first clinical trial of experimental hookworm infection in people with allergic asthma.

Objectives To determine the effects of experimental hookworm infection in asthma.

Methods Thirty-two individuals with asthma and measurable airway responsiveness to adenosine monophosphate (AMP) were randomized and double blinded to cutaneous administration of either ten Necator americanus larvae, or histamine solution (placebo), and followed for 16 weeks. The primary outcome was the change in provocation dose of inhaled AMP required to reduce forced expiratory volume in 1 s by 20% (PD(20)AMP) from baseline to week 16. Secondary outcomes included change in several measures of asthma control and allergen skin sensitivity and the occurrence of adverse effects.

Results Mean PD(20)AMP improved in both groups, more in the hookworm [1.49 doubling doses (DD)] than the placebo group (0.98 DD), but the difference between groups was not significant (0.51 DD; 95% confidence interval: -1.79 to 2.80; P=0.65). There were no significant differences between the two groups for other measures of asthma control or allergen skin sensitization. Infection was generally well tolerated.

Conclusions: Experimental infection with ten hookworm larvae in asthma did not result in significant improvement in bronchial responsiveness or other measures of asthma control in this study. However, infection was well tolerated and resulted in a non-significant improvement in airway responsiveness, indicating that further studies that mimic more closely natural infection are feasible and should be undertaken.

PMID: 20030661 [PubMed - as supplied by publisher]

Antibiotic Resistance, My Illness (death?)--Big Pharma's role

2010-01-04T16:21:00.000-08:00

Over the last six weeks I have been fighting an infection in my nose and sinuses that has defeated antibiotic after antibiotic. I am scared.

I have a hypersensitivity disorder and have been hospitalized twice before with reactions to antibiotics and have had a couple of near death experiences. NOT FUN.

So far the only antibiotic I have tried that actually KILLED the damn bacteria in my nose was a sulfa drug, but after five doses I had a hypersensitivity reaction and was forced to stop.

The quinolone, Avalox, did not kill the bacteria.

Even the highly restricted super drug, Zyvox, has done no more than knock back the infection. The bacteria has not died and I have only two more days left on my two week prescription. Because Zyvox is so dangerours if I continue with it passed two weeks I must have frequent blood tests to monitor for damage to my various blood cells.

Yet as soon as I stop an antibiotic, the infection roars back causing intense pain in my sinuses and nose. It feels like it is eating into the cartilage and bone, just like a nail being pushed in. The pain is almost unbearable, my fever returns.

I need the new antibiotic. But there are no more that I can take. Even if I could it is unlikely that they would work any better than Avelox or Zyvox. There are virtually no new antibiotics in the drug research pipeline. So the rapidly fading almost hopeless place I am in today, you or a loved one could be in tomorrow.

Today I saw immunologist in Carmel Valley north of San Diego who told me he would try a rapid desensitization to sulfa if all else fails. Good news. But still VERY scary, I have at least a one in four chance of dying during the rapid desensitization, as it is very dangerous procedure. The patient is brought to verge of death by increasing doses of the drug, then pulled back repeatedly over a six to eight hour period. And of course, rapid desensitization only works, if I get it in time before the bacteria gets into my blood and goes septicemic. Then I have little chance of survival.

Now I read that this problem with bacteria that will not die, is most likely caused by feeding HEALTHY farm animals and poultry low doses of antibiotics as growth promoters, NOT because the animal is sick. Somehow low dose antibiotics make the HEALTHY animals and birds put on a little more weight a little faster than those not feed low dose antibiotics.

We have known since the mid 1930's that low doses of an antibiotic quickly cause bacteria to be selected which are then resistant to even high doses of the antibiotic.

Shortly after sulfa drugs were discovered the US army tried an experiment on a group of soldiers giving them low doses of sulfa hoping they would stay healthier than other soldiers who were given none. The experiment failed. After several months the low dose soldiers not only got sick as often as non dosed soldiers, but worse for them, the same infections, that were easily cured among the other soldiers, no longer responded to even high doses of sulfa drugs in the low dosed group.

Now we have good evidence that the last of the broad spectrum antibiotics--cephalosporins and quinolones no longer work on many human bacterial infections due to low dose antibiotic use on farms.

Who is prevented the FDA from banning use of low dose antibiotics on HEALTHY farm animals--BIG PHARMA! Why because they sell more antibiotics to farmers for low dose use, then they do to ill Americans. It is all about profit!

We are about to enter a POST antibiotic era in which children die of ear infections and pink eye, most surgeries are not possible, and one in four women die during childbirth.

Is that what we want for our children's future? Fight back against BIG PHARMA. Call your congressman today. Call a radio talk show host and ask them to support the ban.

Read more here:
http://news.yahoo.com/s/ap/20091229/ap_on_he_me/when_drugs_stop_working_the_meat_we_eat/print

Pressure rises to stop antibiotics in agriculture
By MARGIE MASON AND MARTHA MENDOZA, Associated Press Writers Margie Mason And Martha Mendoza, Associated Press Writers
Tue Dec 29, 7:49 am ET

FRANKENSTEIN, Mo. – The mystery started the day farmer Russ Kremer got between a jealous boar and a sow in heat.

The boar gored Kremer in the knee with a razor-sharp tusk. The burly pig farmer shrugged it off, figuring: "You pour the blood out of your boot and go on."

But Kremer's red-hot leg ballooned to double its size. A strep infection spread, threatening his life and baffling doctors. Two months of multiple antibiotics did virtually nothing.

The answer was flowing in the veins of the boar. The animal had been fed low doses of penicillin, spawning a strain of strep that was resistant to other antibiotics. That drug-resistant germ passed to Kremer.

Like Kremer, more and more Americans — many of them living far from barns and pastures — are at risk from the widespread practice of feeding livestock antibiotics. These animals grow faster, but they can also develop drug-resistant infections that are passed on to people. The issue is now gaining attention because of interest from a new White House administration and a flurry of new research tying antibiotic use in animals to drug resistance in people.

Researchers say the overuse of antibiotics in humans and animals has led to a plague of drug-resistant infections that killed more than 65,000 people in the U.S. last year — more than prostate and breast cancer combined. And in a nation that used about 35 million pounds of antibiotics last year, 70 percent of the drugs went to pigs, chickens and cows. Worldwide, it's 50 percent.

"This is a living breathing problem, it's the big bad wolf and it's knocking at our door," said Dr. Vance Fowler, an infectious disease specialist at Duke University. "It's here. It's arrived."

The rise in the use of antibiotics is part of a growing problem of soaring drug resistance worldwide, The Associated Press found in a six-month look at the issue. As a result, killer diseases like malaria, tuberculosis and staph are resurging in new and more deadly forms.

In response, the pressure against the use of antibiotics in agriculture is rising. The World Health Organization concluded this year that surging antibiotic resistance is one of the leading threats to human health, and the White House last month said the problem is "urgent."

"If we're not careful with antibiotics and the programs to administer them, we're going to be in a post antibiotic era," said Dr. Thomas Frieden, who was tapped to lead the Centers for Disease Control and Prevention this year.

Also this year, the three federal agencies tasked with protecting public health — the Food and Drug Administration, CDC and U.S. Department of Agriculture — declared drug-resistant diseases stemming from antibiotic use in animals a "serious emerging concern." And FDA deputy commissioner Dr. Joshua Sharfstein told Congress this summer that farmers need to stop feeding antibiotics to healthy farm animals.

Farm groups and pharmaceutical companies argue that drugs keep animals healthy and meat costs low, and have defeated a series of proposed limits on their use.

_______

America's farmers give their pigs, cows and chickens about 8 percent more antibiotics each year, usually to heal lung, skin or blood infections. However, 13 percent of the antibiotics administered on farms last year were fed to healthy animals to make them grow faster. Antibiotics also save as much as 30 percent in feed costs among young swine, although the savings fade as pigs get older, according to a new USDA study.

However, these animals can develop germs that are immune to the antibiotics. The germs then rub into scratches on farmworkers' arms, causing oozing infections. They blow into neighboring communities in dust clouds, run off into lakes and rivers during heavy rains, and are sliced into roasts, chops and hocks and sent to our dinner tables.

"Antibiotic-resistant microorganisms generated in the guts of pigs in the Iowa countryside don't stay on the farm," said Union of Concerned Scientists Food and Environment director Margaret Mellon.

More than 20 percent of all human cases of a deadly drug-resistant staph infection in the Netherlands could be traced to an animal strain, according to a study published online in a CDC journal. Federal food safety studies routinely find drug resistant bacteria in beef, chicken and pork sold in supermarkets, and 20 percent of people who get salmonella have a drug resistant strain, according to the CDC.

Here's how it happens: In the early '90s, farmers in several countries, including the U.S., started feeding animals fluoroquinolones, a family of antibiotics that includes drugs such as ciprofloxacin. In the following years, the once powerful antibiotic Cipro stopped working 80 percent of the time on some of the deadliest human infections it used to wipe out. Twelve years later, the New England Journal of Medicine published a study linking people infected with a Cipro-resistant bacteria to pork they had eaten.

Johns Hopkins University health sciences professor Ellen Silbergeld, who has reviewed every major study on this issue, said there's no doubt drug use in farm animals is a "major driver of antimicrobial resistance worldwide."

"We have data to show it's in wastewaters and it goes to aquaculture and it goes here and there," agreed Dr. Stuart Levy, an expert on antibiotic resistance at Tufts University in Boston. "Antibiotic use in animals impacts everything."

_______

Farmer Craig Rowles remains unconvinced.

It's afternoon in one of his many rural Iowa pig barns, roaring with snorting and squealing pigs. Some snooze in corners, while others hustle toward their troughs, their slop laced with a steady supply of antibiotics.

"If there was some sort of crossover between the use of the antibiotics in animals and the antibiotics in humans, if there was in fact a real issue there, wouldn't you think we would have seen it?" said Rowles, also a veterinarian who sells 150,000 hogs a year. "That's what the science says to me."

The modular modern barn, home to 1,000 pigs, is a hygienic place. Manure plops through slatted floorboards; an invisible funk steams back up. Rowles dons a sanitary white paper jumpsuit and slips plastic booties over his shoes; he's anxious that his 100-pound pigs aren't exposed to outside germs. A few sick swine are isolated, corralled in a pen near the entrance.

Antibiotics are a crucial part of Rowles' business, speeding growth and warding off disease.

"Now the public doesn't see that," he said. "They're only concerned about resistance, and they don't care about economics because, 'As long as I can buy a pork chop for a buck 69 a pound, I really don't care.' But we live in a world where you have to consider economics in the decision-making process of what we do."

Rowles gives his pigs virginiamycin, which has been used in livestock for decades and is not absorbed by the gut. He withdraws the drug three weeks before his hogs are sent for slaughter. He also monitors his herd for signs of drug resistance to ensure they are getting the most effective doses.

"The one thing that the American public wants to know is: Is the product that I'm getting, is it safe to eat?" said Rowles, whose home freezer is full of his pork. "I'm telling you that the product that we produce today is the safest, most wholesome product that you could possibly get."

_______

Some U.S. lawmakers are fighting for a new law that would ban farmers like Rowles from feeding antibiotics to their animals unless they are sick.

"If you mixed an antibiotic in your child's cereal, people would think you're crazy," said Rep. Louise M. Slaughter, D-N.Y.

Renewed pressure is on from Capitol Hill from Slaughter's bill and new rules discussed in regulatory agencies. There is also pressure from trade issues: The European Union and other developed countries have adopted strong limits against antibiotics. Russia recently banned pork imports from two U.S. plants after detecting levels of tetracycline that the USDA said met American standards.

Farmers and drugmakers are battling back. Pharmaceutical companies have spent $135 million lobbying so far this year, and agribusiness companies another $70 million, on a handful of issues including fighting the proposed new limits. Opponents, many from farm states, say Slaughter's law is misguided.

"Chaos will ensue," said Kansas Republican Congressman Jerry Moran. "The cultivation of crops and the production of food animals is an immensely complex endeavor involving a vast range of processes. We raise a multitude of crops and livestock in numerous regions, using various production methods. Imagine if the government is allowed to dictate how all of that is done."

He's backed by an array of powerful interests, including the American Farm Bureau, the National Pork Producers Council, Eli Lilly & Co., Bayer AG, Pfizer Inc., Schering-Plough Corp., Dow AgroSciences and Monsanto Company, who have repeatedly defeated similar legislation.

The FDA says without new laws its options are limited. The agency approved antibiotic use in animals in 1951, before concerns about drug resistance were recognized. The only way to withdraw that approval is through a drug-by-drug process that can take years of study, review and comment.

In 1977 the agency proposed a ban on penicillin and tetracycline in animal feed, but it was defeated after criticism from interest groups.

There has been one ban: In 2000, for the first time, the FDA ordered the poultry medication Baytril off the market. Five years later, after a series of failed appeals, poultry farmers stopped using the drug.

In 2008 the FDA issued its second limit on an antibiotic used in cows, pigs and chickens, citing "the importance of cephalosporin drugs for treating disease in humans." But the Bush Administration — in an FDA note in the federal register — reversed that decision five days before it was going to take effect after receiving several hundred letters from drug companies and farm animal trade groups.

Laura Rogers, who directs the Pew Charitable Trusts Campaign on Human Health and Industrial Farming in Washington D.C., says the federal government, from Congress to the administration, has failed to protect the public.

"Because of poor regulations and oversight of drug use in industrial farm animals, consumers in the U.S. do not know what their food is treated with, or how often," she said. "Nor is there a system in place to test meat for dangerous antibiotic resistant bacteria."

_______

Back in Missouri, farmer Kremer finally found an antibiotic that worked on his leg. After being released from the hospital, Kremer tested his pigs. The results showed they were resistant to all the same drugs he was.

Kremer tossed his hypodermic needles, sacked his buckets of antibiotic-laced feed, slaughtered his herd and started anew.

"I was wearing a syringe, like a holster, like a gun, because my pigs were all sick," he recalled. "I was really getting so sick and aggravated at what I was doing. I said, 'This isn't working.'"

Today, when Kremer steps out of his dusty and dented pickup truck and walks toward the open-air barn in the foothills of the Ozark Mountains, the animals come running. They snort and root at his knee-high gum boots. There are no gates corralling the 180 pigs in this barn. He points to a mound of composting manure.

"There's no antibiotics in there," he says proudly.

Kremer sells about 1,200 pigs annually. And a year after "kicking the habit," he says he saved about $16,000 in vet bills, vaccinations and antibiotics.

"I don't know why it took me that long to wake up to the fact that what we were doing, it was not the right thing to do and that there were alternatives," says Kremer, stooping to scratch a pig behind the ear. "We were just basically killing ourselves and society by doing this."

____

Martha Mendoza is an AP national writer based in Mexico City. Margie Mason is an AP medical writer who reported from Missouri and Iowa while on a fellowship from The Nieman Foundation at Harvard University.

GMO bacteria as a cure for IBD?

2009-12-31T17:11:00.000-08:00

http://www.physorg.com/news181465961.html

Bacteria Wins First Round Against Inflammatory Bowel Disease
December 31, 2009 By Ann Perry

ARS microbiologist Terry Whitehead is part of a team that found and altered a microbe so it might one day help treat inflammatory bowel disease and other chronic intestinal diseases in people.

(PhysOrg.com) -- A group of British scientists and their Agricultural Research Service (ARS) colleague used a benign bacterium from the human gut to develop a microbe that someday might help treat inflammatory bowel disease (IBD) and other chronic intestinal diseases.

IBD erodes the delicate lining of the intestine, and its symptoms—often severe—include cramping, abdominal pain and other gastrointestinal discomfort. IBD cannot be cured, and current treatments can have adverse side effects. Medical practitioners and patients are anxious for the development of more effective therapies, particularly protocols that deliver drugs directly to the intestine.

So ARS microbiologist Terry Whitehead, who works at the National Center for Agricultural Utilization Research in Peoria, Ill., and his partners began searching for a solution. Simon Carding, who works at the Institute of Food Research and the University of East Anglia in Norwich, Great Britain, led the research project with Zaed Hamady, who works at the University of Leeds in Great Britain and St. James University Hospital, also in Leeds.

The group focused on the bacterium Bacteroides ovatus (B. ovatus), which is one of an assortment of intestinal microflora in humans. B. ovatus thrives in the oxygen-free environment of the large intestine, where it breaks down xylan—a fiber found in plants—and other sugars for energy and growth.

The team created a strain of B. ovatus that used xylan to induce secretion of human keratinocyte growth factor, a protein that helps repair and restore the intestine’s delicate lining. This increased the ability of the intestine to repair IBD-inflicted damage.

The researchers found that IBD-affected mice treated with oral doses of xylan and the engineered strain of B. ovatus had intestinal tissues that healed more rapidly. This group of mice also lost less weight and had lower levels of rectal bleeding. In addition, dosing mice with B. ovatus provided protection from induced IBD and limited the development of subsequent intestinal inflammation.

An abstract of this research was published online in the journal Gut.
Provided by USDA Agricultural Research Service

Autoimmune disease can no longer be lumped together

2009-12-31T15:54:00.000-08:00

From the beginning of this blog, I have maintained that what works to help one autoimmune disease ought to help many if not all other autoimmune diseases. It appears I was wrong.

I based my views on the following facts. I knew that the tendency for autoimmune disease runs in families. I also knew that once a person is diagnosed with one autoimmune disease that person is often likely to get diagnosed with more autoimmune diseases. For instance my youngest son, Paul, has three autoimmune diagnosis.

I thought an autoimmune disease is an autoimmune disease is an autoimmune disease and it was time to stop dividing the community of autoimmune sufferers into separate camps. Each camp pursuing its own agenda. I thought all the various groups should join together in one focused attempt to solve all autoimmune disease. But I was at least partly wrong if Stanford researchers are correct with their latest research findings.

Researchers at Stanford have looked at genetics of various autoimmune diseases and found that instead of all the genes falling into one category, they seem to lump together in at least two groups. One group of genetically similar autoimmune disease lumps the following together: multiple sclerosis, Type I diabetes, autoimmune thyroid disease. Let's call that group A.

The other group seems to be rheumatoid arthritis and Ankylosing Spondylitis (AS) and likely psoriatic arthritis (PsA) due to similar drugs helping PsA as help RA. If PsA is in the group than psoriasis is probably there as well. Call this group B.

Patients with PsA and psoriasis were not genetically screened by the researchers, so this is just my educated guess at the moment. It is NOT the conclusion of the Stanford researchers.

Hopefully this research will begin to give the NIH scientific justification to allow clinical trials of several autoimmune diseases at once. Perhaps all of Group A autoimmune diseases could be tested in one clinical trial and if the new therapy worked for all, then FDA could approve the drug for multiple autoimmune diseases at the same time. Clinical trials would also be streamlined giving us new meds faster.

When a new medical breakthrough for RA in Group B is discovered, this breakthrough could be tested on AS and PsA patients at the same time. If it worked for all three, then the FDA could approve it for all at once rather than forcing the company that developed the therapy to do a completely different, time consuming and costly tests for each autoimmune disease separately.

Let's hope more research confirms what Stanford researchers seem to have found. This is the kind of basic research that brings us closer to cures.
---------------
Personal note: My two antibiotics that my hypersensitive immune system is barely tolerating (incredible itching even with H1 and H2 antihistamines) seem to be failing at controlling the infection in my right nostril.

The infection is an incredibly resistant micro-organism. I go to a doctor on Monday who says he can desensitize anyone to any chemical. We will see.

I imagine he will say it takes at least several months. Sadly I do not seem to have that much time on my current regime. I am having red blood drainage from nostril today, first time since I started the oral antibiotic Zyvox, twelve days ago.

Zyvox is top of the line restricted antibiotic, so it is very strange it is beginning to fail. It worked pretty good at the beginning and cleared my sinuses of mucus.

We really need new and truly novel antibiotics. Where is Big Pharma? Hundreds of millions to bribe "opinion makers' on radio and cable 'news' organizations to stop universal health insurance and millions more to 'lobby' Joe Liberman and others in the Senate to kill the last bits of insurance reform, but nothing for research into new antibiotics? Should we ask if our current system of drug development is setting the right agendas?
-------------------------------------------------------
Here is the article:

http://www.medicalnewstoday.com/articles/174835.php

Genomic Toggle Switches Divide Autoimmune Diseases Into Distinct Clusters,
Stanford Study Shows
31 Dec 2009

Genomic switches can predispose an individual to one set of autoimmune disorders but protect the same person against another set of them, scientists at Stanford University School of Medicine have found.

"Maybe we should stop considering all autoimmune diseases in one lumped category," said Atul Butte, MD, PhD, assistant professor of pediatrics and of biomedical informatics and director of the Center for Pediatric Bioinformatics at Lucile Packard Children's Hospital. "It looks as if there may be at least two different kinds."

Pairs of autoimmune diseases have been linked in clinical practice, Butte said. People with type-1 diabetes are routinely screened for autoimmune thyroid disease, for which they are known to be at heightened risk. But no one has ever known why.

A study published online Dec. 24 in PLoS-Genetics provides a genetic basis for this clustering effect, while extending it to show how two such clusters tend to be mutually exclusive. Butte, who is the study's senior author, and his colleagues looked at data from several large genome-wide association studies of single-nucleotide polymorphisms, or SNPs: tiny genomic variations that constitute the genetic underpinning for inter-individual human differences from eye color to nose shape to personality quirks.

The human genome can be thought of as a 3-billion-unit-long sequence, with each unit consisting of one of four different chemical residues. At almost every specific location along two different people's genomes, the resident chemical unit is the same. But at about one or two out of every 1,000 positions, the first person's genome may boast one variety of chemical unit, while the second's hosts another type. This single-unit difference is a SNP (pronounced "snip").

There are several million SNPs in the human genome, making for a gigantic number of possible different versions of a human being, said the study's lead author, Marina Sirota, a fourth-year PhD student under Butte's supervision in Stanford's Biomedical Informatics Program. In so-called genome-wide association studies, SNPs linked to disease susceptibility are found by assessing genomes from two large groups of people, one composed of patients with, say, rheumatoid arthritis or heart disease and another of people without the condition. If, at a given SNP location, the frequency of one particular chemical unit is significantly greater or smaller among the diseased people than in the healthy ones, that SNP is presumed to lie close to or within a biologically important genomic region that increases or diminishes genetic susceptibility to the disease, Sirota said.

In the past few years the industrial-scale characterization of SNPs has been hugely enhanced by sophisticated electronic devices called gene chips, pioneered at Stanford about a decade ago. Gene chips can quickly scan an individual's genome to identify the chemical unit occupying each of more than a million SNP locations.

"More than 400 genome-wide association studies have been published since gene-chip technology took off a few years ago," said Butte. From these published studies, Sirota, Butte and their colleagues culled about a half-dozen that had been conducted on patients with or without autoimmune diseases including type-1 diabetes, rheumatoid arthritis, multiple sclerosis, autoimmune thyroid disease and a spinal condition called ankylosing spondylitis. The investigators restricted their attention to SNPs that were examined in all the studies they were focusing on.

That worked out to 573 SNPs. Of those, the researchers found 15 SNPs for which having a particular chemical unit at that site predisposed an individual to several autoimmune diseases.

That wasn't surprising, said Sirota. "We had started out looking for just such similarities. What was surprising was our finding that at nine locations generally associated with autoimmunity risk, where a particular chemical unit conferred a heightened risk of certain autoimmune diseases, but reduced risk of getting certain others."

For instance, a particular chemical unit at a SNP site shown to predispose people to multiple sclerosis also rendered them, as a group, more likely to have autoimmune thyroid disease, while the alternative chemical unit at the same site predisposed them to rheumatoid arthritis and ankylosing spondylitis. Most intriguing of all, people predisposed to one pair of diseases were protected against the other.

The scenario is akin to switches controlling banks of Christmas-tree lights. In addition to a master on/off switch that determines whether electricity (a general predisposition to autoimmune disease) will flow through the circuit, a second set of toggle switches determines whether, say, red or blue lights (one versus another autoimmune-disease cluster) will be on.

"As more genomic information becomes available on increasingly advanced platforms, this sort of analysis can be done on more diseases, possibly hundreds of them. Plus, the original set of 573 common SNPs we were able to inspect will grow much larger. So we'll be able to find more relationships like these," Sirota said.

Butte said finding SNPs predisposing people to one or another cluster of autoimmune diseases may help catch the onset of a disease earlier. "And if a patient has a particular autoimmune disease, this might help us know what else to screen that patient for, or guess whether a drug that works well in a different autoimmune disorder could be useful in treating this patient."

It might also help guide drug development, he added. "Several of these nine interesting SNPs we've found are located in or near genes that code for molecules found on cell surfaces, which makes them potentially easier targets for the drugs pharmaceutical researchers are best at producing."

Other Stanford co-authors were PhD student Marc Schaub and associate professor Serafim Batzoglou, PhD, of the computer science department, and William Robinson, MD, PhD, assistant professor of immunology and rheumatology. The study was funded by the Lucile Packard Foundation for Children's Health, National Institute of General Medical Sciences, National Library of Medicine, Howard Hughes Medical Institute and Pharmaceutical Research and Manufacturers of America Foundation.

Source:
Bruce Goldman
Stanford University Medical Center

Zinc fingers may give us gene therapy after all

2009-12-30T13:37:00.000-08:00

Zinc fingers are one way to modify our DNA and the products our DNA produces for us.

The zinc fingers techniques is part of a larger field of study called epigenetics. This science studies how our DNA code is modified to produce more or less of certain gene products. Zinc fingers seems to be a leading candidate for the first success in targeting and modifying specific genes.

Certain genetic diseases are caused when too much of a gene product is produced. Many others like cystic fibrosis are caused when too little or no product is made. Hopefully the manipulation of our DNA with techniques like these zinc fingers will one day lead to cures or permanent long term fixes for many now intractable genetic diseases.

Read the following for more info on zinc fingers:
http://www.nytimes.com/2009/12/29/health/research/29zinc.html?hpw=&pagewanted=print

December 29, 2009
In New Way to Edit DNA, Hope for Treating Disease
By NICHOLAS WADE

Only one man seems to have ever been cured of AIDS, a patient who also had leukemia. To treat the leukemia, he received a bone marrow transplant in Berlin from a donor who, as luck would have it, was naturally immune to the AIDS virus.

If that natural mutation could be mimicked in human blood cells, patients could be endowed with immunity to the deadly virus. But there is no effective way of making precise alterations in human DNA.

That may be about to change, if a powerful new technique for editing the genetic text proves to be safe and effective. At the University of Pennsylvania, Dr. Carl June and colleagues have used the technique to disrupt a gene in patients’ T cells, the type attacked by the AIDS virus. They have then infused those cells back into the body. A clinical trial is now under way to see if the treated cells will reconstitute a patient’s immune system and defeat the virus.

The technique, which depends on natural agents called zinc fingers, may revive the lagging fortunes of gene therapy because it overcomes the inability to insert new genes at a chosen site. Other researchers plan to use the zinc finger technique to provide genetic treatments for diseases like bubble-boy disease, hemophilia and sickle-cell anemia.

In principle, the zinc finger approach should work on almost any site on any chromosome of any plant or animal. If so, it would provide a general method for generating new crop plants, treating many human diseases, and even making inheritable changes in human sperm or eggs, should such interventions ever be regarded as ethically justifiable.

Zinc fingers are essential components of proteins used by living cells to turn genes on and off. Their name derives from the atom of zinc that holds two loops of protein together to form a “finger.” Because the fingers recognize specific sequences of DNA, they guide the control proteins to the exact site where their target gene begins.

After many years of development, biologists have learned how to modify nature’s DNA recognition system into a general system for manipulating genes. Each natural zinc finger recognizes a set of three letters, or bases, on the DNA molecule. By stringing three or four fingers together, researchers can generate artificial proteins that match a particular site.

The new system has been developed by a small biotech company, Sangamo BioSciences of Richmond, Calif., and, to some degree separately, by academic researchers who belong to the Zinc Finger Consortium.

Sangamo was founded in 1995 by Edward O. Lanphier II, a former executive with a gene therapy company. Reading an article by Aaron Klug, the British crystallographer who discovered the zinc finger design, he saw the technique’s potential for genetic manipulation. He bought a company Dr. Klug had founded and worked with him and researchers like Carl O. Pabo to improve the technique and develop combinations of zinc fingers to match any sequence of DNA letters.

“We now have a full alphabet of zinc fingers,” Mr. Lanphier said, “but when we started the company it was like typing a novel with two fingers.”

Zinc finger proteins have many potential uses. One is to link them to agents that turn on or turn off the gene at the site recognized by the fingers.

More powerfully, the zinc fingers can be deployed as a word processing system for cutting and pasting genetic text. Two sets of zinc fingers are attached to a protein that cuts the DNA in between the two sites matched by the fingers. The cell quickly repairs the break but sometimes in a way that disrupts the gene. This is the approach used in destroying the gene for the receptor used by the AIDS virus to gain entry to white blood cells.

Or, if DNA for a new gene is inserted into a cell at the same time as the zinc fingers that scissor the DNA, the new gene will be incorporated by the cell’s repair system into the DNA at the break site. Most gene therapy techniques use a virus to carry new genes into a cell but cannot direct the virus to insert genes at a specific site.

“I think it’s a broadly applicable technology which has already allowed experiments that would not have been possible before,” said J. Keith Joung, a biologist who designs zinc finger proteins at the Massachusetts General Hospital.

Daniel F. Voytas, a plant geneticist at the University of Minnesota, said the zinc finger technique would allow breeders to change the oil composition of any plant, the types of carbohydrates produced or the way carbon dioxide is captured. “We can go in and make any change we want to any plant species,” Dr. Voytas said.

Zinc fingers can also be used for “trait stacking,” the positioning of several beneficial genes at a single site. This avoids heavy regulatory costs because genetically altered plants must be tested for safety for each site that is modified.
The zinc finger technology has taken many years to prepare because of the difficulty of designing the fingers and also of preventing them from cutting the genome in the wrong places. Only a handful of laboratories are currently using the technique, but proponents expect to see rapid growth.

The Zinc Finger Consortium, founded by Dr. Joung and Dr. Voytas, makes the method available free, and researchers need only pay for materials. But there are some 200 steps in Dr. Joung’s recipe for making zinc fingers, and it takes time and dedication to do them all correctly.

The alternative is to buy zinc fingers. Sangamo has a commanding patent position and has licensed Sigma-Aldrich, a large life science company in St. Louis, to make zinc finger proteins for researchers. Sigma-Aldrich’s charge for a zinc finger protein that cuts the genome at the site of your choice is $39,000, with a discount for academic researchers. Zinc fingers that cut well-known human genes cost $12,000. Sigma-Aldrich has used the technology to generate rats with genetic defects that mimic human disease. A schizophrenic rat can be had for $100.

David Smoller, president of Sigma-Aldrich’s biotechnology unit, licensed the technology from Sangamo in 2006 when he felt the company had proved it worked. “This technology is just amazing,” Dr. Smoller said. “It’s a game changer.”

Sangamo has licensed the use of zinc fingers to Dow Agrosciences for creating new crop plants, and has reserved medical uses for itself. It has four Phase 2 clinical trials in progress, including treatments for diabetic neuropathy and amyotrophic lateral sclerosis.

In an ambitious effort to cure AIDS, Sangamo and the University of Pennsylvania started a clinical trial in February.

The AIDS virus enters the T cells of the immune system by latching on to a receptor called CCR5, but about 10 percent of Europeans have a mutation that disables the CCR5 gene. People who inherit two disabled copies of the gene do not have CCR5 on the surface of their T cells, so the AIDS virus has nothing to grab. These people are highly resistant to H.I.V.

In the zinc finger approach, the patient’s T cells are removed, and zinc finger scissors are used to disable the CCR5 gene. The treated cells are allowed to multiply, then reinjected into the patient. In experiments with mice, the treated cells turned out to have a strong natural advantage over the untreated ones, since those are under constant attack by the AIDS virus.

Whether or not zinc fingers will make gene therapy practical remains to be seen. “It’s a little too early to know since clinical trials are in their early stages,” said Dr. Katherine A. High, a hemophilia expert at the University of Pennsylvania.

Dr. Matthew H. Porteus, a pediatric geneticist at the University of Texas, said, “I think it has the potential to solve a lot of the problems that have plagued the gene therapy field.” But Dr. Porteus noted that even the most carefully designed zinc fingers seemed to do some snipping away from their target site, a potentially serious safety problem.

Zinc fingers could be the gift that stem cell researchers have been waiting for. Stem cells taken from a patient may need to be genetically corrected before use, but until now there had been no way of doing so.

Dr. Rudolf Jaenisch, a stem cell expert at the Whitehead Institute in Cambridge, Mass., reported in August that he had successfully singled out three genes in induced embryonic stem cells with the help of zinc finger scissors designed by Sangamo. “This is a really important tool for human embryonic stem cells,” Dr. Jaenisch said. The technology has not yet reached perfection. Some of the zinc fingers Sangamo provided “worked beautifully,” he said, but some did not.

Zinc fingers may also make technically possible a morally fraught procedure that has been merely a theoretical possibility — the alteration of the human germ line, meaning the egg or sperm cells. Genetic changes made in current gene therapy are to body cells, and they would die with the individual. But changes made to the germ line would be inherited. Many ethicists and others say this is a bridge that should not be crossed, since altering the germ line, even if justifiable for medical reasons, would lower the barrier to other kinds of change.

Several scientists were reluctant to discuss the issue, or dismissed it by saying that even zinc fingers did not meet the error-free standards that would be required for germ-line engineering. But zinc finger scissors are so efficient that only 5 to 10 embryos need be treated to get one with the desired result. This could make it practical to alter the germ line.

Since the germ lines of rats and zebra fish have already been altered with zinc finger scissors, “in principle there is no reason why a similar strategy could not be used to modify the human germ line,” Dr. Porteus said. The kind of disease that might be better treated in the germ line, if ethically acceptable, is cystic fibrosis, which affects many different tissues.
The disease could be corrected in unfertilized eggs, using the zinc finger technique, Dr. Porteus said. But he added, “I don’t think our society is ready for someone to propose this.”

http://www.nytimes.com/2009/12/29/health/research/29zinc.html?hpw=&pagewanted=print

MIT's BIG News--novel delivery of Gene Silencing--siRNA seems ready for "the show"

2009-12-28T12:51:00.000-08:00

Researchers at the Massachusetts Institute of Technology have perfected a delivery technique that appears to make gene silencing therapy ready for clinical trials. This is big news for a lot of genetic conditions possibly including autoimmune disease.

If malfunctioning immune genes could be ‘silenced’ for a time then our out of control immune systems might be able to be brought under control.

Gene silencing techniques have been available for last eight or ten years, but were not practical due to delivery problems. MIT researchers seem to have solved the problem by wrapping the gene silencing materials (siRNA) in a special coating of a fat like molecule that is readily absorbed by cells. Once inside the cell the silencing RNA is released to turn off the defective genes.

Sounds promising to me, but I have been disappointed before. Can you say Prochymal from Osiris?

I think this particular technique is a much more likely to work than not. MIT researchers have reputations to protect. Let’s hope they get funding for the quick development of effective treatments and cures for so many diseases, now untreatable.
____________________________
Personal note: I am still fighting a resistant bacterial infection of my right nostril. At present I seem to be losing both sides of the battle. My immune system itches more and more with the top of the line restricted antibiotic (Zyvox) each time I take it and sadly the bacteria seems to be less and less affected by the Zyvox. Initially it died nicely. Not as good as the sulfa drug killed it but very nicely.

This morning’s dose of Zyvox barely affected the bacteria. I felt the rush of Zyvox hit me about an hour and half after ingesting the pill at 7am. Within minutes I felt a few of the scabs losing up and coming off as the bacteria were killed. But most scabs and sores were unaffected. Pain in the bones around my eye and cheekbones are increasing.

I am taking the maximum dose of Zyvox so the doctor also prescribed mupirocin spray and ointment in combination with the Zyvox. Sadly mupirocin also has lost its power over these bacteria. Originally it seemed that it alone would kill them. Now they act like it does not bother them at all to be drenched in the stuff. yet my immune system reacts in violent itching which I try to control with pre treatment of H1 and H2 antihistamine blockers (Zyrtec, Chlortrimeton, and Zantac)

I see the ear nose and throat guy tomorrow. He could try IV antibiotics, but it is unlikely that my immune system would tolerate them for as long a time as I would need to kill the bacteria.

Hypersensitivity reactions are life threatening and often treated as a joke on TV with someone swollen up or covered with hives being used for a punchline to a gag. However, when there is a systemic (whole body) malfunction of the immune system, like swelling (angioedema) or hives, that is not a joke. It is very often a medical emergency.

The odds were stacked against me when I acquired the infection and have gotten worse as either I reacted to medications like sulfa or the bacteria fought off the medication like Avelox. This country and the world desperately need new and completely novel antibiotics.

All Big Pharma ever seems to give us are the same old antibiotics just with new chemical side groups and other minor tweeks that allow the companies to market as a “new” antibiotic, a very similar one to what we already had.

Unless something positive happens quickly, things look a bit bleak for me. But hopefully the new gene silencing delivery system from MIT will make a difference for cures for you and for my son, Paul. Sure wish there were a gene silencing technique for hypersensitivity genes right about now.
________________________

http://www.physorg.com/news181225412.html

New RNA interference technique can silence up to 5 genes
December 28, 2009

Researchers at MIT and Alnylam Pharmaceuticals report this week that they have successfully used RNA interference to turn off multiple genes in the livers of mice, an advance that could lead to new treatments for diseases of the liver and other organs.

Since the 1998 discovery of RNA interference — the naturally occurring phenomenon in which the flow of genetic information from a cell's nucleus to the protein-building machinery of the cell is disrupted — scientists have been pursuing the tantalizing ability to shut off any gene in the body. Specifically, they have been trying to silence malfunctioning genes that cause diseases such as cancer.

The new delivery method, described in the Proceedings of the National Academy of Sciences, is orders of magnitude more effective than previous methods, says Daniel Anderson, senior author of the paper and a biomedical engineer at the David H. Koch Institute for Integrative Cancer Research at MIT.

"This greatly improved efficacy allows us to dramatically decrease the dose levels, and also opens the door to formulations that can simultaneously inhibit multiple genes or pathways," says Anderson.

The key to success with RNA interference is finding a safe and effective way to deliver the short strands of RNA that can bind with and destroy messenger RNA, which carries instructions from the nucleus.

Anderson and his colleagues believe the best way to do that is to wrap short interfering RNA (siRNA) in a layer of fat-like molecules called lipidoids, which can cross cells' fatty outer membrane. Using one such lipidoid, the researchers were able to successfully deliver five snippets of RNA at once, and Anderson believes the lipidoids have the potential to deliver as many as 20.

How they did it: The team at MIT, along with Alnylam researchers, have developed methods to rapidly produce, assemble and screen a variety of different lipidoids, allowing them to pick out the most effective ones.

In a previous study, the researchers created more than 1,000 lipidoids. For their latest study, they picked out one of the most effective and used a novel chemical reaction to create a new library of 126 similar molecules. The team focused on one that appeared the most promising, dubbed C12-200.

Using C12-200, the researchers achieved effective gene silencing with a dose of less than 0.01 milligrams of siRNA per kilogram of solution, and 0.01 milligrams per kilogram in non-human primates. If the same dosing were translated to humans, a potential therapy would only require an injection of less than 1 milliliter to specifically inhibit a gene, compared with previous formulations that would have required hundreds of milliliters, says Anderson.

Other authors from MIT include Kevin T. Love, Kerry P. Mahon, Christopher G. Levins, Kathryn A. Whitehead and Institute Professor Robert Langer.

Next steps: The MIT/Alnylam team hopes to start clinical trials within the next couple of years, after figuring out optimal doses and scaling up the manufacturing capability so they can produce large amounts of the siRNA-lipidoid complex.
More information: "Lipid-Like Materials for Low Dose, in vivo Gene Silencing," Kevin T. Love, Kerry P. Mahon et al. Proceedings of the National Academy of Sciences, week of Dec. 28, 2009.
Provided by Massachusetts Institute of Technology

Jonsson Comprehensive Cancer Center discovery: Lower dCK levels, turn off autoimmune, GvHD, and hypersensitivity?

2009-12-23T12:59:00.000-08:00

New immune enzyme discovered at Jonsson Comprehensive Cancer Center that has great potential in a number of terrible diseases including autoimmune disease, Graft versus Host Disease, and perhaps hypersensitivity reactions to foods and drugs.

The discovery indicates very good work being done at UCLA.

Let's hope the research teams work quickly to develop drugs that can turn down this dCK signal and thereby modulate our out of control immune systems. We desperately need new approaches to our diseases and new drugs. This discovery might give us both.

http://www.medicalnewstoday.com/articles/174701.php

Enzyme Necessary For Development Of Healthy Immune System

Mice without the deoxycytidine kinase (dCK) enzyme have defects in their adaptive immune system, producing very low levels of both T and B lymphocytes, the major players involved in immune response, according to a study by researchers with UCLA's Jonsson Comprehensive Cancer Center.

The finding could have ramifications in treating auto-immune disorders, in which the body attacks itself, and possibly certain cancers of the immune system. A drug could be developed to create lower levels of dCK in the body, thereby tamping down immune response. Such a drug might also be effective in transplant patients to decrease risk for rejection, said Dr. Caius Radu, an assistant professor of Molecular and Medical Pharmacology, a Jonsson Cancer Center researcher and senior author of the study.

The study, part of a long-term research project that has resulted in the development of a new probe for Positron Emission Tomography (PET) scanning and the creation of a non-invasive approach to observe chemotherapy at work in the body, appears this week in the early online edition of the Proceedings of the National Academy of Sciences.

"It would be desirable to have drugs that can inhibit immune response when that response is detrimental and increase response when needed," said Radu, who also is a scientist with the Broad Stem Cell Research Center. "We are now trying to identify drugs that inhibit or activate dCK in the hopes of testing them on certain diseases."

The dCK enzyme helps recycle the products of DNA degradation, allowing cells to efficiently replicate their DNA during cell division. Until now, the enzyme was thought to play a relatively minor role in providing cells the material for DNA replication. However, this finding challenges that view and indicates the enzyme plays a profound role in normal lymphocyte development.

Wayne Austin, a graduate study in Molecular and Medical Pharmacology and first author of the study, said the research team expected to find widespread defects in development when they knocked out the dCK enzyme in the mice.

"Surprisingly, we found that the gene had a highly specific role in the development of organs crucial to a normally-functioning immune system," Austin said. "Mice lacking the dCK enzyme have thymuses that are reduced in size by 90-fold. That defect in thymus size resulted in mice having 5 to 13-times fewer lymphocytes circulating throughout the body."

This finding is part of research that was launched several years ago and represents the third significant discovery. The first was the development of a new probe for PET scanning created by modifying a common chemotherapy drug, an advance that allowed UCLA researchers to model and measure the immune system in action and monitor response to new therapies.

Researchers created the molecule, called FAC, by slightly altering the molecular structure of gemcitabine, a chemotherapy drug that is activated by dCK activity. They added a radiolabel so the cells that take in the probe can be seen during PET scanning.

The probe was based on a fundamental cell biochemical pathway called the DNA Salvage Pathway, which includes dCK. All cells use this biochemical pathway to different degrees. But in lymphocytes, which are the active players in the adaptive immune system, the pathway is activated at very high levels. Because of that, the probe accumulates at high levels in those cells, said Dr. Owen Witte, director of the Broad Stem Cell Research Center and a Howard Hughes Medical Institute investigator.

That work was published June 8, 2008 in the journal Nature Medicine.

The second significant finding was the development of a non-invasive approach that may allow doctors to evaluate a tumor's response to a drug before prescribing the treatment, enabling physicians to personalize therapy to the patient's unique biochemistry.

In this study, the UCLA team injected the FAC probe into mice that had developed leukemias that either had or did not have active dCK enzyme. After an hour, the researchers imaged the animals' bodies with a PET scan, which operates like a molecular camera, enabling the researchers to watch biological processes inside animals and people.

The PET scan offered a preview for how the tumor will react to a specific therapy because tumor cells that retained the probe also will be sensitive to chemotherapy drugs that also are activated by dCK. If the cells didn't absorb the probe, the tumor might respond more favorably to the drugs that don't need interaction with dCK to be effective.

That work appeared Feb. 2, 2009 in the Proceedings of the National Academy of Sciences.

The next step, outlined in this study, was to determine what would happen without any dCK in the body at all, and what ramifications that might have on certain diseases and their treatment.

The study was funded by grants from the National Cancer Institute/National Institutes of Health, the U.S. Department of Energy, California Institute for Regenerative Medicine and the Dana Foundation.

Source: Kim Irwin
University of California - Los Angeles

Stop Th17 cells, stop inflammation and autoimmune, more evidence from study of T.B.

2009-12-23T10:16:00.000-08:00

For us Th17 immune cells seem to be the ones that produce the out of control inflammation and the "cytokine storms" that can be so damaging.

Cytokine storms happen when our immune cells release too many and too much of several kinds of inflammatory cytokines (immune signals) which drive our defensive cells into a frenzy of destruction. This frenzy can cause these normally helpful cells to damage or kill the person they are supposed to defend.

Apparently having too many TH17 cells is a primary cause of at least some of these inflammatory cytokine storms. The importance of blocking IL-17 the seemingly 'master' inflammatory cytokine that drives inflammation as been know since at least 2003.

http://74.125.155.132/scholar?q=cache:NWZCGiBN9N4J:scholar.google.com/+author:%22Lubberts%22+intitle:%22Treatment+with+a+neutralizing+anti-murine+interleukin-17+...%22+&hl=en&as_sdt=2000

Currently creating a monoclonal to use therapeutically in autoimmune arthritis is a goal of the research community, and big pharma.
http://www.nature.com/nrrheum/journal/v5/n10/abs/nrrheum.2009.179.html

If you are interested in Eli Lily's Rheumatoid Arthritis phase II study of its anti IL-17 compound read here:
http://clinicaltrials.gov/ct2/show/NCT00966875

The study is currently enrolling patients as of December 2009. Study locations are here:

http://clinicaltrials.gov/ct2/show/study/NCT00966875?show_locs=Y#locn

Here basic research on TB leads to answers in autoimmune disease. Let's keep funding basic research at high levels. Information gleaned leads to quicker cures for all of us.

http://www.eurekalert.org/pub_releases/2009-12/nlmc-npd122209.php

NYU Langone Medical Center / New York University School of Medicine
New pathway discovered that may prevent tissue damage resulting from inflammation
Study could pave the way for new treatments for immune diseases

(New York, New York – December 22, 2009): Interferon gamma is a protein secreted by lymphocytes that is used to fight the bacteria in white blood cells that cause tuberculosis. In a study published this week in Immunity, scientists at NYU Langone Medical Center have discovered that in addition to white blood cells, other cells such as epithelial and endothelial cells, also respond to interferon gamma and also protect mice from uncontrolled tuberculosis infection. This new pathway could lead to the developments of treatments that could limit or prevent tissue damage resulting from inflammation.

"Through research on tuberculosis, we discovered a new way that the immune system response is controlled," said lead author Joel Ernst, MD, director of the Division of Infectious Diseases and the Jeffrey Bergstein Professor of Medicine at NYU Langone Medical Center. "Further study may reveal treatments that could be useful in control of inflammation and tissue damage in certain infections and autoimmune diseases."

In this study, researchers looked at interferon gamma responses in epithelial and endothelial cells to control tuberculosis in mice. Cells such as epithelial and endothelial cells were found to respond to interferon gamma by producing an enzyme, indolelamine-2-3-dioxygenase (IDO), that converts the amino acid tryptophan to products called kynurenines. These kynurenines inhibit the production of Th17 cells, the lymphocytes that contribute to tissue-damaging inflammation.

###

The study's co-author is Ludovic Desvignes, PhD of the Department of Microbiology at NYU Langone Medical Center. The research was funded by grants from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health in Bethesda, Maryland.

About NYU Langone Medical Center

NYU Langone Medical Center is one of the nation's premier centers of excellence in healthcare, biomedical research, and medical education. For over 168 years, NYU physicians and researchers have made countless contributions to the practice and science of health care. Today the Medical Center consists of NYU School of Medicine, including the Smilow Research Center, the Skirball Institute of Biomolecular Medicine, and the Sackler Institute of Graduate Biomedical Sciences; the three hospitals of NYU Hospitals Center, Tisch Hospital, a 705-bed acute-care general hospital, Rusk Institute of Rehabilitation Medicine, the first and largest facility of its kind, and NYU Hospital for Joint Diseases, a leader in musculoskeletal care; and such major programs as the NYU Cancer Institute, the NYU Child Study Center, and the Hassenfeld Children's Center for Cancer and Blood Disorders.

CAPTURED! When a non-profit accepts corporate sponsors, agendas change

2009-12-22T07:23:00.001-08:00

Too many of our non-profits accept money from Big Pharma and Big Health Insurance corporations to 'sponsor' an activity or a website. It is hard to resist the money for the financially struggling non-profit.

Having once been a trustee of non profit Trust (SCEET) that was supposed to provide low cost health related insurance to local school districts in southern California, I have some insight into what happens to the non-profit as its being captured.

The good intentioned directors of the non profit see that with a bit more financial support they can do so much more to help victims of disease or disability that their organization was formed to help. Besides the company representative offering financial support assures the director that there are no strings attached to the financial offer. the offer is pure charity to help the organization. The rep for the big corporation is such a nice guy. Why he invited me to a sky box in XYZ stadium to watch our local professional sports team. The rep said the sky box was already paid for by his company, why don't I come along to the game? I really like this guy and with no strings attached, how could accepting the money being offered hurt anyone?

The problem is in a short time the extra income becomes crucial to running the non-profit. The directors do not see how they can do all they want to do without this money. When an issue comes up that might make that "nice rep" unhappy or perhaps result in less or no 'sponsorship' the following budget year, it becomes so easy to just go along with what that nice rep wants the board of directors to do. The rep is a lot more real and present than the victims of disease or disability that the board of directors is supposed to represent. It is such an easy slide from accepting a sponsorship to making the easier decision that helps the company to complete capitulation to the wishes of the sponsors.

I wrote about this problem before regarding the Lupus Foundation of America. Read here:
http://autoimmunenews.blogspot.com/2009/10/lupus-foundation-of-america-sells-out.html

Here is an editorial in the Anderson Indiana, Herald Bulletin by someone who agrees with me on this issue. He is specifically speaking about the seemingly unwholesome relationship between the AARP and one of its main corporate sponsors, United Health Care.

http://www.theheraldbulletin.com/opinion/local_story_353192120.html?keyword=secondarystory

Published December 19, 2009 11:00 pm - The Beatles might have been right, money might not buy you love. But the insurance companies seem to know something else, money buys you the AARP’s betrayal of seniors.

Viewpoint: AARP gets money top promote insurance company

The Beatles might have been right, money might not buy you love. But the insurance companies seem to know something else, money buys you the AARP’s betrayal of seniors.
A few days ago June Lyle, state director for the AARP, commented at a local Triad meeting that AARP was supporting legislation on the health care reform bill that would “allow” seniors under 65 to seek health insurance through the private sector. Those over 65 could keep their Medicare and Medicaid coverage.

In other words, seniors under 65 will be at the mercy of the insurance companies until they reach an age when they can no longer be profitable for the companies.
Am I the only one that sees a problem here? AARP endorses United Health Care for a fee. That’s right. The AARP receives money to endorse an insurance company. The AARP presents itself as an advocate for seniors. Seniors rely on the AARP for information the way some consumers rely on Consumer Reports magazine. The difference, Consumer Reports does not accept money from the companies it reports on, the AARP is receiving money from an insurance company to endorse it.

Making matters worse, their ads would lead you to believe AARP was the insurance company. If AARP is to remain a nonprofit organization it would be to their best interest not to blatantly become involved in this type of conflict of interest. Until then, the AARP is no more credible than any other paid celebrity endorsement.
What insurance company would not like to take the money paid on insurance premiums until you become a major health risk, like someone over 65, and say let Medicare take of them from here on out? How long do you think the Medicare fund would last until it was totally depleted?

The answer seems to lie in not trusting either the government, AARP, or the insurance industry.

If you remember, Medicaid Part D was draining the seniors of their money with exorbitant pricing of medicine. It was not until several large discount stores, grocery stores, and drug stores started selling generic medicine for $4 a prescription that the cost came down. All along, we had been price gouged by the drug companies and the government was totally complacent.

It appears the government decided not to compete with the unregulated health care program (similar to not competing with communication companies, oil companies and food industries). We can only hope the same companies that saved us from outlandish costs of medicine will step forward and do the same for health care.

Public option appears to be dead, and with the health care and HMO industries spending 52.8 million and employing approximately three lobbyists per law maker, it is doubtful they won’t get their money’s worth. With the AARP in the insurance industry’s pocket, they obvious can’t be counted on to defend us.

In the end, maybe only the discount stores will be able to save us.
How does WAL-CARE sound to you?

Darrell E. Baylor, president of United Senior Action, Anderson Chapter, is an Anderson resident

Closing in on environmental causes for autoimmune diseases

2009-12-21T20:29:00.000-08:00

Below is an identical twins study of identical twins with identical DNA and indentical genes however ONLY ONE has autoimmune disease.

The problem is as we age and are exposed to environmental insults, chemicals, disease etc, these insults change the way are genes work. This change in function is called an epigenetic change. The genes remain the same but something affects their ability to function.

In this study one twin had genes whose functions were changed to cause autoimmune disease and the other twin did not.

These Cold Springs Harbor researchers were able to determine the difference in gene function that lead to autoimmune disease in this case lupus.

The next step is to find out what causes the changes--those pesky environmental insults-- and then how to reverse those changes to get normal HEALTHY gene function back again.

We know that autoimmune disease turns on suddenly. It likely can be turned off just as quickly when we find the right switches which our friends at Cold Harbor have done. Next let's get those switches back on and all of us back to good health.

There are already a class of drugs that can reverse changes to genes that go by the acronym HDAC. We need a lot more work done on these drugs so they can target specific parts of our genes that need turning back on.

Finding the gene that have been affected to cause autoimmune disease is a big step forward.

Come on researchers let's get to the cures sooner than later. Get those genes turned on again.

Good job Cold Harbor Laboratory on this first big step.

Cold Spring Harbor Laboratory
Genomes of identical twins reveal epigenetic changes that may play role in lupus
Identical twins look the same and are nearly genetically identical, but environmental factors and the resulting cellular changes could cause disease in one sibling and not the other. In a study published online in Genome Research (www.genome.org), scientists have studied twins discordant for the autoimmune disease lupus, mapping DNA modifications across the genome and shedding light on epigenetic changes that may play a role in the disease.

Because the genetic makeup of monozygotic twins (commonly known as identical twins) is nearly identical, phenotypic traits and heritable diseases are often concordant, manifesting in both siblings. However, some phenotypes and diseases such as autoimmune disease can arise in only one sibling, suggesting other factors such as environment likely play a role in determining phenotypic differences.

Epigenetic modifications, cellular changes that can influence expression of genes, are now widely recognized to influence phenotype and frequently occur in disease. Furthermore, environmental factors such as diet and chemical exposure can change the epigenetic status of genes. Recent research has identified epigenetic modifications at several aberrantly regulated genes in autoimmune diseases such as systemic lupus erythematosus (SLE), and other studies have suggested that epigenetic differences are associated with phenotypic discordance between identical twins.

In this work, researchers from Spain and the United States performed the first genome-wide high-throughput analysis of a specific epigenetic modification, DNA methylation, in the context of autoimmune disease. Taking advantage of the identical genetic background in monozygotic twins, the group directly compared DNA methylation in healthy twins and twins discordant for autoimmune diseases, including SLE, looking for changes that could be related to pathogenesis in one sibling and not the other.

In the case of SLE, the group found widespread changes in DNA methylation status at a significant number of genes. Dr. Esteban Ballestar, senior author of the study, noted that this is the largest number of genes exhibiting DNA methylation changes observed in an autoimmune disease to date, and includes genes previously implicated in SLE pathogenesis. Importantly, Ballestar's team found that a significant number of the novel differentially methylated genes are related to multiple immune system functions and are potentially linked to SLE.

"Our study suggests that the effect of the environment or differences in lifestyle may leave a molecular mark in key genes for immune function that contributes to the differential onset of the disease in twins," Ballestar said. Most studies of DNA methylation and human disease have been in the context of cancer research, Ballestar noted, and he hopes that this work will attract more researchers to also investigate DNA methylation alterations in autoimmune disease and other disorders for the development of therapies.
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Scientists from Bellvitge Biomedical Research Institute (Barcelona, Spain), Christian-Albrechts-University Kiel (Kiel, Germany), Centro de Investigacion Principe Felipe (Valencia, Spain), the Broad Institute of MIT and Harvard (Cambridge, MA), Brigham and Women's Hospital (Brookline, MA), the National Institute of Environmental Health Sciences (Bethesda, MD), Gregorio Marañon Hospital (Madrid, Spain), ISCIII Center for Biomedical Research on Rare Diseases (Valencia, Spain), Institut de Medicina Predictiva i Personalitzada del Càncer (Badalona, Spain), and the University of Oklahoma Health Sciences Center (Oklahoma City, OK) contributed to this study.
This work was supported by the Spanish Ministry of Science and Innovation, the National Institute of Environmental Health Sciences, the National Institutes of Health, the Alliance for Lupus Research, the US Department of Veterans Affairs, and a BEFI Predoctoral Fellowship from the Carlos III Health Institute, Spain.
Media contacts:
Esteban Ballestar, Ph.D. (Bellvitge Biomedical Research Institute; eballestar@idibell.cat, +34 932607133) and Diomaris Gonzalez (Alliance for Lupus Research; dgonzalez@lupusresearch.org) have agreed to be contacted for more information.
Interested reporters may obtain copies of the manuscript from the Genome Research Editorial Office (genomere@cshl.edu; +1-516-422-4012).
About the article:
The manuscript will be published online ahead of print on December 22, 2009. Its full citation is as follows: Javierre BM, Fernandez AF, Richter J, Al-Shahrour F, Martin-Subero JI, Rodriguez-Ubreva J, Berdasco M, Fraga MF, O'Hanlon TP, Rider LG, Jacinto FV, Lopez-Longo FJ, Dopazo J, Forn M, Peinado MA, Carreño L, Sawalha AH, Harley JB, Siebert R, Esteller M, Miller FW, Ballestar E. Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus. Genome Res doi:10.1101/gr.100289.109.
About Genome Research:
Launched in 1995, Genome Research (www.genome.org) is an international, continuously published, peer-reviewed journal that focuses on research that provides novel insights into the genome biology of all organisms, including advances in genomic medicine. Among the topics considered by the journal are genome structure and function, comparative genomics, molecular evolution, genome-scale quantitative and population genetics, proteomics, epigenomics, and systems biology. The journal also features exciting gene discoveries and reports of cutting-edge computational biology and high-throughput methodologies.

About Cold Spring Harbor Laboratory Press:
Cold Spring Harbor Laboratory is a private, nonprofit institution in New York that conducts research in cancer and other life sciences and has a variety of educational programs. Its Press, originating in 1933, is the largest of the Laboratory's five education divisions and is a publisher of books, journals, and electronic media for scientists, students, and the general public.
Genome Research issues press releases to highlight significant research studies that are published in the journal.

Dose of sibling stem cells, can cure sickle cell, autoimmune disease next?

2009-12-20T08:55:00.000-08:00

Our tax dollars are at work and paying off in chances for new cures for a host of genetic diseases by using new less toxic and less fatal techniques to fix our immune systems.

Where is it happening? At a division of the National Institute of Health called the National Institute of Diabetes, Digestive and Kidney Disease

What is happening? The researchers at this institute and the Institutional Review Board had the courage to try a new kind of stem cell transplant that can cure without the patient's immune system being destroyed in its entirety. The patient/recipient's bone marrow is only partially destroyed to give room for HEALTHY donor cells to grow. The two bone marrows grow together as one in a process called mixed chimerism. The healthy part of the new bone marrow/immune and blood system cures the defective part of the patient's immune system.

The procedure written about below is being used in this case for a blood disorder, sickle cell anemia, but it could just as well be used for an autoimmune disease.

For most of us only need a few healthy immune cells to stop our disease.

In traditional therapies the bone marrow, the seat of the blood and immune system in a patient/recipient's body, is TOTALLY destroyed by radiation and/or drugs before donor blood and immune system cells are given to the patient/recipient. The donor cells can then have room in the now empty patient/recipient's bone marrow to reproduce and fully replace the destroyed immune system in the patient. Most of the time that happens, but not always.

Sometimes there is only
(1) partial replacement and the patient/recipient is left with a less than fully functioning immune system for the rest of their lives.
(2)Sometimes an infection appears in the patient/recipient before the immune system has time to fully regrow. The infection then often kills the patient/recipient.
(3)Sometimes GvHD starts a few years later after an apparently completely successful transplant. For unknown reasons the new immune system of the donor starts attacking the patient recipient's body. This horrible process is called Graft Versus host Disease or GvHD. The skin and mucous membranes of the patient/recipient are dissolved away by the donor's immune system. Overwhelming infection results, the patient often dies.

The lifetime success rate for full replacement of bone marrow and immune system is about 75% at best which is far better than zero chance for a cure. This full replacement procedure does work and is a life saver.

A teacher friend of mine contracted leukemia in the early 1990's and was given a full bone marrow/immune system replacement using her siblings bone marrow cells. That teacher is alive and well today. She would have died of the leukemia, more than 15 years ago without the full replacement of her bone marrow. In cancer full replacement is necessary to make sure all the cancer cells are gone.

In autoimmune diseases and blood disorders without cancer, only a relatively small number of healthy cells are needed.

While full replacement can work, researchers continue to look for better methods with higher life time success rates. This mini transplant protocol at NIDDK looks like a good one.

The idea of not completely destroying the patient's immune system has been used before with different drugs and amounts of radiation. Read about recent try with this technique at Johns Hopkins here:

http://autoimmunenews.blogspot.com/2009/12/mini-transplants-reverse-sickle-cell.html

If a best practices procedure can be found and codified, then many other hospital bone marrow centers might FINALLY have the courage to give it a try. I am hoping for someone at the UCLA or UCSD bone marrow transplant centers here in Southern California to have this kind of courage soon. I would like to see my youngest son walk and run again.

I especially hope they take note of the remarkable success of the Italian and Israeli teams of researchers in using massive infusions of donor T regs days before the donor's immune cells are given to the patient. Read more here:

http://autoimmunenews.blogspot.com/2009/12/new-hope-for-autoimmune-cure-massive.html

Here is the article from NIDDK a division of our NIH paid for by our federal income tax dollars. Hooray for the federal government!

http://www.docguide.com/news/content.nsf/PaperFrameSet?OpenForm&refid=2&id=48dde4a73e09a969852568880078c249&c=&newsid=852576140048867A85257690002FD0BB&ref=/news/content.nsf/AllNews?OpenForm&dt=g&abd=yes&id=48dde4a73e09a969852568880078c249&u=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=20007560

N Engl J Med. 2009 Dec 10;361(24):2309-17.

Allogeneic hematopoietic stem-cell transplantation for sickle cell disease.
Hsieh MM, Kang EM, Fitzhugh CD, Link MB, Bolan CD, Kurlander R, Childs RW, Rodgers GP, Powell JD, Tisdale JF.

Molecular and Clinical Hematology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA.

BACKGROUND: Myeloablative allogeneic hematopoietic stem-cell transplantation is curative in children with sickle cell disease, but in adults the procedure is unduly toxic. Graft rejection and graft-versus-host disease (GVHD) are additional barriers to its success. We performed nonmyeloablative stem-cell transplantation in adults with sickle cell disease.

METHODS: Ten adults (age range, 16 to 45 years) with severe sickle cell disease underwent nonmyeloablative transplantation with CD34+ peripheral-blood stem cells, mobilized by granulocyte colony-stimulating factor (G-CSF), which were obtained from HLA-matched siblings. The patients received 300 cGy of total-body irradiation plus alemtuzumab before transplantation, and sirolimus was administered afterward.

RESULTS: All 10 patients were alive at a median follow-up of 30 months after transplantation (range, 15 to 54). Nine patients had long-term, stable donor lymphohematopoietic engraftment at levels that sufficed to reverse the sickle cell disease phenotype. Mean (+/-SE) donor-recipient chimerism for T cells (CD3+) and myeloid cells (CD14+15+) was 53.3+/-8.6% and 83.3+/-10.3%, respectively, in the nine patients whose grafts were successful. Hemoglobin values before transplantation and at the last follow-up assessment were 9.0+/-0.3 and 12.6+/-0.5 g per deciliter, respectively. Serious adverse events included the narcotic-withdrawal syndrome and sirolimus-associated pneumonitis and arthralgia. Neither acute nor chronic GVHD developed in any patient.

CONCLUSIONS: A protocol for nonmyeloablative allogeneic hematopoietic stem-cell transplantation that includes total-body irradiation and treatment with alemtuzumab and sirolimus can achieve stable, mixed donor-recipient chimerism and reverse the sickle cell phenotype. (ClinicalTrials.gov number, NCT00061568.) 2009 Massachusetts Medical Society

Finally! New kind of asthma treatment--blocking mast cell activation

2009-12-15T16:09:00.000-08:00

For that last twenty years all we have gotten from Big Pharma and drug researchers for new treatments of asthma is the same old steroids and antihistamines just slightly reformulated, so they can be patented over and over again. Nevertheless these "new", "reformulated" same old, same old medications do exactly the same job and help in the exactly the same way. Those that have symptoms not helped by these medications (like me) are given nothing new. Just big hype as a 'brand new' antihistamine is released.

However, now finally someone out there is running clinical trials for what could be a revolution for allergies, asthma, and those like me with hypersensitivities to many foods and meds apparently due to dysregulated mast cells. (Mast cells are a kind of stationary white blood cell. Millions and millions line the surfaces of all wet and dry epithelial tissue--skin and mucous membranes).

Improperly functioning mast cells are not just a problem for allergy and asthma. There has also been evidence that when mast cell activation (degranulation) is not well controlled in folks with autoimmune disease that their disease progression is faster and more severe. So this new med has the potential to alleviate some autoimmune symptoms as well. Fingers crossed. My typing to G-d's ear.

I hope this new med is a home run and not another Osiris Prochymal disappointment (scam?). I dare not hope too much. I was crushed by the failure of Prochymal after my hopes were raised so high. If only there really was a way to get healthy immune cells to live inside of us who have immune related disorders. Imagine if healthy immune cells could get inside and regulate our malfunctioning immune cells. Cure! Freedom! Life again!

I hate being stuck with the crummy immune system I was born with. Far worse is the immune system that gave my youngest son, Paul, psoriasis, psoriatic arthritis, and ankylosing spondylitis. If only my wife could give a few of her immune cells to Paul. There is supposed to be mother/son privilege for cell swaps. Come on someone give it a try with Paul and my wife. Or if my mother (or brother or sister) were healthy enough to give me some of their nicely functioning immune cells. I want a big batch of IL-10 producing T regs first.

Not that everyone in my birth and married families is not willing to donate and receive. But try to find a researcher/doctor who will try such things. No luck. None zero. All a bunch of cowards out to protect their "career investment" instead of finding cures as fast as possible. That is why Prochymal's promise of not needing to match HLA types when infusing someone else's immune cells seemed so wonderful. Too good to be true always is. I hope the folks who hyped the lie at Osiris are happy with their piles of stock money that they undoubtedly made by hyping the "lie".

Anyway here is the article about blocking mast cells to stop allergies. Please immune god(s), please let this one work. Aren't you tired of torturing us?
---------------------------------------
Still seem to have nasal infection. Seems no worse. Saw another doctor today. A really nice one. He is trying a different formulation of the same topical ointment I am using it to stop the infection so that I do not have to apply ointment with a super long "Q tip" which may be irritating the tissue.
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Oxagen Announces Completion Of Recruitment In Phase IIb Dose Range-Finding Clinical Trial In New Oral Treatment For Asthma
Main Category: Respiratory / Asthma
Also Included In: Clinical Trials / Drug Trials
Article Date: 10 Dec 2009

Oxagen Limited, a drug discovery and development company specializing in inflammation, announced that the recruitment for its double blind, randomised, placebo controlled Phase IIb clinical trial in asthma with OC000459, its lead oral CRTH2 (DP2) antagonist, has now been completed.

The study, which was initiated in mid May 2009, is expected to complete by the end of Q2 2010. It involves 440 asthmatic patients with moderate persistent asthma who will be randomised to one of three possible dose levels of OC000459 or placebo by oral tablet for a 12 week dosing period, with lung function (improvement in clinic FEV1) being the primary end point.

The purpose of the study is to determine the magnitude of further improvement in lung function and asthma symptoms on longer term therapy and to define the optimal once daily oral dose of OC000459.

Mark Payton PhD, Oxagen's Chief Executive Officer said "This represents an exciting time for Oxagen and a key phase in the clinical development of this compound following our recent successful proof-of - concept studies in both asthma and allergic rhinitis. We believe oral CRTH2 antagonists offer a valuable contribution to respiratory medicine and this study maintains Oxagen's position as one of the leading players in this field."

The Phase IIb trial follows the successful completion of a Phase IIa programme in which four Phase IIa trials were completed with efficacy demonstrated in asthma and allergic rhinoconjunctivitis. Over 600 subjects have been treated with OC000459 to date and results so far indicate the drug to be well tolerated.

Oxagen recently completed a £16 Million ($26.7 Million) Series C financing led by Novartis Venture Funds. The proceeds of the funding are being used primarily to advance the Company's CRTH2 antagonist programme in inflammatory and respiratory diseases, including the completion of this Phase IIb clinical study of OC000459 in moderate persistent asthma.

About Oxagen

Oxagen is a biopharmaceutical company building a novel drug pipeline with a focus on inflammatory and respiratory diseases. Oxagen's pipeline of novel small molecule drugs is based on targets validated in man.

Oxagen was established in April 1997. The Company is based in Milton Park, south of Oxford. For more information on Oxagen, please visit http://www.oxagen.co.uk

About CRTH2 and OC000459

The G-protein coupled receptor, CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells also known as DP2) mediates allergic responses by interaction with the mast cell product prostaglandin D2. There is now overwhelming evidence that CRTH2 plays a central role in the recruitment of leukocytes and their activation to elaborate Th2 cytokines in allergic disease, findings which highlight the potential therapeutic utility of CRTH2 antagonists.

OC000459 is a potent, selective and orally active CRTH2 antagonist, effective in reducing the recruitment and activation of Th2 lymphocytes, eosinophils and other cell types to sites of allergic inflammation.

Tuberculosis research discovery lends hope for autoimmune diseases

2009-12-14T20:03:00.000-08:00

Researchers at the University of Washington discovered that a protein secreted by skin and mucous membranes (wet and dry epidermis) called MMP9 causes infections to be more severe. Blocking it in mice leads to less inflammation and less disease.

Perhaps it will become a target for autoimmune diseases as well. I cannot help wondering if my susceptibility to infections and my son's terrible set of autoimmune diseases might be tied to a biochemical pathway that has this or a similar protein in it.
----------------------------------------
I go to another ENT tomorrow. I still have an active infection in my nose that is 'controlled' by the topical I put way up inside but not killed. It is painfully bloody high up inside. The topical in now being noticed by my insane immune system and I am beginning to itch intently, but have no choice but to use it. I will try to get Zyvox, a new pill antibiotic, but its use is restricted. I went to the ER today to talk to the doctor I saw a week ago that gave me the sulfa drugs that caused my immune system to itch so violently, but after parking in the lot and getting out of the truck, I just could not get up the courage to go in. There were so many sick people and I just could not get over an illness. Stupid in the 21st century to force immune compromised folks to go to the most infectious dangerous places to get care. Why not use the computer. i have a camera built in to this one. Most do now a days. Doctors sure do not like to change practices.

Instead of the ER I drove to a nearby salt water lagoon near the corner of Highway 78 and Interstate 5 I had not been to since I memorized all the names and photos of California birds a couple of years ago. I have been housebound for eight years. I used to get bored sometimes and it was fun memorizing the pictures and names in a couple of bird books. At the lagoon, I saw a Belding or Savannah sparrow at the edge of the road, western Grebe in the middle of the lagoon, and I am pretty sure I saw a Sora come out of the reeds for a second and go back in. Great birding as they say.
______________________--

Here is the article: The URL is at the end of the article.

Finding How To Block The Infection Pathway May Lead To New Therapies For TB And Other Disorders
12 Dec 2009

Scientists have discovered a signaling pathway that tuberculosis bacteria use to coerce disease-fighting cells to switch allegiance and work on their behalf. Epithelial cells line the airways and other surfaces to protect and defend the body. Tuberculosis bacteria co-opt these epithelial cells into helping create tubercles: the small, rounded masses characteristic of TB. The tubercles enable the bacteria to expand their numbers and spread to other locations.

By inciting parts of the immune system to go into overdrive, this same molecular signaling pathway may play other roles in inflammatory conditions such as arthritis and some forms of heart disease and cancer

"If we could keep this pathway from inciting the host immune system, we may be well on the way to finding innovative new therapies against TB, as well as other serious disorders," said the senior researcher on the study, Dr. Lalita Ramakrishnan, University of Washington (UW) associate professor of microbiology, medicine, and immunology. The results appear in the Dec. 10, 2009 express edition of Science.

Global health researchers are eager for new treatments for TB because many strains worldwide have become resistant to standard antimicrobials. Blocking a host pathway that the bacteria use would be an entirely different approach, Ramakrishnan explained, because it would keep the body from allowing the infection to take hold and be sustained, rather than a treatment aimed at killing the bacteria themselves. A host pathway blocker, if one becomes available, might also be quicker than current therapies, which take a long time to subdue the TB infection.

"Most diseases, such as high blood pressure and depression, are already being treated by blockers and inhibitors of host enzymes and pathways," Ramakrishnan noted, "Many of these turn down certain cell signals as part of their therapeutic action. We and some other researchers are now exploring the possibility of blocking or inhibiting molecular mechanisms in the body to prevent or treat infectious diseases as well. "

Earlier studies in the zebrafish by the Ramakrishnan lab demonstrated that TB tubercles were not, as previously thought, the way that the body walls off the bacteria to protect itself. Instead, these nodules (also called granulomas) are hubs for bacteria production and distribution. Uninfected macrophages - the body's frontline soldiers that can eat and destroy many bacteria - are recruited to the nodules, where they become TB-infected. However, the TB bacteria are able to grow in the macrophages, rather than being killed, likely by dampening the macrophages' defenses.

So by wooing more macrophages into the granuloma, the bacteria can use them to expand further. Some germ-laded macrophages then move to a new location, where they again attract more macrophages. New tubercles form and the scene is repeated.

Ramakrishnan and her research team have identified a molecular mechanism by which the mycobacteria that cause TB induce the body to form these production and distribution nodules. Researchers have long known that TB virulence is associated with a small protein the bacteria secrete, called ESAT-6.

Ramakrishan's group now has found that this secreted bacterial protein induces epithelial cells - the cells that make up membranous tissue covers inside the body - to produce an enzyme called MMP9. This enzyme has many functions including breaking down gelatin - a connective tissue protein - into its components. In people, the presence of MMP9 is associated with increased susceptibility to infection and worse outcomes. The findings of this new study explain why this might be the case. MMP9 is also implicated in the development of several non-infectious inflammatory conditions, like arthritis, as well as heart disease and cancer.

Epithelial cells were once thought to be bystanders as tuberculosis took hold, according to the research group. However, their latest findings suggest that secretion of MMP9 by epithelial cells is amplified in the vicinity of a single TB infected macrophage. The activity of this enzyme draws in uninfected macrophages to join the infected macrophage to form and expand the granuloma.

"TB bacteria may have a two-prong strategy," said the first author of the Dec. 10 Science Express report, Dr. Hannah E. Volkman, who recently received her Ph.D. from the UW Molecular and Cellular Biology Program, "whereby the bacteria simultaneously suppress the macrophages inflammatory programs in order to create a hospitable niche inside them, while prodding epithelial cells to signal more macrophages to arrive and be unwitting participants in their home expansion project."

The researchers genetically "knocked out" MMP9 production in zebrafish embryos to see if that made them more resistant to TB. After TB infection, these embryos indeed had greater survival rates, fewer bacteria, and fewer granulomas than their normal, MMP9-producing siblings. This finding suggested that intercepting the production of MMP9 in epithelial cells should be further studied as a possible TB therapy.

"These novel findings," said Dr. William Parks, a UW professor of medicine and director of the UW Center for Lung Biology who was not part of this study, "point to new ways in which the body's resident cells can effect an inflammatory response and may have relevance beyond TB infection. The pathogen-to-epithelium-to-macrophage pathway they uncovered should provide several new avenues that could be targeted for intervention."

Co-authors of the article, "Tuberculous Granuloma Induction via Interaction of a Bacterial Secreted Protein with Host Epithelium," in addition to Volkman and Ramakrishnan, are Tamara C. Pozos, a former UW infectious disease fellow who is now on the faculty of Children's Hospital and Clinics of Minnesota; John Zheng, a UW medical student; J. Muse Davis, an M.D./Ph.D. student at Emory University; and John F. Rawls, assistant professor of cell and molecular physiology, University of North Carolina, Chapel Hill.

The study was funded by the Burroughs Wellcome Fund, Pew Scholars Program, National Institutes of Health, American Heart Association, Pediatrics Infectious Disease Society, Children's Health Research Center, and a National Defense Science and Engineering fellowship

Source: Leila Gray
University of Washington
--------------------------------------------------------------------------------

Article URL: http://www.medicalnewstoday.com/articles/173788.php

Main News Category: Tuberculosis

New B cell hope, a humanized Rituxan from Genetech

2009-12-11T16:12:00.000-08:00

A humanized B cell depletion therapy is successful in phase III clinical trials. This means that the FDA approval can likely be no more than two or three slow agonizing years away.

The only sad thing about this news is that this new B cell depletion therapy, monoclonal antibody is only "humanized". It is not a fully human monoclonal. Humanized means it is about 90% human. There will still be a chance for adverse reactions to the 10% of it that is mouse protein.

But since a portion of our B cells drive our autoimmune process with autoantibodies that they produce any new B cell depletion therapeutic product is a welcome addition to our arsenal against autoimmune.

Currently Rituxan is the only B cell depletion therapy on the market and it is about half mouse protein. No drug can be in the US market without FDA approval and Rituxan has that approval exclusively among drugs that could deplete B cells.

We know from many many trials with various autoimmune diseases that B cell depletion can turn off almost any autoimmune disease for months or even years. On the downside of B cell depletion it that dormant viruses, particularly the deadly PML virus, can be awaken when B cells are depleted. These virus without B cell to keep them in check can be fatal. Luckily reawakening of potentially deadly viruses is rare.

Here is the story:
http://sanfrancisco.bizjournals.com/sanfrancisco/stories/2009/12/07/daily71.html?t=printable

Business News - Local News
Friday, December 11, 2009, 11:04am PST
Genentech, Biogen: RA drug study positive
San Francisco Business Times - by Ron Leuty

A late-stage rheumatoid arthritis drug under development by Genentech Inc. and Biogen Idec Inc. showed that it improved the signs and symptoms of the disease.

South San Francisco-based Genentech, a subsidiary of the Roche Group, and Cambridge, Mass.-based Biogen Idec (NASDAQ: BIIB) said they will submit the data from the Phase III trial for presentation at an upcoming medical meeting.

The study is the first of four needed to win approval of the humanized monoclonal antibody ocrelizumab, which is similar to Genentech and Biogen Idec’s Rituxan, from the Food and Drug Administration.

The study combined ocrelizumab with methotrexate —the gold standard for treating rheumatoid arthritis — in patients with active RA but who had an inadequate response to prior treatment with methotrexate. It consisted of 1,015 patients and recorded their responses at 24 weeks and 48 weeks.

"These results are significant because they are the first data from a large Phase III trial to show that a humanized antibody targeted at B-cells improves the signs and symptoms of rheumatoid arthritis," said Dr. Hal Barron, Genentech's chief medical officer.

Deeper data about the study wasn’t released, but the companies said a higher percentage of serious infections occurred in those receiving ocrelizumab versus those receiving a placebo. Overall adverse events were comparable between the two groups, the companies said.

Results of the three other required Phase III studies of ocrelizumab are expected in the first half of 2010, the companies said.

Roche and Biogen split Rituxan profits, with 60 percent of the U.S. profit going to Roche, according to the Reuters news agency. Biogen would receive 30 percent of the profit from both Rituxan and ocrelizumab if the new product is approved, Reuters said.

A radiographic study of ocrelizumab in patients who hadn’t previously been exposed to methotrexate was placed on clinical hold and dosing was stopped.

Email Ron Leuty at rleuty@bizjournals.com / (415) 288-4939.

Mast Cells and hypersensitivity a connection

2009-12-11T10:08:00.000-08:00

Another article that seems to confirm my suspicions that my hypersensitivity reactions to foods, drugs especially antibiotics and insect stings are all caused by defective mast cells. In addition my son's autoimmune disease severity could also be as a result of mast cell malfunction. I mentioned that to a rheumatologist who was treating Paul three years ago. She called it nonsense. Of course she also was the rheumy who did not know the names of all six biologicals approved at that time.

Notice in the article below that our old friend, IL-10 is mentioned. What ever happened to the genetically engineered gut microbs that produce high levels of IL-10? There was a guy in England that created them several years ago. He thought they could help in asthma and allergy. He was going to give them to patients. There was a small problem with them being GMOs but I thought he could have gotten past that problem. Sadly I have not heard anything since the initial article.

Read more here:
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B7GGW-4K1295R-2&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_searchStrId=1132327709&_rerunOrigin=google&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=4d7bacc1b069893c56b5ac192b77af86
and here:
http://informahealthcare.com/doi/abs/10.1517/14712598.4.4.439

Last night I took a few grains of crushed up Xanax which was enough to calm me and allow sleep. I was able to get nine hours, best night in a week.

I woke up in the middle of the night with breathing difficulties, centering on my lower right lung. It would not clear with my usual steaming and asthma breathing exercises. I woke up my wife and she brought me tea which helped. This morning I am feeling pain inside that lung in the same place as the congestion last night. Hope it is not the bacteria in my lungs now. I think it might be from hunching over the computer and typing. I am not in my usual computer typing place as I am restricted to master bedroom and bath to protect our son Paul from catching what I have.

Have not gone to ER. I hate the place. Sick people are one thing but the disrespect the medical community shows to those of us with hypersensitivity reactions is really insulting. Infection control procedures seemed good at the ER unlike the EMT's office where they seemed to be practicing in a 19th century pre microbe theory of disease mode.

I have found a code under Zyvox restrictions that would allow me to get it due to failure of first line antibiotics. The last time I had it I had a syncope episode after sixth pill, may not have been related to the medication but I stopped anyway as the infection had ended. If I have another episode this time I figure it is better to faint away than to have my skin itch so bad I could hardly keep from tearing off. What torture hypersensitivity reactions are. Too bad our doctor friends do not seem to be able to emphasize with people who get these kinds of reactions.

Am waiting to feel worse before I go to hospital ER. The ER folks like you to be really well advanced with an infection before they take you seriously.

Here is the article about mast cells with its link:

http://journals.lww.com/waojournal/Abstract/2009/10000/Mast_Cell_Regulation_of_the_Immune_Response.2.aspx

World Allergy Organization Journal:
October 2009 - Volume 2 - Issue 10 - pp 224-232
doi: 10.1097/WOX.0b013e3181c2a95e
Review Article

Mast Cell Regulation of the Immune Response
Ryan, John J. MD; Morales, Johanna K. MD; Falanga, Yves T. MD; Fernando, Josephine F. A. MD; Macey, Matthew R.

Abstract

Mast cells are well known as principle effector cells of type I hypersensitivity responses. Beyond this role in allergic disease, these cells are now appreciated as playing an important role in many inflammatory conditions.

This review summarizes the support for mast cell involvement in resisting bacterial infection, exacerbating autoimmunity and atherosclerosis, and promoting cancer progression.

A commonality in these conditions is the ability of mast cells to elicit migration of many cell types, often through the production of inflammatory cytokines such as tumor necrosis factor.

However, recent data also demonstrates that mast cells can suppress the immune response through interleukin-10 production.

The data encourage those working in this field to expand their view of how mast cells contribute to immune homeostasis.

Last post

2009-12-10T17:12:00.000-08:00

I made it though the night with a dose of sulfa in the morning, I still itched terribly but my nose was better.

I went to my doctor today and told him about the problem. He said I should stop taking the oral antibiotics and concentrate on the topical.

I did that today. Sadly it did not work. The infection is back with a vengeance. My the inside of nose really hurts again for the first time since I started the oral antibiotics. It is very bloody with bright red blood again. This morning it was all dead with only brown blood coming out. Had I been able to tolerate the sulfa drug antibiotic a few more days, I would have been cured.

I expect to go to the hospital in next day or two. I expect to die there. The infection is growing so fast that they will give me intravenous antibiotics. I cannot live. My immune system is too reactive. I will go into anaphylaxis or have my airways swollen shut.

Sure wish I could go back in time and know how I got this bacteria and make sure I did not get it. Too bad.

Life has been great except for my allergies.

I made it to 56 years way past my expiration date. Most folks with my allergies die much younger. I was hoping for a cure. It did not happen.

My only chance would be Tblisi, Georgia half a world away. I would be dead before I got my passport and transportation there. This is a VERY aggressive bacterial strain. It must have multiple ways to disarm the human immune system.

Actually I just thought of one more hope, the antibiotic Zyvox. It is supposed to kill staph but it is also supposed to be restricted to hospital acquired multi drug resistant strains of enterococcus according to my primary care doctor. Perhaps I can get an exemption. Perhaps it will work.

IL-22 too much or too little implicated in psoriasis, colitis, and pneumonia

2009-12-09T22:16:00.000-08:00

Below is a series of articles showing the critical importance of controlling IL-22. We need ways to boost it for some diseases and ways to turn it down for others. When will drugs be developed for IL 22?
--------------
Update on my progress with the sulfa reaction I have been mentioning in last few blogs.
I itch so bad now. Really terrible. Yep the sulfa drug was a mistake. Stuck between a rock and a hard place. I had to try. If I do not, then the infection wins. Worse I continue to expose my son to this horrible resistant and 'rare' bacteria. His immune suppresants would allow the bacteria to grow even faster than it has in me. And it has been pretty agressive in me. Just does not want to die. Started Thanksgiving day after a series of dry Santa Anas. My right nasal passages cracked a little. The the infection came. Was the bacteria in the cat dander I breathed as I brushed the cat? Was it on my skin and in my nasal passages already from some silent colonization of my body that I was not aware of util the bacteria found a way through my skin? just waiting for a chance to grow? Was it my neighbor who sneezed a giant uncovered juioy sneeze ten yards up wind from me--a stong wind. I always move away from neighbors and others outside but I did not see him or hear him until he sneezed. Does it matter how I got the infection or just whether it dies or I do. Itch Itch Itch
-----------------------------

Children's Hospital of Pittsburgh
Children's Hospital scientists identify possible target for prevention and treatment of pneumonia

Results of first-of-its-kind research published in the Feb. 10 online edition of Nature Medicine

Researchers at Children’s Hospital of Pittsburgh of UPMC have identified a key protein target that may be a crucial factor in the development of a vaccine to prevent and new therapies to treat pneumonia, the leading killer of children worldwide.

Research led by Jay K. Kolls, MD, chief of the Division of Pediatric Pulmonary Medicine, Allergy and Immunology at Children’s, identified for the first time the importance of a protein known as interleukin 22 (IL-22) in the immune response to a strain of bacterial pneumonia. In the laboratory, the researchers were able to effectively treat mice with pneumonia by using purified IL-22.

Results of the study are published in the February online issue of Nature Medicine.
“Currently there is no vaccine that covers all kinds of pneumonia and antibiotic treatment is sometimes limited by antibiotic resistance. As acute respiratory infections are the no. 1 killer of children in the world, progress in the development of novel vaccines or new, more effective treatments is critical,” said Dr. Kolls, the Neils K. Jerne Professor of Pediatrics and Immunology at the University of Pittsburgh School of Medicine. “Our results raise the possibility of developing new protein-based therapies using IL-22 to limit or prevent pneumonia.”

Pneumonia causes almost one in five deaths in children under age 5 worldwide – more than 2 million children each year, according to the World Health Organization. It kills more children than any other disease – more than AIDS and malaria combined.

IL-22 and interleukin 17A (IL-17A) are produced by a recently discovered lineage of cells known as T Helper Type 17 (Th17). Children’s researchers found evidence that the Th17 cell lineage and its cytokines IL-22 and IL-17A have evolved to promote host defense against certain infections in the lung caused by extracellular pathogens.

This is an important discovery because the Children’s research team proposes that by stimulating the Th17 arm of the immune system, they can more efficiently treat bacterial pneumonia. Furthermore, the researchers propose that Th17 is a less critical pathway for intracellular bacteria such as those that cause listeria and tuberculosis – thus raising the potential to target this pathway in diseases of chronic inflammation such as rheumatoid arthritis or inflammatory bowel disease without increasing susceptibility to these intracellular pathogens.
---------------------------------------------------------
--Scientists discover cells that control inflammation in chronic disease Clucy.goodchild@imperial.ac.uk
44-207-594-6702
Imperial College London ontact: Lucy Goodchild
A new type of immune cell that can be out of control in certain chronic inflammatory diseases, worsening the symptoms of conditions like psoriasis and asthma, is described for the first time this week in the Journal of Clinical Investigation.
The authors of the study, from Imperial College London, the Istituto Dermopatico dell'Immacolata in Rome and the Center of Allergy and Environment (ZAUM) in Munich, hope their discovery could lead to new treatments for these diseases that would bring the cells under control.

The new cell described in the study, called a Th22 cell, is a kind of T-helper cell. These cells are white blood cells that help to activate other immune cells when the body is infected by a pathogen, such as a virus or bacterium. They also control inflammation in the body to help fight off infection.

According to the new study, Th22 cells play a special role in overseeing and coordinating immune cells that cause inflammation. In chronic and allergic inflammatory diseases like psoriasis and allergic eczema, Th22 cells appear to be malfunctioning, leading to excessive inflammation, which can worsen symptoms.
The researchers hope that it may ultimately be possible to treat chronic skin and possibly also airway diseases by targeting Th22 cells with new drugs.

Dr Carsten Schmidt-Weber, one of the lead authors of the study from the National Heart and Lung Institute at Imperial College London, said: "We are seeing an increase in chronic diseases like skin and airway disease because of changes in people's lifestyles. These diseases can have a big impact on people's lives and patients can face a constant battle to keep their symptoms at bay. We are very excited about discovering this new subset of T-helper cells, as we believe it could provide a new target for the treatment of chronic inflammatory diseases in the future."

The researchers discovered Th22 cells by looking at skin samples from people with psoriasis, atopic eczema and allergic contact dermatitis. They analysed the samples and found a completely new type of cell. The researchers examined the molecules the cells made and found that one of them was a signalling molecule called interleukin-22 (IL-22). This signalling molecule warns tissues that inflammation or infection is going to occur, so the tissues can get ready to recognise and attack pathogens or protect themselves against inflammation. The effect of this can be either protective or detrimental - for example, IL-22 molecules and Th22 cells can cause skin cells to grow too quickly, resulting in painful, flaking skin.

The authors of the new study hope that their new discovery will provide scientists developing treatments for inflammatory disorders with a new cellular drug target. The researchers are now investigating the role of these cells in greater detail and exploring their role in disease progression. In addition, Dr Schmidt-Weber and his colleagues want to know how the cells are generated in the body and whether there is any way to control these cells before they cause unwanted damage.
--------------------

Gut Instincts: What Harms Some Cells May Protect Against Inflammatory Bowel Disease
19 Dec 2008

In a finding that could lead to improved treatment of chronic inflammatory bowel disease (IBD), Yale University researchers have uncovered a key mechanism in the immune system that appears to offer protection from the disorder. Their work appears in the December 19 issue of Immunity.

IBD is caused by an immune response gone awry. Detecting an inflammatory threat, T helper cells, which boost the body's defense system, overreact. They secrete harmful proteins (cytokines) that destroy the lining of the gastrointestinal tract, causing further inflammation. The Yale team, led by Richard A. Flavell, chair of the Department of Immunobiology, found that the cytokine interleukin-22 (IL-22), which can damage tissue in diseases such as psoriasis, actually seems to play a protective role in the case of inflammatory bowel disease.

"It seems likely that this relates to the type of cell that responds to the IL-22 signal," Flavell said. "Skin cells respond in an inflammatory manner and increase in number - that's psoriasis. In the gut, however, the response to the IL-22 signal is to preserve the life of cells that would otherwise die. IL-22 switches on genes that keep cells alive. We don't yet know why the reaction in the gut is different from that in the skin."

Flavell's team induced colitis in mice and found those that were deficient in interleukin-22 had more severe forms of the disease and higher mortality. In the mice that were protected by IL-22, researchers were surprised to find certain types of white blood cells of the immune system, commonly known as "natural killer cells," acting in ways they had not been known to act.

"Natural killers cells were previously thought to play a role in fighting infection and tumors," Flavell said. "Now, we can see that they also play a role in protecting host tissue from damage caused by an overreacting immune system."

More than half a million Americans suffer from inflammatory bowel disease each year. The most common forms of IBD are Crohn's disease and ulcerative colitis. Treatment most often consists of powerful anti-inflammatory drugs such as prednisone, which can weaken the body's immune response. Severe cases may require bowel resection or permanent colostomy.

Yale scientist Lauren A. Zenewicz, first author of the paper, said the discovery of interleukin-22's protective qualities could lead to treatment for IBD that avoids the side effects of current drug therapies, which can lead to increased susceptibility to disease.

According to Zenewicz, IL-22 only impacts tissues and has no direct effect on the immune response. "This specific targeting will allow us to modulate tissue responses to alleviate tissue destruction during inflammation, while having limited effects on the immune response itself."

Before a new drug treatment based on IL-22 can become reality, however, Zenewicz cautions that more study is needed on its dual nature, to learn why it reacts differently in the context of different diseases. In addition, she said, researchers need to study the impact of a continuous course of IL-22 stimulation. "Gaining a better understanding of both the short-term and long-term effects of IL-22 on different tissues is needed to be able to develop IL-22-related therapeutics," she said.

In addition to Zenewicz, Flavell's team included George D. Yancopolous, David M. Valenzuela, Andrew J. Murphy and Sean Stevens, all of Regeneron Pharmaceuticals, Tarrytown, New York.

Citation: Immunity; Volume: 29; Issue: 6

Source:
Helen Dodson
http://www.yale.edu
-------------------------------
Contact: Vijay Reddy, MD, PhD
vijay.reddy.md@flhosp.org
352-846-1749
Cell Transplantation Center of Excellence for Aging and Brain Repair
Predicting acute GVHD by gene expression could improve liver stem cell transplant outcomes
Tampa, Fla. (July 21, 2008) – Many cell transplants involve the use of stem cells from another human being (known as an allograft), which raises the major concern of the potential for acute graft-versus-host disease (GVHD). GVHD occurs when an immune response is elicited by the grafted cells against the recipient, resulting in tissue damage for the treated individual.
Presently, there are no definitive markers for predicting the development of acute graft-versus-host disease (GVHD) or its progression following the transplant of allogenic stem cells as therapy for liver cancer.
However, in a study published in the current issue CELL TRANSPLANTATON (17:5), researchers at the University of Florida offer a preliminary "molecular signature" based on gene expression for the development of acute GVHD following allogenic hematopoietic stem cell transplants (HSCT).
Despite immunosuppressive drugs, acute GVHD can develop within 100 days post-transplant. Where tissue damage in the skin, liver and gastrointestinal tract is extensive, prognosis can be poor. Although clinicians can identify a well-defined pathophysiological mechanism for acute graft-versus-host disease (GVHD), being able to uncover molecular markers for a patient's potential to develop GVHD would be a significant breakthrough.
"Our study enrolled four acute GVHD patients and four acute GVHD-free patients and noted significant differences in the expression of 1,658 genes between the control and acute GVHD patients," explained Vijay Reddy, MD, PhD, the study's lead author.
Of the 1,658 genes observed, immune-related genes showed the greatest amount of change.
"We observed a predominately pro-inflammatory gene expression profile in acute GVHD patients, consistent with our knowledge of how GVHD develops," concluded Reddy. "Perhaps the most valuable finding was having discovered the possible role for IL-27, IL-22 and Th17 cellular inflammatory responses in the development of acute GVHD."
Future research, said Reddy and colleagues, may want to address gene expression profiling of acute GVHD immediately after noting clinical symptoms, yet before immunosuppressive drugs are administered.
"Nevertheless, this is an important study to help develop biomarkers for determining who is at risk for GVHD following current and future stem cell treatments," said Dr. Paul Sanberg, Distinguished Professor at University of South Florida Health and coeditor-in-chief of Cell Transplantation.
###
The editorial offices for CELL TRANSPLANTATION are at the Center of Excellence for Aging and Brain Repair, College of Medicine, the University of South Florida and the Diabetes Research Institute, University of Miami Miller School of Medicine. Contact, Dr. Paul Sanberg at psanberg@health.usf.edu or Dr. Camillo Ricordi at ricordi@miami.edu.

B cell breakthrough Children's Hospital Boston

2009-12-09T21:51:00.000-08:00

This breakthrough in B cell understanding has to do with how they get out of control and cause cancer. It applies to autoimmune disease because something similar happens to us. We get an out of control clonal group of B cells that make autoantibodies. If it is a similar gene to the one for lymphomas, then any treatment for B cell lymphomas might help us, too.
-------------------
One hour since the sulfa drug, damn I itch arms legs neck. Itchy prickles every where. Throat feels better not as tight. Maybe I will not suffocate tonight. I have gone that route several times before, not fun. Gee if it wasn't so cold I would consider driving to the ER parking lot and try to fall asleep in my truck waiting to see if it got bad enough go into ER. Oh well, what could they do anyway? Not much. Solumedrol is not the miracle that the docs pretend. an awful lot of us die even with everything they have at the ER.
---------------------

Children's Hospital Boston

A new target for lymphoma therapy
Gene enhancer is responsible for activating cancer-causing genes in B cells

Researchers at the Program in Cellular and Molecular Medicine and the Immune Disease Institute at Children's Hospital Boston (PCMM/IDI) have found a link between a common mutation that can lead to cancer and a distant gene regulator that enhances its activity. Discovery of this relationship could lead to drugs targeting B-cell lymphomas, including Burkitt's lymphoma, an aggressive cancer in children, as well as multiple myelomas and other blood-related cancers.

Lymphomas often originate in B cells, the same cells that produce antibodies to help fight infections. A B cell can become cancerous if a gene known as c-myc leaps to another section of DNA (the IgH region, responsible for building antibodies), fuses with it, and somehow becomes over-activated. Scientists have wondered for years how this oncogenic activation occurs, in particular what component in the IgH region activates c-myc. The new study, published in the Dec. 10 issue of Nature, identifies this regulatory component, and marks the first time researchers are able to understand how this movement of genes, or "chromosomal translocation," can hijack a B cell's operation badly enough to lead to cancer.

"IgH-to-myc translocation is the classic example of activation of an oncogene in cancer," says Frederick Alt, PhD, scientific director of PCMM/IDI and senior author of the study. "But nobody really understood how it works."

Aberrant DNA translocations can occur during two different stages of a B cell's development: during a process known as VDJ recombination, when a progenitor B cell creates an antibody to fight a specific pathogen, or during class switch recombination, when a mature B cell gives its antibody a different strategy to fight infection (changing from an IgM to an IgG antibody, for example). Based on their past research , Alt and his colleagues decided to focus on one part of the IgH region called IgH 3' regulatory region (IgH3'RR). They had already shown IgH3'RR to be a far-reaching gene regulator that enhances the transcription of neighboring genes in the IgH region during class switch recombination.

To investigate the relationship between IgH3'RR and lymphoma, the team, led by Alt and first author Monica Gostissa, PhD, of PCMM/IDI, deleted the IgH3'RR in a line of mutant mice previously generated in the Alt lab. These mice routinely develop a B-cell lymphoma in which c-myc is translocated to the IgH region of the DNA. However, without IgH3'RR, mature B cells did not become cancerous, suggesting that mature B cells -- from which most human lymphomas originate -- need IgH3'RR in order to develop into lymphoma.

"The study shows that the IgH3'RR is a key element for turning on the cancer-causing activity of c-myc after it is translocated to the IgH locus," says Alt. He noted that the study also shows that the cancer-causing activity of the IgH3'RR on c-myc can extend over surprisingly long chromosomal distances.

The study suggests the IgH3'RR as a new target for arresting lymphomas and other blood-related cancers that arise from mature B cells. Though inactivating IgH3'RR can impair a B cell's versatility in creating different classes of antibodies, it would not leave a patient immune-deficient because the B cells would retain some of their activity, says Gostissa. Furthermore, such a treatment would be reversible.

The next step is for the researchers to see what eliminating IgH3'RR will do to existing tumors, and then to create a cell-based drug screening assay to test for possible IgH3'RR inhibitors.

###
The study was funded by grants from the National Institutes of Health and the Leukemia and Lymphoma Society of America (including funds from the de Villiers International Achievement Award). Alt is an investigator of the Howard Hughes Medical Institute.

Monica Gostissa, Catherine T. Yan, Julia M. Bianco, Michel Cogne, Eric Pinaud and Frederick W. Alt. "Long-range Oncogenic Activation of IgH/c-myc Translocations by the IgH 3' Regulatory Region."
Nature. Dec. 10, 2009.

Children's Hospital Boston is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 500 scientists, including eight members of the National Academy of Sciences, 13 members of the Institute of Medicine and 12 members of the Howard Hughes Medical Institute comprise Children's research community. Founded as a 20-bed hospital for children, Children's Hospital Boston today is a 396-bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families. Children's also is the primary pediatric teaching affiliate of Harvard Medical School. For more information about the hospital and its research visit: www.childrenshospital.org/newsroom.

Mini transplants reverse sickle cell anemia, autoimmune disease next?

2009-12-09T21:18:00.000-08:00

Johns Hopkins Medical Institutions

'Mini' transplant may reverse severe sickle cell disease
Results of a preliminary study by scientists at the National Institutes of Health and Johns Hopkins show that "mini" stem cell transplantation may safely reverse severe sickle cell disease in adults.

The phase I/II study to establish safety of the procedure, published December 10 in the New England Journal of Medicine, describes 10 patients with severe sickle cell disease who received intravenous transplants of blood-forming stem cells. The transplanted stem cells came from the peripheral blood of healthy related donors matched to the patients' tissue types.

Using this procedure, nine of 10 patients treated have normal red blood cells and reversal of organ damage caused by the disease.

Jonathan Powell, M.D., Ph.D., associate professor at the Johns Hopkins Kimmel Cancer Center, says the intravenous transplant approach for sickle cell disease, caused by a single mutation in the hemoglobin gene, does not replace the defective gene, but transplants blood stem cells that carry the normal gene.

Sickle cell disease, named for the "deflated" sickle-shaped appearance of red blood cells in those with the disease, hinders the cells' ability to carry oxygen throughout the body. In severe cases, it causes stroke, severe pain, and damage to multiple organs, including the lungs, kidneys and liver.

All patients in the study, ranging in age from 16 to 45, were treated at the NIH with what researchers call a non-myeloablative or "mini" transplant, along with an immune-suppressing drug called rapamycin.

Conventional transplant methods use high doses of chemotherapy to wipe out the immune system before the transplanted cells are injected, a process that has many side effects, including serious bacterial and fungal infections, which may kill some patients. In mini-transplants, lower doses of medication and radiation are used to make room for the donor's cells, the new source for healthy red blood cells in the patient.

According to Powell, side effects, including low white blood cell counts, were few and very mild compared with conventional bone marrow transplantation. But in nine of the 10, donor cells now coexist with the patients' own cells. One patient was not able to maintain the transplanted cells long term.

Minitransplants for sickle cell disease were tested in patients almost a decade ago, but were unsuccessful because the patients' immune systems rejected the transplanted cells, according to Powell, but by employing the drug rapamcyin, he says this new approach promotes the coexistence of the host and donor cells.

Powell's earlier research in mice showed that rapamycin inhibits an enzymatic pathway that suppresses the immune system and makes the host and donor cells tolerant to each other.

The NIH/Johns Hopkins team is conducting further studies on immune cells gathered from patients in their study, and looking at a combination of rapamycin with a well-known cancer drug called cyclophosphamide.

Other teams at Johns Hopkins are studying the use of half-matched donors for transplants in sickle cell patients, helping to widen the pool of potential donors for stem cell transplantation.

###
Funding for the study was provided by the National Institute of Diabetes, Digestive, and Kidney Diseases and the National Heart, Lung and Blood Institute at the NIH.

Study authors at the NIH include principal investigator John Tisdale, as well as Matthew Hsieh, Elizabeth Kang, Courtney Fitzhugh, M. Beth Link, Roger Kurlander, Richard Childs, and Griffin Rodgers.

On the Web: www.hopkinskimmelcancercenter.org

TSO helmith therapy fails to stop allergies Danish study

2009-12-09T21:04:00.000-08:00

I got this from the helminth yahoo group post today. Very sad, result. I am glad someone did a study but I wish it had worked for allergies. So sad. So very sad. I wanted parasites to be a cure. The idea sounded so good. The parasite would secret substances (IL-10 analogs?) that would turn down the immune system allowing the parasite to survive and turning down allergy and autoimmune. What could be wrong with that? Apparently it does not work.
--------------------------------
Now I itch so much worse. I took the sulfa drug about a half an hour ago. How bad will it get? Will the damn bacteria die with this dose or will I need to risk Stevens Johnson skin falling off tomorrow morning as well when the next dose is due?

Why do people have adverse reactions with hives? At least one percent of us do so why does it happen. When will someone find out and rescue us?
--------------------------------------------

http://health.groups.yahoo.com/group/helminthictherapy/message/3648

--- In helminthictherapy@yahoogroups.com, "Donna Beales" wrote:
>
> I came across this article & wondered if anyone on this list would care to comment. Apparently a well-structured trial revealed that T. suis had no effect on allergic rhinitis:
>
> 1. J Allergy Clin Immunol. 2009 Oct 2. [Epub ahead of print]
>
> Trichuris suis ova therapy for allergic rhinitis: A randomized, double-blind,
> placebo-controlled clinical trial.
>
> Bager P, Arnved J, Rønborg S, Wohlfahrt J, Poulsen LK, Westergaard T, Petersen
> HW, Kristensen B, Thamsborg S, Roepstorff A, Kapel C, Melbye M.
>
> Statens Serum Institut, Department of Epidemiology Research, Copenhagen, Denmark.
>
> BACKGROUND: Parasitic helminth infections can protect against allergic airway
> inflammation in experimental models and have been associated with a reduced risk
> of atopy and a reduced course of asthma in some observational studies. Although
> no clinical evidence exists to support the use of helminth therapy for allergic
> disease, the helminth Trichuris suis has demonstrated efficacy in treatment of
> inflammatory bowel disease.

OBJECTIVE: To determine efficacy of helminth therapy
> for allergic rhinitis.

METHODS: We conducted a double-blind, placebo-controlled,
> parallel group trial in which 100 subjects age 18 to 65 years with grass
> pollen-induced allergic rhinitis were randomly assigned to ingest a total of 8
> doses with 2500 live T suis ova or placebo with an interval of 21 days. The
> primary outcome was a change in mean daily total symptom score for runny, itchy,
> sneezing nose (maximum change, 9.0) or in percentage of well days during the
> grass pollen season.

RESULTS: Treatment with T suis ova (N = 49) compared with
> placebo (N = 47) caused transient diarrhea peaking at day 41 in 33% of
> participants (placebo, 2%), and increased eosinophil counts (P < .001) and T > suis-specific IgE (P < .05), IgG (P < .001), IgG(4) (P < .003), and IgA (P < > .001), whereas there was no significant change in symptom scores (0.0; 95% CI,
> -0.5 to 0.4; P = .87), well days (3%; 95% CI, -9% to 14%; P = .63), total
> histamine (P = .44), grass-specific IgE (P = .76), or diameter of wheal reaction
> on skin prick testing with grass (P = .85) or 9 other allergens.

CONCLUSION:
> Repeated treatment with the helminth T suis induced a substantial clinical and
> immunologic response as evidence of infection, but had no therapeutic effect on
> allergic rhinitis.
>
> PMID: 19800680 [PubMed - as supplied by publisher]
>
>
>
> Donna Beales, MLIS
>
> Lowell General Hospital
>
> Health Science Library
>

R-Roscovitine Hope for asthma allergy and possibly adverse drug reactions

2009-12-09T20:38:00.000-08:00

Let's hope the folks in Edinburgh are right about this drug. I sure would like a way to stop having allergic attacks and adverse reactions to drugs. I am fighting a scary infection that could be killed if I could just tolerate sulfa. They cause terrible itching but I have taken one a few minutes ago and am letting it dissolve in my mouth to see if I can slowly absorb it without a big itchy reaction. It really knocks down the bacteria but damn does it make me itch. I can feel the itching already in my legs. Tiny intense pinpricks of itching. I hope I do not go into anaphylaxis again. I hate that tunnel of death and I hate hospitals.

You lose all control in the hospital. If you are one of the one percent club that has big adverse reactions it seems to really annoy the doctors. They seem to get angry and outraged when you tell them about your problems with drugs. It is so darn inconvenient for their protocols. Of course the other problem is that there are so few drugs that really kill bacteria any more. So I can understand their frustration.

I am told I have a 'rare' gram positive bacteria. How wonderful! Now I can be host to an interesting zoo animal that will excite the doctors. They really liked seeing my whole body hives when I was in the hospital before. They called me a 'textbook' example. Come see the man with the hives. He is an interesting specimen. We usually only see this in textbooks. I felt like a zoo animal. Now I have a zoo animal living inside me.

Before my last reactions with Vantin a cephalosporin I told the doctor that it was making me itch a lot. He said well what's wrong with putting up with a little itching? Which was fine with me except the intense itching which I felt for a few hours after a dose of the drug, suddenly became whole body hives. Actually it was not fine the intense itching was pretty darn bad and I did not like him belittling me and implying that I was a coward. I really hate doctors.

I thought the hives would go away after a few hours like the intense itching had. But no, once you convert to whole body hives, the symptoms last for weeks. I remember itching so bad that I had to sit on my hands so I did not tear at my skin. Unbelievable torture. How could a good god crate such misery in the world?

I guess I stopped being religious when my talented son at age twenty was struck down with a series of autoimmune diseases that left him unable to walk without a cane, use his hands to even control a computer mouse, froze his neck and even his ribs which made it hard for him to breathe. Twice we sat by his bedside all night expecting him to die. A brilliant boy who had so many friends. Everybody liked Paul. Everybody. He was on the verge of a wonderful life. All taken away.

The itching is becoming worse. I understand that sulfa drugs can give you Stevens Johnson Syndrome which causes your skin to fall off. Then you die.

Here is the latest allergy cure possibility.

University of Edinburgh

Potential cancer drug may offer new hope for asthma patients

A drug being tested to treat cancer could also help patients suffering from asthma, research has suggested.

Scientists at the University of Edinburgh found that the drug – R-Roscovitine – helps to kill certain immune cells which can exacerbate symptoms associated with asthma.

The findings could lead to an alternative way to treat asthma in patients who are resistant to steroids, which are commonly used in asthma treatments.

Researchers studied the effect that the drug had on immune cells known as eosinophils

Eosinophils, found in the lungs and airways, help the body fight off parasitic infection. However, too many uncontrolled eosinophils can damage other cells that line the lung, contributing to inflammatory conditions such as asthma.

Researchers found that use of the drug caused the eosinophil cells to undergo a form of cell death known as apoptosis, a natural process where unwanted cells are removed from the body.

Professor Adriano Rossi, of the Centre for Inflammation Research at the University of Edinburgh who directed the study, said: "Steroids are commonly used to treat asthma but can have unwanted side-effects, while some asthma patients are also resistant to steroid treatment. It may well be that use of a drug, such as R-Roscovitine, or one that works in a similar same way, could offer an alternative to steroids, or be used in conjunction with steroid treatment for asthma patients."

###

The research has been published in the journal FEBS Letters.

histone deacetylases (HDACs) helps cystic fibrosis, autoimmune next?

2009-12-07T20:23:00.000-08:00

Scripps Research Institute
Scripps research team restores some function to cells from cystic fibrosis patients
The dramatically new approach to protein misfolding could lead to new therapies for a number of diseases

LA JOLLA, CA, December 4, 2009 –In an encouraging new development, a team led by Scripps Research Institute scientists has restored partial function to lung cells collected from patients with cystic fibrosis. While there is still much work to be done before the therapy can be tested in humans, the discovery opens the door to a new class of therapies for this and a host of other chronic diseases.
The results were published on December 6, 2009 in an advance, online edition of the high-impact journal Nature Chemical Biology.

"We are very excited by these results," said team leader Professor William Balch, a professor in the Departments of Cell Biology and Chemical Physiology and member of the Institute for Childhood and Neglected Diseases, who also receives support from the Skaggs Institute for Chemical Biology, all at Scripps Research. "Because we came at the problem of restoring cell function from a new perspective—using biology to correct biology—these findings have the potential to be game-changing.

The new study, performed in collaboration with a large number of cystic fibrosis investigators across the United States and Canada, showed that a compound called suberoylanilide hydroxamic acid (SAHA), which is already approved by the U.S. Food and Drug Administration as a treatment for lymphoma, can restore about 28 percent of normal function to lung surface cells with the most common, yet severe, cystic fibrosis mutation that results in complete loss-of-function in homozygous patients (those receiving a copy of the mutated gene from both parents).

"The results are very promising," said Balch. "We know that cystic fibrosis individuals with 15 to 30 percent of normal cellular function, as can occur with certain mutations, have milder cases of the disease and a more normal lifestyle than patients carrying a severe mutation. The added degree of function conveyed by SAHA or a compound like SAHA could make a tremendous difference to patients with acute disease."

A Life-Shortening Condition
Cystic fibrosis is an inherited disease that affects about 30,000 children and adults in the United States, and 70,000 worldwide, according to the Cystic Fibrosis Foundation.

In cystic fibrosis, patients produce thick, sticky mucus, which can clog the lungs and result in damaging inflammation and life-threatening infections. This thick mucus can also obstruct the pancreas and interfere with the proper digestion and absorption of food. Other symptoms include diabetes and infertility.

People with cystic fibrosis have mutations in the cystic fibrosis gene, which leads the body to produce a defective protein—called the cystic fibrosis transmembrane conductance regulator (CFTR) protein—which is normally found at the cell surface and is necessary for the proper movement of sodium and chloride (salt) in and out of cells. This process is necessary for the proper hydration of the lung, intestine, and pancreas.

Although more than 1,400 different mutations can lead to defects in CFTR, the most common mutation is a deletion of a phenylalanine residue at position 508 of the protein (DF508 CFTR). This mutation, which causes a severe form of the disease, is responsible for more than 90 percent of cystic fibrosis cases worldwide.

While 50 years ago few children with cystic fibrosis lived to attend elementary school, today it is not unusual for people with cystic fibrosis to live into their 30s and 40s. Most treatments available today focus on symptom management—specifically clearing the airways through lung compression vests, antibiotics, inhaled medications, and anti-inflammatory drugs, as well as promoting proper nutrition through a healthy diet, substantive digestive enzyme supplements, and other dietary aids.

Unfortunately, still lacking are approved medications that address problems with the DF508 cystic fibrosis protein. (Balch notes that a potentiator drug (Vertex 770) affecting a very rare mutant population of cystic fibrosis patients (G551D CFTR) which is at the cell surface, but unable to mobilize chloride, did achieve significant clinical benefit in a recent clinical trial). A broadly effective therapeutic correcting DF508 CFTR protein delivery to the cell surface and restoring function would be a great boon for most cystic fibrosis patients and their families.
Such a development could alleviate the chronic need for the many drugs and therapies that attempt to mitigate the onslaught of symptoms and to enable patients to sustain a normal lifestyle.

Turning a Classical Approach on Its Head

In the new study, Balch took an original approach to correcting cystic fibrosis defects. This new approach grew out of a unique understanding of protein folding and misfolding that Balch had been working out for some time with Scripps Research colleague Jeffery Kelly, chair of the Department of Molecular and Experimental Medicine, Lita Annenberg Hazen Professor of Chemistry, and member of the Skaggs Institute for Chemical Biology. This perspective may also have implications for conditions as diverse as type II diabetes, arthritis, osteoporosis, and amyloid disease (including Alzheimer's).

While in many genetic diseases specific mutations within a particular gene cause the protein product of the gene to misfold, Balch and colleagues note that is not the end of the story. Critically, this defective protein must interact with the general biological machinery of the cell, which controls the protein folding and stability environment. This can contribute significantly to the protein's loss of function and a breakdown in tissue/organism function. This biological machinery controlling the folding and function environment of the cell is referred to as the proteostasis network and is central for life.

"Our network biology approach challenges the current thinking and practices of the pharmaceutical industry that focuses on drugging single targets," Balch said. "This traditional view limits our ability to tackle pharmacologically many complex loss-of-function sporadic and inherited diseases which are really systems disorders. These diseases have multiple steps in the biological network that must be adjusted to regain a more normal function of the compromised protein and tissue."

In the case of cystic fibrosis, Balch suspected that the endoplasmic reticulum—a compartment in the cell responsible for the synthesis of CFTR which normally works to protect the body by degrading potentially dangerous abnormal proteins—could be viewed as doing its job too efficiently, eliminating mutant CFTR proteins that could still provide some function to the cell and tissue if given the opportunity.

In the new Nature Chemical Biology study, Balch and colleagues drew on their previous theoretical and experimental work to turn the classical model of drug development on its head. Rather than attempting to directly target or replace the mutant CFTR proteins present in cystic fibrosis patients—an approach that had so far failed to yield dramatic new treatments for the DF508 disease—Balch and colleagues sought instead to adjust the cell folding or maintenance proteostasis machinery of the cell to make a new cellular environment that would "work" with the mutant CFTR proteins.

In so doing, the scientists hoped that the mutated CFTR proteins, while not perfect, could now function more effectively in the cell, reducing the more severe effects of cystic fibrosis symptoms in the common DF508 variant.
Positive Results on Multiple Levels

To tweak the cellular machinery in this fashion, Balch and the team enlisted compounds that were known to inhibit a family of enzymes known as histone deacetylases (HDACs). Studies have shown that HDACs affect the packaging of the DNA in chromosomes and regulate gene expression. Based on earlier studies of the folding environment required for CFTR function published in the journal Cell, the scientists reasoned that altering HDAC function might also rebalance proteostasis networks in the cell to favor functional restoration.

For expertise in these compounds, Balch teamed up with Scripps Research colleague Professor Joel Gottesfeld and his group.

"Joel's lab and my lab worked very closely together on this," said Balch. "That's what's great about Scripps Research—its collaborative nature. People just walk in next door and two hours later you are doing an experiment together!"

Working with Ray Frizzell and Joe Pilewski, cystic fibrosis investigators at the University of Pittsburg School of Medicine, the Balch laboratory treated human lung epithelial cells isolated from patients with the devastating ΔF508 mutation with known HDAC inhibitors. Intriguingly, the FDA-approved HDAC inhibitor SAHA was shown to be most effective in restoring surface channel activity—one of the main markers of cystic fibrosis that is responsible for rehydration of the cells' surface.

Control cells demonstrated negligible levels of channel activity, while SAHA-treated cells were restored to 28 percent of the normal level found in healthy individuals.

"It's a pretty solid rescue with some intriguing properties," commented Balch.

Using a bioinformatics approach led by the Gerard Manning laboratory at the Salk Institute of Biological Sciences, the team showed that the compound increased the functioning of mutated CFTR proteins at multiple levels in the proteostasis network. Not only were mutant CFTR proteins more protected from destruction in the endoplasmic reticulum, they were also more efficiently transported to the lung cell surface where they were found at comparable levels to that of wild-type (normal) CFTR. In addition, once at the surface of HDAC inhibitor-treated cells, mutant CFTR proteins were better able to resist destruction by additional degradation pathways than DF508 CFTR proteins in untreated cells.

"By rebalancing the proteostasis program to provide a more supportive cellular environment," said Balch, "the cells appear to treat the mutation more like a polymorphism [genetic differences that are responsible for individual diversity] rather than something dangerous needing to be completely eliminated."

Balch also likened this process to evolutionary adaptations to changes in protein structure, which support mutations providing a selective functional advantage.

The study showed that one specific HDAC—HDAC7, one of 18 known human HDACs—appeared to be largely responsible for the effects on the treated cells. Little is known about the function of HDAC7 in human physiology and efforts are currently under way by the laboratories of Balch, Gottesfeld, Manning, and Scripps Research Professor John Yates to understand its mechanism of action.
The Way Forward

Mindful that dosing would be a key issue in any attempts at drug development, the researchers also began to address dosing issues in the current study.

"We know that a compound won't make it into the clinic if patients have to take the equivalent of a cereal bowl of it several times a day," said Balch. "That's especially true because, given the nature of cystic fibrosis, this would need to be a sustained, life-long treatment to protect the patient from disease."

Remarkably, the team found that low doses of SAHA not only worked in cultures of cystic fibrosis lung cells, but also offered some significant advantages over acute doses. While acute doses of SAHA produced an increase in the surface channel activity the next day, the effects stopped soon after the drug was withdrawn. In contrast, much smaller doses began working efficiently after six to eight days and strong channel activity was observed after the drug was withdrawn, gradually declining over the following week. This feature is reminiscent of its potential mechanism of action, Balch said, perhaps involving chromatin remodeling leading to an altered, protective proteostasis environment in the lung cell that could be sustainable.

While thrilled with the results, Balch cautions that "there is much work to do"—including further drug development, preclinical work, and clinical trials—before any new therapy for cystic fibrosis becomes a reality using this approach. The FDA-approved drug SAHA, while initially approved as an acute dose regimen for cancer therapeutics, remains to be carefully examined for use in a low-dose, chronic treatment regimen that would be required for protecting cystic fibrosis patients from disease over a lifetime.
###
First authors of the paper, titled "Reduced Histone Deacetylase 7 Activity Restores Function to Misfolded CFTR in Cystic Fibrosis," are Darren Hutt and David Herman of Scripps Research. In addition to Balch, Hutt, and Herman, other authors include: Jeanne Matteson, Ben Hoch, Wendy Kellner, Jeffery Kelly, J. R. Yates IIIrd and Joel M. Gottesfeld of Scripps Research; Ana Rodrigues and Gerard Manning of the Salk Institute for Biological Studies; Sabrina Noel, Joe Pilewski and Ray Frizzell of University of Pittsburgh School of Medicine; Andre Schmidt and Philip Thomas of the University of Texas Southwestern Medical Center; Yoshihiro Matsumura and William Skach of Oregon Health and Sciences University; Martina Gentzsch and John R. Riordan of University of North Carolina, Chapel Hill; Eric J. Sorscher of University of Alabama at Birmingham; and Tsukasa Okiyonad and Gergely L. Lukacs of McGill University. Frizzel, Skach, Thomas, and Lukacs are members of the Cystic Fibrosis Consortium, a team of investigators supported by the Cystic Fibrosis Foundation that are encouraged to collaborate and share results to accelerate the pace for a cure for cystic fibrosis. Finanical disclosure: Balch is a Consultant and equity holder in Proteostasis Therapeutics Incorporated (PTI), 200 Technology Square, Boston MA, whose goal is to develop drugs that correct human misfolding disease. Kelly is a founder and equity holder in PTI.

This research was supported by National Institutes of Health (NIH) grants HL79442 (WEB/JRY), GM42336 (WEB), and the Cystic Fibrosis Consortium (CFC)(WEB/JRY); NS055781 to JMG; AG03197 to GM; AG84567 to JWK; DK68196, DK72506, and the CFC to RAF and JP; UR98647 and the CFC to ES; DK075302, the Canadian Institutes of Health Research and the CFC to GLL; DK51818 and the CFC to WRS; DK23567 to JRR. D. Hutt was supported by fellowships from the Canadian Cystic Fibrosis Foundation and the Canadian Institutes of Health Research; D. Herman was supported by a fellowship from the Friedreich's Ataxia Research Alliance.

About The Scripps Research Institute

The Scripps Research Institute is one of the world's largest independent, non-profit biomedical research organizations, at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine development. Established in its current configuration in 1961, it employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel. Scripps Research is headquartered in La Jolla, California. It also includes Scripps Florida, whose researchers focus on basic biomedical science, drug discovery, and technology development. The Scripps Florida campus is in Jupiter, Florida.

For information about the commercialization of this technology, please contact Scott Forrest, (858) 784-9388 or sforrest@scripps.edu in the Scripps Research Office of Technology Development.

Bortezomib, hope for Stevens-Johnson Syndrome and TEN?

2009-12-07T13:54:00.000-08:00

Stevens-Johnson Sydrome and Topic Epidermal Necrolysis may be at hand. These are extreme hypersensitivity reactions to medications. They are similar in symptoms to Graft versus Host Disease. There is no good protocol for treatment. Death is a very common among those with SJS and especially those who have TEN.

Solumedrol which works to turn off the immune system actually seems contraindicated. Perhaps Bortezomib should be considered as a treatment option to stop both SJS and TEN.

If this drug "inhibits the activity of antigen presenting cells' stopping GvHD than why can't it stop the ones attacking the skin in SJS and TEN?

Read the article below and see what you think.

Dana-Farber Cancer Institute

Bortezomib shows promise in reducing GVHD and reconstituting immune system in some patients
NEW ORLEANS—A drug that has become a mainstay of multiple myeloma treatment may outperform alternative therapies in re-establishing the immune system of patients who have received stem cell transplants from unrelated, partially matched donors, according to early clinical trial results to be presented by

Dana-Farber Cancer Institute investigators at the American Society of Hematology's (ASH) annual meeting on Sunday, Dec. 6 (Abstract 48, Ernest N. Morial Convention Center, Room 243-245, 5:45 pm CT).

The trial was designed to determine whether the drug bortezomib (trade name Velcade), when added to routine agents (tacrolimus, methotrexate), can improve control of graft-versus-host disease (GVHD) and improve immune system recovery following a transplant from a mismatched-unrelated donor. GVHD is a common and potentially severe side effect of blood-forming stem cell transplants, in which donor immune cells attack normal patient cells and tissues. GVHD is more frequent in patients receiving transplants from mismatched-unrelated donors (in comparison with matched-related donors).

Based on bortezomib's effect in preclinical models, and in multiple myeloma patients who have received donor stem cell transplants, Dana-Farber's John Koreth, MBBS, DPhil, and colleagues theorized that it could help control the overactivity of immune cells responsible for GVHD in stem cell transplant patients.

Bortezomib inhibits the activity of antigen-presenting cells, which help initiate the immune attack in GVHD, and reduces activity of an important protein called nuclear factor-B in T cells, which undertake the immune attack. In preclinical studies, bortezomib has been shown to selectively deplete T cells that can target patients' normal cells. Mouse transplant studies have shown that early administration of bortezomib protects against GVHD without reducing the transplanted stem cells' ability to settle in the bone marrow.

The new, Phase 1 clinical trial involved 23 patients who received bortezomib-based therapy (bortezomib, tacrolimus, and methotrexate) after reduced-intensity stem cell transplants from mismatched-unrelated donors. Three dosage levels of bortezomib were tested. In updated results on 35 bortezomib-based mismatched-unrelated patients reported at ASH, GVHD rates and extent of immune system reconstitution were compared with patients who had received sirolimus-based therapy (sirolimus, tacrolimus, and methotrexate) after transplants from matched-related donors, matched-unrelated donors, and mismatched-unrelated donors.

The results show that the bortezomib-based therapy was safe and had little toxicity. Transplanted stem cells took root, or "engrafted" reliably, and the rate of GVHD in the bortezomib-based mismatched-unrelated transplants was comparable to that in sirolimus-based matched-related transplants. Interestingly, immune cell reconstitution was significantly improved in the bortezomib-based patients in the early post-transplant period (3-6 months), compared with the sirolimus-based patients.

"Our results suggest that borezomib is a promising novel immunomodulatory agent in donor stem-cell transplantation," Koreth says. "A Phase 2 trial is now accruing patients to help determine its ultimate effectiveness."

###

The study's senior author is Dana-Farber's Edwin Alyea, MD. Co-authors are Kristen Stevenson, Haesook Kim, PhD, Michael Garcia, Vincent Ho, MD, Philippe Armand, MD, Corey Cutler, MD, Jerome Ritz, MD, Joseph Antin, MD, and Robert Soiffer, MD, all of Dana-Farber.

The study was supported by Millennium Pharmaceuticals Inc. and the National Institutes of Health.

Dana-Farber Cancer Institute (www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute. It is the top ranked cancer center in New England, according to U.S. News & World Report, and one of the largest recipients among independent hospitals of National Cancer Institute and National Institutes of Health grant funding.

Pregnant mothers, get yourself to a barnyard

2009-12-07T13:35:00.000-08:00

Eating active culture yogurt during pregnancy is supposed to reduce allergies in the developing child. Exposing young children to barnyard animals is supposed to reduce their chances for allergies and asthma. Various intestinal parasites are supposed to help turn off allergies and autoimmune disease (if the parasites don't make you sicker). Now perhaps we should encourage all expectant mothers to spend time in a barnyard to protect their developing offspring from an over active immune system.

Well at least it seems true for mouse mothers. Humans maybe, maybe not.

There are certainly some dangerous bacteria in barnyards that could kill the mother and child (E. coli being just one). So caution needs to be applied.

Rockefeller University Press

Microbes help mothers protect kids from allergies

A pregnant woman's exposure to microbes may protect her child from developing allergies later in life. Researchers in Marburg, Germany find that exposure to environmental bacteria triggers a mild inflammatory response in pregnant mice that renders their offspring resistant to allergies. The study will be published online on December 7, 2009 in the Journal of Experimental Medicine (www.jem.org). In an accompanying Commentary, Patrick Holt and Deborah Strickland discuss the biological mechanisms behind these findings and how they might one day prevent allergies in people.

The progressive rise in allergies in the past several decades is often attributed to an increasing tendency to keep kids too clean—a theory known as the hygiene hypothesis. According to this theory, exposure of young children to environmental microbes conditions the developing immune system to tolerate microbes and allergens later in life. Studies have shown, for example, that children raised on farms, which teem with microbes, developed fewer allergies than those raised in cities or non-farming rural regions. But it may not be the kids' exposure that counts; children of farming mothers are also less susceptible to allergies regardless of their own exposure. But the biological mechanisms behind this phenomenon were a mystery.

According to the new study by Harald Renz and colleagues at the Phillips-University of Marburg, pregnant mice exposed to inhaled barnyard microbes gave birth to allergy-resistant pups. The exposure triggered a mild inflammatory response in the moms, characterized by the increased expression of microbe-sensing "Toll-like" receptors (TLRs) and the production of immune molecules called cytokines. The maternal TLRs were essential for transmitting protection, but how TLR signals translate into allergy resistance in the offspring is not yet known. It also remains to be seen whether the protection applies to a broad range of allergens, including those found in food.

About The Journal of Experimental Medicine

The Journal of Experimental Medicine (JEM) is published by the Rockefeller University Press. All editorial decisions on manuscripts submitted are made by active scientists in conjunction with our in-house scientific editors. JEM content is posted to PubMed Central, where it is available to the public for free six months after publication. Authors retain copyright of their published works and third parties may reuse the content for non-commercial purposes under a creative commons license. For more information, please visit www.jem.org.

Conrad, M.L., et al. 2009. J. Exp. Med. doi:10.1084/jem.20090845.

Holt, P.G., and D.H. Strickland. 2009. J. Exp. Med. doi:10.1084/jem.20092469.

mom's T regs end autoimmunity problems between fetus and mother

2009-12-07T11:11:00.000-08:00

February 3, 2009
Transfer of Mother’s Cells Molds Baby’s Immunity
By AMANDA SCHAFFER

Researchers have long wondered how pregnant women might shape their fetuses’ development — by protecting them against later disease, perhaps, or instilling an appreciation of Mozart.

Now a group in California has discovered a surprising new mechanism by which women train their fetuses’ budding immune systems: the mother’s cells slip across the placenta, enter the fetus’s body and teach it to treat these cells as its own.
A crucial task of the developing immune system is to learn to distinguish between foreign substances and the self. It is tricky: the system must respond to outside threats but not overreact to harmless stimuli or the body’s own tissues.

The new findings show “how Mom is helping to tune that whole system early on,” said William J. Burlingham, an immunologist at the University of Wisconsin, who is not connected with the research. “It’s a major advance, very new and very exciting.”
The work could have relevance to research on topics as diverse as organ transplantation, mother-to-child transmission of H.I.V. and autoimmune disorders like Type 1 diabetes.

“It points the way to a huge range of biologically significant questions that are worth exploring,” Dr. Burlingham said.

The researchers, based at the University of California, San Francisco, worked with lymph nodes and spleens from aborted second-trimester fetuses. They also drew blood from the women who had been carrying these fetuses to test for specific immune responses.

The team examined 18 samples of fetal lymph nodes and found evidence of maternal cells in 15 of them.

Researchers have known for decades that some maternal cells cross the placenta and can be observed in fetal tissue. But experts said the new work suggested a strikingly high frequency of maternal cells.

“It tells us that we need to pay more attention to what these cells are doing,” said Dr. J. Lee Nelson, an immunologist at the Fred Hutchinson Research Center in Seattle, who conducted early research suggesting that maternal cells may persist in the tissue of normal adults.

The San Francisco team also observed that regulatory T cells, a particular type of immune cell, were present in large numbers in the fetal lymph nodes. Regulatory T cells typically act to suppress immune responses. In a pregnant woman, for instance, these cells may help to prevent the immune system from treating the fetus as foreign and attacking it.

The scientists wondered whether a symmetrical mechanism might be at work in the fetus. “We wanted to get at what was inducing these cells to proliferate and what role they were playing specifically in fetal tissue,” said Jeff E. Mold, an immunology graduate student at U.C.S.F.

The group was able to demonstrate that cells from the mother directly cause fetal tissue to produce more regulatory T cells. These, in turn, help keep the fetal immune system from attacking the mother’s cells.

The fetus is genetically distinct from the mother and the father, since some of its DNA comes from each parent. This means that its immune system could reject cells from its mother as foreign, since these cells have some surface characteristics that were not inherited. The current work may help to explain why that does not seem to happen in the course of a normal pregnancy.

“We found a specific mechanism for how the mother’s cells induce the fetal immune system to be more tolerant,” said Mr. Mold, who was the first author of the paper, which appeared in Science on Dec. 5.

Other experts say the findings could have important implications for work on transplants.

When patients receive transplanted organs, they generally have to take drugs to suppress their immune system and keep it from attacking the foreign tissue. But these drugs may be associated with greater susceptibility to kidney problems, infection and bone weakness, said Dr. Burlingham, of Wisconsin.

“We would like to find ways of transplanting tissue without creating lifelong dependence on these drugs,” he said. “That might be possible if researchers took the immune profiles of patients’ mothers into account to a great degree when selecting organs for transplant.”

As early as the 1980s, scientists in the Netherlands observed that many patients who were waiting to receive kidney transplants and who had formed antibodies against most potential donors did not react against their own mothers’ white blood cells. That suggested that during fetal development, a process was allowing the fetus to tolerate tissue with motherlike surface molecules.

The new research explains “precisely how that works,” said Dr. Jon J. van Rood, a professor of internal medicine at the University of Leiden who conducted the original research. By homing in on regulatory T cells in fetal lymph nodes, “they found the crucial clue.”

The discovery may also be relevant to the study of mother-to-child transmission of infectious disease.

When pregnant women are infected with H.I.V., for instance, they often do not pass the disease to the fetus, said Dr. Joseph M. McCune, the immunologist who led the U.C.S.F. group. Fewer than half of all babies born to H.I.V.-positive mothers are infected themselves, and of those, only a small fraction are infected in the womb, he said.

If H.I.V. is crossing the placenta in the same way as the mother’s cells and if the fetus is also suppressing an immune response against the virus, it is surprising that more fetuses are not infected, he said.

Dr. McCune said he wondered whether the same mechanism that prevents the fetus from attacking its mother’s cells might also help to protect it from infection. And he wonders whether tolerance could be central to both processes.

“These are some of the major questions we’re interested in now,” he said.
The new finding may also bolster wide-ranging work on autoimmune diseases.
Researchers already know that during development, the fetal immune system can kill off specific populations of immune cells that have the capacity to attack the body’s own tissue. But the new work suggests another mechanism for avoiding unwanted attacks on the self. “We now have another handle on how the fetus may learn to distinguish between self and nonself,” Dr. McCune said. If problems with regulatory T cell mechanisms occur in utero, that might set the stage for some autoimmune disorders, he said.

In the long run, he added, by manipulating patients’ regulatory T cells — perhaps by modifying the number or activity of these cells — scientists may someday develop new therapies for these diseases.

Research groups around the world are studying the role of regulatory T cells in a wide range of basic processes and disease models. “It’s an explosive area,” Dr. Burlingham said.

And now, he said, it appears that critical processes are set in motion because early on, “we must all learn to tolerate our mothers.”

Resistant sinus infection

2009-12-07T10:21:00.000-08:00

I have been fighting an infection in my upper nose since Thanksgiving day. It is not dying. Worse in the past I easily became allergic to antibiotics breaking out in hives and having anaphylaxis. There is a limit to how long I can take any antibiotic or any med for that manner. My immune memory thinks all kinds of harmless and even helpful things are a grave enough threat to go into overdrive with hives, angioedema, syncope, and anaphylaxis--nuts, eggs, bees sting, aspirin, the list goes on and on. I guess I was born with defective T regs that are supposed to stop those reactions.

My nose was CT scanned yesterday and it showed a small concha bullosa in the area where the infection is occurring. My readings about concha bullosa indicate that it is a hollow structure with an air pocket inside that can become infected but antibiotics cannot get inside where the air pocket is. So infections reoccur over and over in some people.

I have never before had a nose infection or sinus infection. Very weird it should happen for the first time at age 56.

I have taken three doses of a new to me but very very old antibiotic, a sulfa drug,sulfameth TMP that can lead to very terrible problems called Stevens Johnson Syndrome and a worse one called TENS. The skin comes off the body in a wild autoimmune attack on the skin where the sulfa drug gets stuck. The patient usually dies of infection. There are no good treatments. Solumedrol usually given to stop a immune reaction is contra indicated. Cyclosporine is used and IVIG. No good treatments.

I itch all over right now. I was prepared to itch for a while if the bacteria would just die. My hope was that with a few days of the sulfa drug the bacteria would die. But I can feel that the obstruction in my nasal passage that I take to be the concha bullosa is feeling full again and I have bright red blood in my right nasal passage again. Both bad signs.

I have had repeated hospitalizations for antibiotic reactions so right now the out look seems guarded especially since the infection does not feel dead.

My wife had to go to work. No work, no medical insurance for our son. She has taken four days off already.

Today there is no one home to care for my son. She left him with several small bottles of water with less than a half inch in each. They are for him to get water as he gets thirsty. He can barely pick them up with both hands. Luckily he can with the help of a cane get to the bathroom and back by himself.

I am in the master bedroom suite with the heating vents pulled closed and painter's tape all around the double door cracks. We are trying our best not to let any of my bacteria out of the room.

My son is on immune suppressants--Remicade and Imuran and he can not be exposed to an infection. It would run through his body very fast.

I am going to post without comment a few other articles that I found interesting. Do with them what you will. I am trying to distract myself from the itching and from the worry that there will be nothing I can take that will kill the bacteria.

Weird I even got an infection in my nose. I never go out in public except to the dentist twice a year for cleaning and filling any cavities and the dermatologist once a year to cut off skin cancers. I have not met anyone face to face in months, not even with a mask on which I always wear even to work in the yard outside. When I see a neighbor I run inside the house. They all must think I am pretty strange. I clean and alcohol all surfaces in the house that are touched by my wife who has been shopping or coming home from teaching third grade at a nearby elementary school.

Also weird it is just one nostril probably because of the concha bullosa. The infection has not spread to my sinuses or throat.

I thought our lives were pretty sad already with my once college newspaper editor, youngest son, confined to a chair or his bed and unable to even use his hands to work a computer let alone get food or much water.

Then three weeks ago our family suffered a terrible tragedy, the lost of our first grandchildren, triplets, at six months just a little too early for any of them to survive.

Now I am sick with an infection that will not heal. I cannot take care of my youngest son who needs constant care. He is alone in the family room waiting for his mother to come home at her lunch time to give him food and water. I should be helping him.

So awful. Life can sure suck sometimes.

It is raining finally. Great news for southern California and our long drought. But somehow it seems to me that today the sky is crying. I do not feel the enjoyment that rain usually brings to all of us here in southern California.

Massive doses of T regs, new hope for autoimmune?

2009-12-07T09:17:00.000-08:00

Below is an article that lends hope to all of us with immune related problems who are hoping for a bone marrow transplant to replace our defective immune systems.

Teams in Italy and Israel have gotten remarkable success in preventing both the onset of infectious disease after bone marrow transplant and also graft versus host disease later. They were successful in 25 of 26 cases--96%! Remarkable. The success for the standard bone marrow transplant rate is far, far lower.*

How were our Italian and Israeli friends so successful?

By infusing massive doses from the donor of a special white blood cell called T regs three days before giving T cell depleted bone marrow to the recipient.

There are at least two kinds of T cells. The good ones for us are the T regs. They promote tolerance. The bad ones for us are the T effectors. They tend to attack our tissues when they are not fighting viruses and bacteria.

Donor T effectors also seem to be responsible for starting Graft versus Host Disease in recipients. GvHD is a very nasty, and often fatal, attack of the new bone marrow (containing the immune system cells) against the body of the recipient. Because of this bad tendency of T effector cells, the donor bone marrow is routinely depleted of all T cells both the 'good guy, T regs that promote tolerance and the "bad guy" T effectors. In the past no distinction was made between T regs and T effectors. It seems that was a mistake.

Getting rid of both the "good guys" and the "bad guys" T cells meant that when the donor T cell precursor cells were growing back, they might produce more T effector than T regs. The T effectors would see foreign tissue (the patient/recipient's body) and attack those 'foreign" cells. This could set up a feed back that turns into unstoppable GvHD.

However we do want T effectors or we would be susceptible to overwhelming infections. Depleting the transplanted immune cells of ALL T cells both T regs and T effectors also leaves the patient at risk for weeks or months while waiting for T cell precursor cells in the transplant to produce the full set of T cells. Months can pass before there are enough new T effectors, all the while an infection can quickly end the recipient's life. We just want T regs to be in place first to stop the T effectors from attacking the body of the patient recipient.

The Israeli and Italian doctors found that by giving the "good guy" T regs from the donor three days before the main infusion of bone marrow that the donor T regs somehow prepared the way for not only a VERY high rate of success in getting the transplants to grow but also to a much faster recovery of the immune system for the recipient without any Graft versus Host.

Of course no one knows for sure that this is going to be the magic bullet to improve bone marrow transplants until we have seen how the patients are doing at least five years down the line. If any where close to 96% are still alive in five years, then this is a miracle. Get the Nobel Prize for medicine ready for them. Fingers crossed.

For autoimmune folks the incredible initial success rate for this Italian/Israeli technique means that if we chose a bone marrow total or partial (chimeric) replacement as our way to the cure, than the odds of surviving have gone up dramatically. If the healthy donor's bone marrow successfully implants in a patient with autoimmune disease then the autoimmune disease ends. It is our 'sick" bone marrow cells that cause our autoimmune disease.

Right now the death rate for bone marrow transplants is somewhere in the 25% range for first five years. Deaths are caused initially by infections. Later by graft versus host disease. Some of the 75% that survive never regain a complete immune system leaving them vulnerable to infections and cancers. So this Israeli/Italian announcement seems to be a huge breakthrough.

*(Our bone marrow cells contain and make all of our immune system. An autoimmune disease can be cured by a bone marrow transplant from a healthy donor.)

http://wis-wander.weizmann.ac.il/site/en/weizman.asp?pi=371&doc_id=6067

Improving the Odds
07.12.2009
A new method for bone marrow transplantation from mismatched donors restores the immune system faster

Although bone marrow transplants have long been standard for acute leukemia, current treatments still rely on exact matches between donor and patient. Now, scientists at the University of Perugia, Italy, and the Weizmann Institute of Science have improved on a method of transplanting bone marrow-based stem cells from a mismatched donor, making it safer for use when no exact match exists. They were invited to present their findings at the recent annual American Society of Hematology conference in New Orleans.

More than a decade ago, Prof. Yair Reisner of the Weizmann Institute’s Immunology Department pioneered a method for transplanting stem cells from family members who are a partial match. Based on these studies (in mice), he joined forces with Prof. Massimo F. Martelli, Head of the Hematology and Clinical Immunology Section at the University of Perugia, to demonstrate in more than 300 patients that the cure rate of these so-called ”mega dose” transplants is similar to that of transplants from matched, unrelated donors picked from international bone marrow donor registries.

To combat the body’s tendency to reject the foreign cells, these stem cells are stripped of immune cells called T cells and given in high doses that overwhelm the host’s own immune system. Although removing donor T cells from the bone marrow reduces the risk of graft-versus-host disease – caused when the T cells attack the recipient’s tissues – the immune system is slow to recover after the transplant, leaving the patient at risk of serious infection. Doctors are faced with a difficult choice: Either remove the T cells from the bone marrow, increasing the risk of infection, or leave the T cells in the graft, putting the patient at risk for lethal graft-versus-host disease.

Martelli, working with Reisner, has now found a way to facilitate the recovery of the immune responses in recipients of T cell-depleted bone marrow transplants. In a clinical trial, 25 of 26 leukemia and lymphoma patients who received mismatched mega dose T cell-depleted stem cell transplants from relatives showed prompt immune recovery, and their immune systems were functioning well several months later.

The scientists knew that certain regulatory T cells (T regs), rather than causing graft-versus-host disease, could actually help to prevent it in mice. T regs have also been shown to keep other immune responses in check, including preventing autoimmune attacks on the body’s own cells. In the present study, after purifying T regs from the donor’s blood, the cells were infused intravenously into the cancer patients, who had previously undergone standard radiation and chemotherapy treatments. Three days later, the patients received the donor stem cells, along with another kind of T cell – those that fight disease.

The patients who underwent this procedure showed quick, lasting improvements in immune activity; most experienced no symptoms even though they received large doses of the T cells that are generally associated with lethal graft-versus-host disease.

Further follow up on these patients and additional clinical trials will be needed before the procedure can be widely adopted. But these results strongly suggest that T regs used in mega-dose stem cells will further enhance the cure rate for bone marrow transplant patients without a matched donor in the family.
.

Prof. Yair Reisner’s research is supported by the M.D. Moross Institute for Cancer Research; the Kirk Center for Childhood Cancer and Immunological Disorders; the Mario Negri Institute for Pharmacological Research Weizmann Institute of Science Exchange Program; the Gabrielle Rich Center for Transplantation Biology Research; the Russell Berrie Foundation; and Mr. and Mrs. Seymour Spira, Palm Beach Gardens, FL.
Prof. Reisner is the incumbent of the Henry H. Drake Professorial Chair in Immunology.

The Weizmann Institute of Science in Rehovot, Israel, is one of the world's top-ranking multidisciplinary research institutions. Noted for its wide-ranging exploration of the natural and exact sciences, the Institute is home to 2,600 scientists, students, technicians and supporting staff. Institute research efforts include the search for new ways of fighting disease and hunger, examining leading questions in mathematics and computer science, probing the physics of matter and the universe, creating novel materials and developing new strategies for protecting the environment.

Weizmann Institute news releases are posted on the World Wide Web at http://wis-wander.weizmann.ac.il/, and are also available at http://www.eurekalert.org/.

Autoimmune disease: one cause asbestos for RA and SLE

2009-11-03T06:07:00.000-08:00

For most people with autoimmune disease, the disease suddenly starts with no warning. Previous to the first symptoms, people are often perfectly healthy. Then something in the immune system clicks on and won't turn off. This is what happened to my youngest son whose first twenty years were perfectly normal and healthy other than having hay fever. Suddenly in his senior year of college, the autoimmune disease process turned on and now won't turn off.

We have all wondered how we can be healthy for years with what seems like a perfectly normal immune system and then suddenly become horribly ill with a over reactive immune system that will not leave us alone. Researchers too have been wondering what the "trigger" is that turns on autoimmune disease. Many researchers believe it to be an illness. Others think it is a chemical in our environment. Some pesticides have been linked to autoimmune disease.*
However, in the article below, about a town contaminated by asbestos, researchers have linked the autoimmune diseases to apparent exposure to asbestos.

Apparently there can be several triggers for autoimmune, the common link is that they some how break our immune system's ability to self regulate. The immune system "thermostat" once broken just keeps the heat on constantly instead of turning on and off as the situation warrants.

Here is the article about asbestos:

The Mount Sinai Hospital / Mount Sinai School of Medicine
Mount Sinai assessing health impacts of 1 of the nation's largest environmental disasters: To coordinate critical asbestos research in Libby, Mont.

Over nearly a century, thousands of residents and workers in Libby, MT, have been exposed to asbestos-contaminated vermiculite ore, leading to markedly higher rates of lung disease and autoimmune disorders, and causing to Libby in 2002 to be added to the federal Environmental Protection Agency's "National Priorities List."

Researchers at Mount Sinai School of Medicine, leading a team of investigators from four institutions, are now launching three investigations into disease pathology in the town and to determine recommended cleanup efforts.

The Principal Investigator of the project is Stephen Levin, MD, Associate Professor of Preventive Medicine at Mount Sinai School of Medicine and a nationally known expert in occupational medicine and asbestos-related diseases who has also served as PI of the nationwide World Trade Center Medical Monitoring & Treatment Program, coordinated by Mount Sinai since 2002.

"The asbestos-related disease in Libby is far more aggressive and rapidly progressive than what's seen in most asbestos-exposed workers, with high rates of cancers and severe effects on respiratory function," said Dr. Levin. "For that reason alone, the health problems in Libby are important to study and understand."

The first of the three programs will focus on particular risks of exposure to Libby asbestos during childhood, when lungs are still developing and maturing. This research may determine the level of environmental cleanup necessary in Libby to protect children, who are a particularly sensitive target population.

A second study will compare lung scarring among Libby residents who were exposed to asbestos only in their environment (and not at their place of employment) with lung scarring seen in workers with historically long-term, heavy exposure to common commercial forms of asbestos. Researchers hope to discover why Libby residents have advanced rates of lung scarring. They will also investigate the mechanism for asbestos-related scar formation and approaches to preventing scar formation after exposure has already occurred.

The third investigation will examine the relationships between autoimmune disorders, autoimmune antibody abnormalities, and CT-scan evidence of scarring lung disease in the context of exposure to Libby asbestos. Auto-immune disorders such as rheumatoid arthritis and lupus have been found to occur more frequently in Libby, and antibody levels to the body's own tissues are found in Libby residents more frequently and at higher concentrations.

Mount Sinai researchers will collaborate on the research effort, to be known as the Libby Epidemiology Research Program, with Libby's Center for Asbestos Related Disease (CARD), investigators from the University of Montana and Idaho State University, and a national scientific advisory group. The research will be supported by a grant of over $4.8 million from the Agency for Toxic Substances and Disease Registry (ATSDR) of the federal Center for Disease Control and Prevention.

The crisis in Libby, a mining town whose history has been shaped by vermiculite-producing corporations since the 1920s, is the result of community-wide occupational and environmental exposure to Libby's naturally occurring vermiculite, contaminated with asbestos and asbestos-like silicate fibers up to 26% by weight.

Health effects have been detected not just in mine and processing plant workers, area lumber mill workers and loggers (from asbestos dusting of forests) and their families, but also among other Libby residents and their children. Many were exposed through ambient air or to mine tailings and other contaminated materials provided to the town by mining companies for the construction of ball fields, school running tracks, playgrounds, public buildings and facilities, as well as for private gardens and house and business insulation.

There is evidence that even relatively low-level exposures to Libby asbestos can cause serious scarring lung diseases, which markedly impair respiratory function, as well as asbestos-related cancers like lung cancer and mesothelioma, which occur at higher rates among the Libby population than elsewhere in the United States.

The health crisis potentially extends far beyond the borders of Libby, since millions of homes and businesses in North America have used vermiculite from Libby as attic insulation, fireproofing and soil conditioner. The ore from Libby was shipped by rail to 49 plant locations throughout North America and the Caribbean for processing, exposing many more workers and communities to the hazardous dust.

CARD Director Brad Black, MD, said, "The pattern of asbestos disease caused by exposure to Libby amphibole asbestos has led to excessive morbidity and mortality for the Libby population, and has been exceedingly challenging for the medical community. The severity of nonmalignant pulmonary disease in non-occupational exposure has been very unusual, raising question as to the potency of the unique amphibole mixture. We look forward to working with Dr. Levin and Mount Sinai to find some of these answers."

Bacterial hope in the search for an autoimmune cure

2009-10-15T21:07:00.000-07:00

Bacterial find in mice offers up of a bacterial solution to autoimmune disease.

The particular species of bacteria found is one that BOOSTS the immune system which is NOT what we need. But having found this bacteria and proving its ability to manipulate its host's immune system for the BENEFIT of the host offers tangible evidence and real hope of success in the search for a bacteria that could turn down the immune system of the host and turn off autoimmune disease.

Unusual bacteria help balance the immune system in mice
October 15th, 2009

A little-known bacterial species called segmented filamentous bacterium, or SFB, can activate the production of specialized immune cells in mice. This scanning electron microscope image of an SFB colony shows a mass of long hair-like filaments created when the bacteria stay attached to each other after they divide. Credit: Credit: Ivaylo Ivanov and Dan Littman (NYU Langone Medical Center) and Doug Wei (Carl Zeiss SMT, Inc.)

Medical researchers have long suspected that obscure bacteria living within the intestinal tract may help keep the human immune system in balance. An international collaboration co-led by scientists at NYU Langone Medical Center has now identified a bizarre-looking microbial species that can single-handedly spur the production of specialized immune cells in mice.

This remarkable activation of the immune response could point to a similar phenomenon in humans, helping researchers understand how gut-dwelling bacteria protect us from pathogenic bacteria, such as virulent strains of E. coli. The study, published in the Oct. 30, 2009, issue of Cell, also supports the idea that specific bacteria may act like neighborhood watchdogs at key locations within the small intestine, where they sense the local microbial community and sound the alarm if something seems amiss.

In mice, at least, the newly identified neighborhood watchdog looks like something out of Disney's "The Shaggy D.A." Distinguished by long hair-like filaments, "These bacteria are the most astounding things I've ever seen," says Dan Littman, MD, PhD, the Helen L. and Martin S. Kimmel Professor of Molecular Immunology and a Howard Hughes Medical Institute Investigator.

Co-led by Dr. Littman's lab, the collaboration with researchers in Japan, California, and Massachusetts zeroed in on a little-known microbe named segmented filamentous bacterium, or SFB. In mice raised under germ-free conditions, the scientists found that adding SFB was sufficient to trigger the appearance of specialized T helper cells known as Th17 cells. These immune specialists, in turn, can send signals that tell epithelial cells lining the small intestine to increase their output of molecules targeting selected microbes.

For the study's mice, the infection-fighting response was enough to ward off the pathogen Citrobacter rodentium, considered a good model for the type of disease-causing E. coli found in contaminated foods like spinach or ground beef. Without SFB to protect them, mice infected with Citrobacter rodentium became ill before recovering.

In the same way, commensal microbes—beneficial bacteria—could decrease our susceptibility to various pathogenic invaders. "So you can immediately see some practical application of this, if one can mimic the presence of these commensal bacteria to strengthen resistance to pathogenic microbes," Dr. Littman says.

Thanks to rapid progress in the field of genomics, he expects the entire DNA sequence of the SFB species to be completed within a few months. Armed with the sequence, researchers could focus on specific proteins. "For example, can we identify a protein that, when we inject it into an epithelial cell, sets off in motion the whole pathway to make Th17 cells?" he says. "By knowing how to do this, you may be able to give people a peptide or a compound that induces Th17 cells by mimicking the bacterial product, and in that way either protect or ameliorate the effect of the infection."

Too much Th17 cell activation, however, can lead to harmful inflammation, Dr. Littman says. Excessive induction by specific microbes in the gut, then, could contribute to autoimmune diseases such as rheumatoid arthritis, psoriasis, Crohn's disease, and possibly even multiple sclerosis.
Source: New York University School of Medicine

Lupus Foundation of America Sells Out Lupus Sufferers

2009-10-05T11:06:00.000-07:00

The Lupus Foundation of America (LFA) has developed a working relationship with the Lewin Group--the health insurance industry lobbying group for, and developer of, the propaganda campaign against universal, affordable, health care.

Lewin Group and United Health Care are also infamous for considerably UNDERSTATING the "usual and customary charges" for physician services in determining patient reimbursement. Many other insurance companies used this PHONY data produced by a UHC subsidiary as an excuse to pay sick patients far less than the should have been paid. UHC had to pay a 50 million dollar fine for this evil practice when they were finally caught.

Sick patients struggled over uncovered medical bills that were far high then they should have been. The patients were told that 'they were responsible for' the amount above the very low phony usual and customary physician and medical charges. The patients had no recourse but to accept the determination of the insurance company about what was a 'usual and customary" charge.

Sick patients went bankrupt, and went without medication, all so the wealthy United Health Care CEO and his henchman could live the lavish life style of the super rich.

The Lewin Group is fully funded by United Health Care whose 100 million dollar a year CEO has been willing to spend any amount to deny ordinary Americans access to universal affordable health care. Universal affordable medical coverage would mean he could not collect his 30% blood tax (company profit margin) from denying coverage to the ill.

LFA has fallen prey to the lure of money that has undone the good of so many other patient lobbying groups recently. Once the patient group accepts industry money, the interests of the ill have a VERY hard time competing with the interests of the industry who "contributes" to the patient advocacy group. This process of contributing money in order to skew patient advocacy group agendas toward the contributor's agenda is called 'capturing' the group. Big industry brags about how many groups they have 'captured'. Add to that list the Lupus Foundation of America.

LFA's capitulation to the control of industry is disguised in the Press Release (in red) at the end of this post. The PR with the LFA is designed to give the evil Lewin Group cover and credibility as a legitimate medical group rather than a purchased hired gun predator.

Purchasing the LFA's formerly good name, as cover for the Lewin Group, must have meant some nice gifts to the board of directors of the LFA, perhaps sky boxes as at a major league game, perhaps a golf weekend, or a few nice dinners at a fancy restaurants, who knows?

What ever the board of directors got, we know not; but, we do know what the Lupus suffers got and that was the shaft.

See what the Washington Post says about the monstrous evil that is the Lewin Group of hired gun liars and lobbyist here:

Insurer-Owned Consulting Firm Often Cited in Health Debate

By David S. Hilzenrath
Washington Post Staff Writer
Thursday, July 23, 2009

The political battle over health-care reform is waged largely with numbers, and few number-crunchers have shaped the debate as much as the Lewin Group, a consulting firm whose research has been widely cited by opponents of a public insurance option.

To Rep. Eric Cantor (Va.), the House Republican whip, it is "the nonpartisan Lewin Group." To Republicans on the House Ways and Means Committee, it is an "independent research firm." To Sen. Orrin G. Hatch (Utah), the second-ranking Republican on the pivotal Finance Committee, it is "well known as one of the most nonpartisan groups in the country."

Generally left unsaid amid all the citations is that the Lewin Group is wholly owned by UnitedHealth Group, one of the nation's largest insurers.

More specifically, the Lewin Group is part of Ingenix, a UnitedHealth subsidiary that was accused by the New York attorney general and the American Medical Association of helping insurers shift medical expenses to consumers by distributing skewed data. Ingenix supplied UnitedHealth and other insurers with data that allegedly understated the "reasonable and customary" doctor fees that insurers use to determine how much they will reimburse consumers for out-of-network care.

More from this Washington Post article at:
http://www.washingtonpost.com/wp-dyn/content/article/2009/07/22/AR2009072203696.html

Below in red is the PR where LFA announces their sell out of all sick lupus patients in America who try so hard and unsuccessfully to get the Health Insurance parasites to pay the costs of the health care that sick lupus patients have paid for in their monthly premiums. Our American Health Insurance thieves take our premium payments for years until we need them, then refuse to pay for the coverage that they took our money with the promise that they would cover us when we got sick.

Spending money on sick patients is considered a business liability by the medical insurance monsters who control access to health care in America.

Please consider contacting the LFA and telling them what you think of selling out to the "FOR PROFIT, not for patients" American medical insurance industry.

Contact: Maggie Maloney
maloney@lupus.org
202-212-6766
Lupus Foundation of America, Inc.

National report shines light on lupus 50-year treatment drought
The Lupus Foundation of America urges key stakeholders to implement report recommendations

Washington, D.C. - October 5, 2009—Today, The Lewin Group, a national health care consulting firm, issued recommendations on ways to overcome the barriers that have obstructed lupus drug development resulting in no new drug approval for this disease in more than 50 years – since the Eisenhower Administration. The recommendations are included in the report, "Overcoming Barriers to Drug Development in Lupus," which is the outcome of a 9-month study commissioned by the Lupus Foundation of America, Inc. (LFA). The recommendations highlight the need for a national collaborative and coordinated effort among key stakeholders, including the FDA, the National Institutes of Health (NIH), researchers and scientists from academia, the LFA, and industry, to implement a range of initiatives that would create a path forward to develop a robust arsenal of safe, effective, and more tolerable treatments for this difficult to treat and devastating disease.

The report provides recommendations for each of the key stakeholders, which include expanding federal support for medical research on lupus, assessing the existing standard of care used in clinical trials, examining the interpretation of regulations pertaining to clinical trial design and related standards of evidence used to evaluate investigational drugs for lupus, expediting the discovery and validation of lupus biomarkers, and more.

As part of the research conducted to prepare this independent report, in June 2009 more than 40 international lupus experts and thought leaders from government, industry, and the scientific community convened in Washington, DC to discuss the barriers to lupus drug development. This groundbreaking effort represents the first time leaders from all sectors with a broad range of informed opinions were brought together to address the unique challenges of lupus drug development and ways to overcome them.

Lupus is a chronic, severe autoimmune disease that affects approximately 1.5 million Americans − primarily women in their childbearing years. In its more severe form lupus can lead to kidney failure, heart attack, atherosclerosis, or even death. According to the report, lupus "stands apart" from other chronic autoimmune diseases because the majority of therapies currently used to effectively manage lupus have not been approved by the FDA for the disease. Many of these medications often have side effects that can be worse than the primary disease, including osteoporosis, weight gain, high blood pressure, diabetes, sterility, liver damage, and the increased risk of infection.

"The recommendations are a call to action requiring the efforts of all key stakeholders," said Sandra C. Raymond, LFA President and CEO. "They provide the foundation for developing and obtaining approval for the arsenal of therapies and personalized treatment that people with this perilous disease require."

The report states that the persistent lack of success of lupus clinical trials has consequences for the willingness of drug manufacturers to pursue FDA approval and indicates "some in industry perceive no clear pathway or system in place for the development of lupus therapies."

"The report findings demonstrate that the pharmaceutical and biotechnology industries cannot develop lupus treatments in a vacuum," said Rick Goulburn, Executive Vice President - Global Autoimmune Therapy Area at Vifor Pharma. "We need more collaboration and partnership across all sectors of the field, greater investment by the federal government in basic lupus research, and continued leadership from the LFA and the entire scientific community."

Lupus drug development has had many setbacks in recent years including the failure of several promising new treatments. However, much has been learned from these trials and potentially greater insight can be gained if the data is evaluated collectively.

An immediate outgrowth of the expert panel meeting held in June is the LFA Collective Data Analysis Initiative (LFA CDAI), chaired by Kenneth Kalunian, M.D., Professor of Medicine, Division of Rheumatology, Allergy and Immunology, at the University of California, San Diego, to advance the knowledge of lupus and optimize clinical trial design by researching data from previous and existing lupus clinical trials.

"The lupus community certainly recognizes the urgent need for collaboration," said Dr. Kalunian. "Following the expert panel meeting, working groups were immediately established to begin tackling the recommendations that were identified. When fully implemented, these initiatives will help gain needed insight on the issues which have plagued lupus clinical trials and develop more effective ways to design them, so ultimately lupus trials can be completed successfully."

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About the LFA

The Lupus Foundation of America, Inc. is the foremost national nonprofit voluntary health organization dedicated to finding the causes of and cure for lupus, and providing support, services, and hope to all people affected by lupus. The LFA and its national network of chapters and support groups operate programs of research, education, and advocacy.

Nanotechnology diagnosis of cancer, autoimmune next?

2009-09-28T22:36:00.000-07:00

All of us who have suffered through dozens of doctors appointments and many many medical tests that come back inconclusive before we finally get a diagnosis of what is wrong can only hope that the following nanotechnology will soon be applied to diagnosing autoimmune diseases.

Here is the article:

University of Toronto

U of T researchers create microchip that can detect type and severity of cancer

TORONTO, ON – UofT researchers have used nanomaterials to develop a microchip sensitive enough to quickly determine the type and severity of a patient's cancer so that the disease can be detected earlier for more effective treatment.

Their groundbreaking work, reported Sept. 27 in Nature Nanotechnology heralds an era when sophisticated molecular diagnostics will become commonplace.

"This remarkable innovation is an indication that the age of nanomedicine is dawning," says Professor David Naylor, president of the University of Toronto and a professor of medicine. "Thanks to the breadth of expertise here at U of T, cross-disciplinary collaborations of this nature make such landmark advances possible."

The researchers' new device can easily sense the signature biomarkers that indicate the presence of cancer at the cellular level, even though these biomolecules – genes that indicate aggressive or benign forms of the disease and differentiate subtypes of the cancer – are generally present only at low levels in biological samples. Analysis can be completed in 30 minutes, a vast improvement over the existing diagnostic procedures that generally take days.

"Today, it takes a room filled with computers to evaluate a clinically relevant sample of cancer biomarkers and the results aren't quickly available," says Shana Kelley, a professor in the Leslie Dan Faculty of Pharmacy and the Faculty of Medicine, who was a lead investigator on the project and a co-author on the publication.

"Our team was able to measure biomolecules on an electronic chip the size of your fingertip and analyse the sample within half an hour. The instrumentation required for this analysis can be contained within a unit the size of a BlackBerry."

Kelley, along with engineering professor Ted Sargent – a fellow lead investigator and U of T's Canada Research Chair in Nanotechnology – and an interdisciplinary team from Princess Margaret Hospital and Queen's University, found that conventional, flat metal electrical sensors were inadequate to sense cancer's particular biomarkers. Instead, they designed and fabricated a chip and decorated it with nanometre-sized wires and molecular "bait."

"Uniting DNA – the molecule of life – with speedy, miniaturized electronic chips is an example of cross-disciplinary convergence," says Sargent. "By working with outstanding researchers in nanomaterials, pharmaceutical sciences, and electrical engineering, we were able to demonstrate that controlled integration of nanomaterials provides a major advantage in disease detection and analysis."

The speed and accuracy provided by their device is welcome news to cancer researchers.

"We rely on the measurement of biomarkers to detect cancer and to know if treatments are working," says Dr. Tom Hudson, president and scientific director of the Ontario Institute for Cancer Research. "The discovery by Dr. Kelley and her team offers the possibility of a faster, more cost-effective technology that could be used anywhere, speeding up diagnosis and helping to deliver a more targeted treatment to the patient."

The team's microchip platform has been tested on prostate cancer, as described in a paper published in ACS Nano, and head and neck cancer models. It could potentially be used to diagnose and assess other cancers, as well as infectious diseases such as HIV, MRSA and H1N1 flu.

"The system developed by the Kelley/Sargent team is a revolutionary technology that could allow us to track biomarkers that might have significant relevance to cancer, with a combination of speed, sensitivity, and accuracy not available with any current technology," says Dr. Fei-Fei Liu, a radiation oncologist at Princess Margaret Hospital and Head of Applied Molecular Oncology Division, Ontario Cancer Institute. "This type of approach could have a profound impact on the future management for our cancer patients."

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The research was funded by the Canada Foundation for Innovation, the Natural Sciences and Engineering Research Council of Canada, the Ontario Genomics Institute, Genome Canada, the Ontario Institute for Cancer Research, the Ontario Ministry of Research and Innovation and the Prostate Cancer Research Foundation of Canada.

Broken bones? Blame it on autoimmune disease. TNF alpha the culprit

2009-09-28T22:04:00.000-07:00

After having had three broken arms, a broken collar bone, a broken pelvis, a broken hand bone, and 12 or so broken ribs, I think I am an expert on broken bones. I know how they feel when they break (like a stick snapping inside--but with a bit of dizzying shock sensation mixed with relatively minor pain initially--later the pain at the site of the break can be excruciating when the spot is lightly touched).

I used to blame my many broken bones on having small diameter bones. Later I found out that the particular kind of immune problems I have caused mal absorbtion in the intestines so that bones did not receive enough calcium and phosphorous. Now I read that it is caused by too much systemic inflammation as in too much TNF alpha--the inflammatory immune signaling molecule that has been found to be a problem in many autoimmune diseases--RA, PsA, AS, and psoriasis to mention a few. Remicade, Enbrel, and Humira are medications that absorb or block TNF alpha thus reducing the effects of several autoimmune diseases.

I remember when my father got made at me for breaking my arm AGAIN! He told me it was expensive to get fixed and I must be more careful. I thought I was being careful. Certainly more so than my friends were being. So when I broke my collar bone and could not raise my right arm, I did not tell my parents. They never noticed. I just laid my right arm against the edge of the table at dinner and used that as a pivot to pick up food with my fork on my plate, then bend my head down and ate. I wanted to use my left hand but thought they would notice I was using the wrong hand. After several weeks the collar bone got better. It healed a little crooked but still works. Later as an adult during a physical, my doctor noticed the crooked bone and mentioned it to me. Other than that I got away with not telling my parents.

I have found over the years that most bones heal on their own with no need for doctors if you do not mind a little pain and a bit of a crooked bone here and there (can't turn over my left hand because one of the wrist bones is pretty crooked but arm works well otherwise.)

Here is the article about TNF alpha causing broken bones and slow healing bones.

American Journal of Pathology

Diabetes weakens your bones

Boston, MA and Newark, NJ – Current research suggests that the inflammatory molecule TNF-α may contribute to delayed bone fracture healing in diabetics. The related report by Alblowi et al, "High Levels of TNF-α Contribute to Accelerated Loss of Cartilage in Diabetic Fracture Healing" appears in the October 2009 issue of the American Journal of Pathology.

Diabetes, a condition where the body either does not produce enough, or respond to, insulin, affects at least 171 million people worldwide, a figure that is likely to double by 2030. Long-term complications of diabetes include cardiovascular disease, chronic renal failure, retinal damage that may lead to blindness, nerve damage, and blood vessel damage, which may cause erectile dysfunction and poor wound healing.

Diabetic patients often experience low bone density, which is associated with increased risk of bone fractures and delayed fracture repair. To examine how diabetes affects bone, Dr. Dana Graves and colleagues of the University of Medicine and Dentistry of New Jersey and the Boston University School of Medicine explored bone repair in a mouse model of diabetes. They observed increased levels of inflammatory molecules, including TNF-α during fracture healing. The diabetic animals had rapid loss of cartilage in the healing bones, which was due to increased numbers of osteoclasts, cells that remove bone and cartilage. Factors that stimulate osteoclast formation were regulated by both TNF-α and a downstream mediator, FOXO1. These results suggest that diabetes-mediated increases in TNF-α and FOXO1 may underlie the impaired healing of diabetic fractures.

Alblowi et al suggest that "TNF-α dysregulation plays a prominent role in the recently identified catabolic events associated with diabetic fracture healing." In future studies, Dr. Graves and colleagues plan to "examine the effect of FOXO1 on mineralized tissue to examine how it may regulate factors that control bone resorption and osteoclastogenesis, in addition to effects it may have on osteoblastic cells."

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This work was supported by grants from the National Institutes of Health.

Alblowi J, Kayal RA, Siqueira M, McKenzie E, Krothapalli N, McLean J, Conn J, Nikolajczyk B, Einhorn TA, Gerstenfeld L, Graves DT: High Levels of TNF-α Contribute to Accelerated Loss of Cartilage in Diabetic Fracture Healing. Am J Pathol 2009 175: 1574-1585

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The American Journal of Pathology, official journal of the American Society for Investigative Pathology, seeks to publish high-quality, original papers on the cellular and molecular biology of disease. The editors accept manuscripts that advance basic and translational knowledge of the pathogenesis, classification, diagnosis, and mechanisms of disease, without preference for a specific analytic method. High priority is given to studies on human disease and relevant experimental models using cellular, molecular, animal, biological, chemical, and immunological approaches in conjunction with morphology.

Drug to help genes make proteins to END genetic diseases like autoimmune

2009-09-28T21:49:00.000-07:00

Chemicals to help cells read genes with "nonsense" mutations that normally stop the reading process, will allow these genes to produce missing proteins whose loss causes many, many genetic diseases including autoimmune diseases, allergy, asthma, muscular dystrophy, hemophilia, Tay Sachs, and a host of others.

These chemicals allow gene to work and to stop the horror of a genetic disease. Up until now we have been stuck with the genes we were dealt at fertilization. With these new chemicals, even those of us with genetic disease have the chance to live normal lives.

In a perfect world, there would be massive interest in these chemicals. Congress would pass vast spending bills to finance their development and testing and within years possible sooner, these chemicals would be in use by suffering and dying patients.

Of course we do not live in a perfect world. I expect these chemicals to be curing my great grand children but not anyone before that. The FDA likes to delay, delay, delay. The NIH only funds a tenth of the good proposals that they get and it is nice to have political pull to assure an NIH grant.

Here is the article about these new wonderful chemicals:

University of California - Los Angeles

UCLA study identifies 2 chemicals that could lead to new drugs for genetic disorders

Discovery could help people with cancer, muscular dystrophy, A-T

UCLA scientists have identified two chemicals that convince cells to ignore premature signals to stop producing important proteins. Published in the Sept. 28 edition of the Journal of Experimental Medicine, the findings could lead to new medications for genetic diseases, such as cancer and muscular dystrophy, that are sparked by missing proteins.

"When DNA changes, such as nonsense mutations, occur in the middle rather than the end of a protein-producing signal, they act like a stop sign that tells the cell to prematurely interrupt protein synthesis," explained Dr. Richard Gatti, professor of pathology and laboratory medicine and human genetics at the David Geffen School of Medicine at UCLA. "These nonsense mutations cause the loss of vital proteins that can lead to deadly genetic disorders."

Gatti's lab specializes in studying ataxia-telangiectasia (A-T), a progressive neurological disease that strikes young children, often killing them by their late teens or early 20s.

For four years, the UCLA Molecular Shared Screening Resources Center of the campus' California NanoSystems Institute has screened 35,000 chemicals, searching for those that ignore premature stop signals.

First author Liutao Du developed the screening technology in Gatti's laboratory.

"Of the dozens of active chemicals we discovered, only two were linked to the appearance and function of ATM, the protein missing from the cells of children with A-T," said Du. "These two chemicals also induced the production of dystrophin, a protein that is missing in the cells of mice with a nonsense mutation in the muscular dystrophy gene."

The UCLA team is optimistic that their discovery will aid pharmaceutical companies in creating drugs that correct genetic disorders caused by nonsense mutations.

This could affect one in five patients with most genetic diseases, including hundreds of thousands of people suffering from incurable diseases.

Because nonsense mutations can lead to cancer, such drugs may also find uses in cancer treatment.

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Gatti's lab is funded by the Los Angeles-based Ataxia-Telangiectasia Medical Research Foundation, the National Institutes of Health and the New York-based Ataxia-Telangiectasia Ease Foundation.

The study's coauthors included Robert Damoiseaux, Shareef Nahas, Kun Gao, Hailiang Hu, Julianne Pollard, Jimena Goldstine, Michael Jung, Susan Henning and Carmen Bertoni, all of UCLA.

More evidence for benefits of Worms--Vietnam study

2009-09-28T21:42:00.000-07:00

Intestinal worms get another boost as a way to modulate improperly functioning immune systems. Allergies, asthma and autoimmune all are possible candidates for immune dysfunctions that may be treatable with intestinal worms. Here is the UARL of the latest article:

http://communications.nottingham.ac.uk/News/Article/Gut-worms-may-protect-against-house-dust-mite-allergy.html

Gut worms may protect against house-dust mite allergy
Mon, 28 Sep 2009 12:35:00 GMT
PA 252/09

A study conducted in Vietnam has added further weight to the view that parasitic gut worms, such as hookworm, could help in the prevention and treatment of asthma and other allergies.

Led by Dr Carsten Flohr, a Clinical Scientist from The University of Nottingham, and Dr Luc Nguyen Tuyen from the Khanh Hoa Provincial Health Service in central Vietnam, the study is the largest double-blind placebo controlled clinical trial to date looking at the potential links between hookworm and other gut worm infections and allergic conditions such as asthma and eczema.

Thanks to improved hygiene practices parasitic worms have been mostly eradicated among human populations living in developed countries. However, experts believe that over millions of years of co-evolution worms have found methods to dampen down host immune responses to prolong their own survival inside humans. This relationship seems to have become so intertwined that without gut worms or other parasites, our immune system can become unbalanced, which in turn could contribute to the development of asthma and other allergies. At the same time, it is important to remember that gut parasites can cause severe disease and are a major cause of iron-deficiency anaemia in developing countries.

Dr Flohr’s study was conducted in a rural area of central Vietnam where two out of three children have hookworm and other gut parasite infections and where allergies are extremely rare. More than 1,500 schoolchildren aged 6-17 took part.

The team investigated whether repeated tablet treatments to clear the body of gut worms made it more likely for children to develop allergic conditions. While the treatment did not demonstrate an effect on asthma or eczema, the treated children had a significantly increased risk of having a positive allergy skin test to house-dust mites and cockroach. This suggests that gut worms have the potential to tone down human immune responses and so further research is now needed to identify precisely how gut worm infection can prevent allergic sensitisation.

Dr Carsten Flohr of The University of Nottingham adds: “The next step is to understand exactly how and when gut parasites programme the human immune system in a way that protects against allergic sensitisation, and for such studies, follow-up from birth will be essential.”

As up to 80 per cent of people with asthma also have allergies to house-dust mites and other environmental allergens, additional research in this area could aid the creation of new treatments that work in the same way as gut parasites, by dampening down or rebalancing the immune system so that the body does not respond to allergens and trigger asthma attacks.

Dr Elaine Vickers, Research Relations Manager at Asthma UK, says: “Asthma affects more than five million people in the UK, with a person being admitted to hospital every seven minutes following an asthma attack. The prospects of further studies in this area are therefore very exciting as we could see groundbreaking treatments for asthma and other allergies developed as a result. It’s now vital that we see more funding being invested in this important area of research, so that we can increase our understanding of the link between gut parasites and the development of allergies from birth.”

Co-applicants on the Asthma UK research grant that funded the work were Professors John Britton, David Pritchard, and Hywel Williams. The Nottingham team collaborated with researchers from the Wellcome Trust Major Overseas Programme at the Oxford University Clinical Research Unit Hospital for Tropical Diseases in Ho Chi Minh City, where Dr Flohr was based for his work. Additional funding was received through the Bastow Award from the Special Trustees for Nottingham University Hospitals. Dr Flohr’s salary was provided by University College, University of Oxford, for two years and by the Wellcome Trust UK for a further nine months.

— Ends —

Notes to editors: The University of Nottingham is ranked in the UK's Top 10 and the World's Top 100 universities by the Shanghai Jiao Tong (SJTU) and Times Higher (THE) World University Rankings.

More than 90 per cent of research at The University of Nottingham is of international quality, according to RAE 2008, with almost 60 per cent of all research defined as ‘world-leading’ or ‘internationally excellent’. Research Fortnight analysis of RAE 2008 ranks the University 7th in the UK by research power. In 27 subject areas, the University features in the UK Top Ten, with 14 of those in the Top Five.

The University provides innovative and top quality teaching, undertakes world-changing research, and attracts talented staff and students from 150 nations. Described by The Times as Britain's “only truly global university”, it has invested continuously in award-winning campuses in the United Kingdom, China and Malaysia. Twice since 2003 its research and teaching academics have won Nobel Prizes. The University has won the Queen's Award for Enterprise in both 2006 (International Trade) and 2007 (Innovation — School of Pharmacy), and was named ‘Entrepreneurial University of the Year’ at the Times Higher Education Awards 2008.

Nottingham was designated as a Science City in 2005 in recognition of its rich scientific heritage, industrial base and role as a leading research centre. Nottingham has since embarked on a wide range of business, property, knowledge transfer and educational initiatives (www.science-city.co.uk) in order to build on its growing reputation as an international centre of scientific excellence. The University of Nottingham is a partner in Nottingham: the Science City.

Asthma UK is one of the major funders of asthma research in the UK. Asthma UK is the charity dedicated to improving the health and well-being of the 5.4 million people in the UK whose lives are affected by asthma. For up-to-date news on asthma, information and publications, visit the Asthma UK website asthma.org.uk. For independent and confidential advice on asthma, call the Asthma UK Adviceline, which is staffed by asthma nurse specialists. It is open weekdays from 9am to 5pm on +44 (0)800 121 62 44.

Stelara APPROVED! by FDA for psoriasis. WHOOPEE!

2009-09-27T10:56:00.000-07:00

The long awaited alternative to TNF-alpha inhibitors has FINALLY been approved. More than TWO YEARS after ALL clinical trials were successfully completed and after more than eighteen months since Centocor submitted the New Drug Application for approval, the FDA (aka F'ing DelAy) is allowing patients with psoriasis to use Stelara, a marvelous new biologic.

It works on a completely different cytokine (immune signal) pathways. It blocks different immune signaling molecues--interleukin 12 and interleukin 23. Down regulating these two pathways is supposed to increase the number of T-regulatory cells in the body. T-regs turn down inflammation the main underlying problem in autoimmune disease (and many other conditions as well i.e. cardiovascular disease and even some cancers).

Of course Canada Health approved Ustekinumab (Stelara )a year ago as did the European Union.

In July of 2008 a panel of independent experts convened by FDA to assess Stellara recommended UNANIMOUSLY for approval to the F'ing DelAY. Now just a short (not!) fourteen months later the incompetents at the FDA finally will allow US citizens the right to use the medication.

Sorry to be bitter.

The STUPID and unnecessary delays of this needed NOVEL, FIRST OF ITS KIND medication in our country just demonstrates how very dysfunctional the FDA is.

Good news is we can use it now. One shot is supposed to last a whole month. Now the only problem is paying for that shot. I have read that in Canada--Centocor charges as much as $10,000! Gee, no problem--only $120.000 a year. Let's hope that Centocor will reduce the price in the US. I know I know Big Pharma reducing prices to consumers--like pigs flying I will only believe it when I see it. Perhaps health care reform will force down prices. Hope so.

Read more at this URL:
http://www.docguide.com/news/content.nsf/news/852576140048867A8525763C006528F6?OpenDocument&c=&count=10&id=48dde4a73e09a969852568880078c249

Here is the article:

FDA Approves Ustekinumab for Moderate to Severe Psoriasis
ROCKVILLE, Md -- September 25, 2009 -- The US Food and Drug Administration (FDA) has approved ustekinumab (Stelara), a biologic product for adults who have a moderate to severe form of psoriasis.

"This approval provides an alternative treatment for people with plaque psoriasis, which can cause significant physical discomfort from pain and itching and result in poor self-image for people who are self-conscious about their appearance," said Julie Beitz, MD, Office of Drug Evaluation in the FDA's Center for Drug Evaluation and Research, Rockville, Maryland.

Three studies of 2,266 patients evaluated the biologic's safety and effectiveness.

The FDA approval was primarily based on 2 phase 3 studies in which a significantly higher proportion of patients receiving either ustekinumab 45 mg or 90 mg achieved at least a 75% reduction in psoriasis as measured by the Psoriasis Area and Severity Index (PASI 75) at week 12 compared with patients receiving placebo.

With every-12-week ustekinumab maintenance therapy, the majority of patients achieving a PASI 75 improvement maintained substantial skin clearance for 1 year.

Since ustekinumab reduces the immune system's ability to fight infections, the product poses a risk of infection. Serious infections have been reported in patients receiving the product and some of them have lead to hospitalisation. These infections were caused by viruses, fungi, or bacteria that have spread throughout the body. There may also be an increased risk of developing cancer.

The FDA is requiring a risk evaluation and mitigation strategy (REMS) for ustekinumab that includes a communication plan targeted to healthcare providers and a medication guide for patients.

SOURCE: US Food and Drug Administration.

Color Blindness Cured points to technique for Autoimmune Cure

2009-09-16T21:19:00.000-07:00

In Florida researchers have used a virus to ferry in a gene to allow red/green color blind monkeys to see those the entire normal monkey and human color spectrum.

This same technology should allow the transfer of genes into humans. The same virus, adeno associated virus, has been used for at least a decade for gene transfers including very large genes which could cure (yes, cure) a host of genetic diseases--muscular dystrophy, sickle cell anemia, hemophilia, and all autoimmune disease.

My interest is autoimmune disease due to my son. There are a number of gene candidates that could be transferred into the cells in our bone marrow that make our blood and immune cells. The genes for IL-10. Variants of the FOXP3 gene found in healthy folks without autoimmune and allergy/asthma problems are another candidate. Other genes are possible as well.

What we need is a facility, free from all possibility of law suits, free of all FDA stupid bureaucratic clinical trial rules, free of competition between different companies and researchers.

This place should be a WIKI place where all drug companies and researchers share their ideas as a group. Where they all also share in any profits that come as a result of any group's discovery. Where ALL researchers eat together and meet together to share ideas of what is working.

It should be a place where patients can come and have the ability to try anything that might help them. No rules EXCEPT complete transparency and complete openness. NO secrets allowed. Nothing held back. Every patient encouraged to go online daily and tell exactly how they feel about their treatments and doctors without any censorship or fear of retaliation (Possibly only published after the patient is cures, quits treatment or dies).

I am convinced that if we, the sick, and their relatives were allowed to create a place of total freedom for research cures for most of the great genetic disease would come in months. Of course, my dream has no chance. Too many people with power at too many corporations make too much money off of people suffering under the current system.

If we cannot even get Medicare for all in the US due to polarization created by big money buying radio and TV con men as spokesman to rile up the mob, we have no chance of a place for quick cures using WIKI type organization. Too bad.

Enough editorialising.

Here is the color blind cure article:

http://www.eurekalert.org/pub_releases/2009-09/uof-scc091409.php

Scientists cure color blindness in monkeys

GAINESVILLE, Fla. — Researchers from the University of Washington and the University of Florida used gene therapy to cure two squirrel monkeys of color blindness — the most common genetic disorder in people.

Writing online Wednesday in the journal Nature, scientists cast a rosy light on the potential for gene therapy to treat adult vision disorders involving cone cells — the most important cells for vision in people.

"We've added red sensitivity to cone cells in animals that are born with a condition that is exactly like human color blindness," said William W. Hauswirth, Ph.D., a professor of ophthalmic molecular genetics at the UF College of Medicine and a member of the UF Genetics Institute and the Powell Gene Therapy Center. "Although color blindness is only moderately life-altering, we've shown we can cure a cone disease in a primate, and that it can be done very safely. That's extremely encouraging for the development of therapies for human cone diseases that really are blinding."

The finding is also likely to intrigue millions of people around the world who are colorblind, including about 3.5 million people in the United States, more than 13 million in India and more than 16 million in China. The problem mostly affects men, leaving about 8 percent of Caucasian men in the United States incapable of discerning red and green hues that are important for everyday things like recognizing traffic lights.

"People who are colorblind feel that they are missing out," said Jay Neitz, Ph.D., a professor of ophthalmology at the University of Washington. "If we could find a way to do this with complete safety in human eyes, as we did with monkeys, I think there would be a lot of people who would want it. Beyond that, we hope this technology will be useful in correcting lots of different vision disorders."

The discovery comes about 10 years after Neitz and his wife Maureen Neitz, Ph.D., a professor of ophthalmology at the University of Washington and senior author of the study, began training two squirrel monkeys named Dalton and Sam.

In addition to teaching the animals, the Neitz research group worked with the makers of a standard vision-testing technique called the Cambridge Colour Test to perfect a way the monkeys could "tell" them which colors they were seeing.

The tests are similar to ones given to elementary children the world over, in which students are asked to identify a specific pattern of colored dots among a field of dots that vary in size, color and intensity. The researchers devised a computer touch screen the monkeys could use to trace the color patterns. When the animals chose correctly, they received a reward of grape juice.

The rest of the article can be found at the URL at the beginning of this post.

Researchers Reply to previous "Deadly Wait" post

2009-09-08T14:24:00.000-07:00

A researcher form Columbia responded to the previous blog saying:

Let me please first clarify that there is currently no drug that is FDA approved for one disease that is helpful for AD.

The drug that was used in this study, TSA, is not currently approved by the FDA, and is just from the same class of HDAC inhibitors of the drug that was investigated in this study. (A currently HDACi that is FDA approved for cutaneous tcell lymphoma, Vorinostat (SAHA), marketed under the name Zolinska, was not used in this study).

He also wrote:

The drug tested in this study is not FDA approved and happens to be from a class of HDAC inhibitors (of which a current cancer drug belongs).

While I very much appreciate his response, I still feel a great amount of rage over delays to cures for my son and for my good friend who had Alzheimer's.

A Wiki approach to finding cures where EVERYONE contributes to the cures and EVERYONE who contributes gets credit and a piece of the profit could give us cures to the easy diseases like autoimmune, allergy, asthma, and Alzheimer's, hemophilia, and sickle cell anemia in months. That is right MONTHS instead of decades under our current system.

The individualized, private, "hide my discoveries, so I can get a bigger profit," drug discovery process in use today will take decades, if not centuries to get to those cures.

Society at large is at increasing risk for each day of delay in implementing a WIKI type drug discovery process. I am talking drug resistant bacteria (including a now completely resistant strain of tuberculosis--NOTHING kills it!). Until we get serious about finding cures for diseases as fast as possible, we are all at risk and that risk increases daily.

Perhaps when enough of us our dying of resistant bacterial infection, we will adopt the WIKI approach and find cures fast. That is the only hope for those of us either personally or with a loved one afflicted with catastrophic disease.

Alzheimer treatment--Deadly Wait for Patient Access to Research Breakthrough

2009-09-07T10:26:00.000-07:00

Alzheimer's is a particularly horrible affliction. A very good friend of mine had the first symptoms of early onset Alzheimer's at age 58 by age 63, he did not know who is wife or daughter were.

He had been a remarkable man. A talented story teller with a wealth of details in his head. He moved from classroom teacher to district administration and finally to a post as the director of our entire county. Brilliant wonderful person. Now gone. His last years a haze for him and a horror for his family.

Today a research breakthrough in Alzheimer's was announced. A drug was found that reverses Alzheimer's disease in mice! Not only that but it has the potential to treat MANY other diseases including autoimmune and other immune disorders.

The mechanism of action of this ALREADY FDA APPROVED cancer drug is the key. The drug opens up improperly closed and shut down patches of DNA. The DNA can then make the proteins that can reverse Alzheimer's and potentially many many more diseases.

Wow, it's already approved! Whoopee! Let's try it out right now! That would be the reaction of the naive patient or loved one of a patient who has a catastrophic disease. But that poor naive person does not understand the Byzantine slowness of our medical approval process.

Should some doctor try using a drug like this approved medication in an "off label' way then the doctor risks losing his licence and perhaps monetary damages as well. Doctors whose first loyalty is to 'their career investment' will not risk the time and money they spent getting their career in medicine by trying to help a patient like my good friend and his family.

The FDA with its Byzantine labyrinth of rules and regulations slow the translation of medical research breakthroughs to the bedside of patients for even more, not just a few years, BUT DECADES!

Our Big Pharma companies do all in their power to keep new revolutionary treatments or cheaper medicines under wraps and off the market. Nothing must be allowed to affect the tremendous profit they extract from patient's forced to only use existing meds.

A medicine like the one described in the article below that can manipulate and repair genes by fixing our DNA should be tried on a multitude of illnesses immediately upon discovery. There should be a RAPID RESPONSE, BROAD SPECTRUM clinical trial set up in a matter of a few weeks. The trial should include a few, fully informed, volunteers who have such genetic defect diseases as muscular dystrophy, cystic fibrosis, Tay Sachs, hemophilia, and various autoimmune diseases like multiple sclerosis, Rheumatoid Arthritis, Crohn's, psoriasis, etc.

Those with few or no treatments like Lupus and Tay Sachs should be at the TOP of the list. Who knows which of these diseases could be treated and ended with this drug.

This kind of BROAD SPECTRUM clinical testing could answer the question of who could be helped in a matter of weeks.

But no that will not happen. This new medical breakthrough that has already gone through one decade of clinical trials to get approved for cancer will now have to go through decades more of clinical trials for each of the above mentioned diseases IF someone will fund those trials. Of course each new set of clinical trials costs about a BILLION dollars. Yes that is a BILLION with a 'B." In effect generations of patients must suffer and die while the FDA, the Big Pharma Companies and cowardly physicians watch without pity. Patients with diseases that do not affect enough people to promise huge profits may NEVER gain access as no one will pay the BILLION dollars.

Previous posts on this blog have discussed the remarkable promise of these HDAC inhibitors. These compounds have been known about for over a decade. Researchers have talked openly about their incredible potential. Patients wait desperately for a chance to use them. But still today and for the foreseeable future most potential applications to create revolutionary cures with these drugs is VERBOTEN.

Here is the article about the Alzheimer's breakthrough:

(Note: the highlighted line at the end of the article "Because this drug is already approved for cancer we hope clinical trials for Alzheimer's can start in three or four years" NOT THREE or FOUR weeks or even three or four months but THREE or FOUR YEARS!!! Why? Because of the FDA "slow down the cures" stupid rules. Imagine how many decades it would take to get to clinical trials if the F'ing DelAy had not already approved the drug for cancer!

If you are as angry and outraged about these delays as I am, please consider joining Abigail Alliance for better patient access to developmental drugs. http://abigail-alliance.org/

-------------------------------

Columbia University Medical Center

Cancer drug may improve memory in Alzheimer's patients

NEW YORK - A drug now used to treat cancer may also be able to restore memory deficits in patients with Alzheimer's disease, according to a new study conducted by scientists at Columbia University Medical Center, which appeared in the September issue of The Journal of Alzheimer's Disease: Volume 18:1.

The loss of short, day-to-day memories is often the first sign of Alzheimer's - a disease that is expected, by the year 2050, to afflict 120 million people worldwide.

"People often joke that they must have Alzheimer's because they can't remember where they put their keys, but for a person with the disease, this type of short-term memory loss is extremely debilitating," says the study's lead author, Ottavio Arancio, Ph.D., associate professor of pathology and cell biology in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain at Columbia University Medical Center.

Dr. Arancio says that the cancer drug targets a previously unknown defect in the brains of mice with Alzheimer's.

The reason why the drug improves memory lies in the way the brain records new memories. To create new memories, the neurons in the brain must manufacture new proteins. The first step is to open up and read the DNA, which contains instructions for making the proteins.

To read the DNA, the neuron attaches a chemical reactive group to the spool around which DNA is tightly wound. "These groups, called acetyls, unwind the DNA to make it more accessible," says co-author Yitshak Francis, Ph.D., a postdoctoral research scientist at Columbia. "It's like unwinding knitting wool from its spool."

This unwrapping step, the researchers found, is impaired in mice with a form of Alzheimer's disease. The mice with Alzheimer's attached about half as many acetyls to DNA as normal mice and had poorer memory.

The researchers then discovered that they could improve memory in the Alzheimer's-afflicted mice with a cancer drug from a family of compounds, called HDAC inhibitors, which increase the DNA's spool acetylation and gene transcription. The drug improved memory performance to the level found in normal mice.

"Because this type of drug has already been approved for some cancer patients," says co-author Mauro Fà, Ph.D., associate research scientist in Columbia's Taub Institute, "we hope that clinical trials for Alzheimer's disease can start in about three to four years."

"For making memories, you need transcription and protein synthesis at the cellular level. If you don't have that, you don't have memory," said Dr. Francis.

###

This work was supported in part by Alzheimer Disease Research Zenith Award ZEN-07-58977, National Institutes of Health Grant R01 NS049442 (to O.A.) and by United Kingdom Alzheimer's Research Trust Pilot Grant, The International Sephardic Educational Foundation (ISEF) Scholarship, The Lewis Family Trust Scholarship, The Sidney & Elizabeth Corob Charitable Trust Scholarship, the Charlotte and Yule Bogue Research Fellowships (to Y.I.F).

Authors of The Journal of Alzheimer's Disease study include: Yitshak I Francis, Mauro Fà, Haider Ashraf, Hong Zhang, Agnieszka Staniszewski, David S. Latchman and Ottavio Arancio.

The Journal of Alzheimer's Disease (http://www.j-alz.com) is an international multidisciplinary journal to facilitate progress in understanding the etiology, pathogenesis, epidemiology, genetics, behavior, treatment and psychology of Alzheimer's disease. The journal publishes research reports, reviews, short communications, book reviews, and letters-to-the-editor. Groundbreaking research that has appeared in the journal includes novel therapeutic targets, mechanisms of disease and clinical trial outcomes. The Journal of Alzheimer's Disease has an Impact Factor of 5.101 according to Thomson Reuters' 2008 Journal Citation Reports. The Journal is published by IOS Press (http://www.iospress.nl).

The Taub Institute for Research on Alzheimer's Disease and the Aging Brain at Columbia University Medical Center is a multidisciplinary group that has forged links between researchers and clinicians to uncover the causes of Alzheimer's, Parkinson's and other age-related brain diseases and discover ways to prevent and cure these diseases. It has partnered with the Gertrude H. Sergievsky Center at Columbia University Medical Center which was established by an endowment in 1977 to focus on diseases of the nervous system. The Center integrates traditional epidemiology with genetic analysis and clinical investigation to explore all phases of diseases of the nervous system. For more information about these centers visit: http://www.cumc.columbia.edu/dept/taub/ http://www.cumc.columbia.edu/dept/sergievsky/

Columbia University Medical Center provides international leadership in basic, pre-clinical and clinical research, in medical and health sciences education, and in patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Established in 1767, Columbia's College of Physicians and Surgeons was the first institution in the country to grant the M.D. degree and is among the most selective medical schools in the country. Columbia University Medical Center is home to the largest medical research enterprise in New York City and state and one of the largest in the United States. For more information, please visit www.cumc.columbia.edu.

B cell cure for autoimmune another step closer

2009-05-12T08:06:00.000-07:00

A cure for multiple sclerosis, rheumatoid arthritis, psoriasis, Crohn's and many other autoimmune diseases appears to be one step closer today.

The announcement by Pharmacyclics that they have developed a method to stop B cells from producing antibodies without the risk of infection or reactivation of dormant viruses allows us that hope

The Pharmacyclics product would still allow T cells to function to stop infections and occult or dormant viruses from reactivating.

Pharmacyclics says in the press release that they are confident that their product will SAFELY work to stop lymphomas and autoimmune disease even though it disables all B cells in a patient's immune system. Their confidence is based information known about a genetic disease called XLA-X linked agammaglobulenemia which naturally disables all B cells but leaves those with the condition with healthy immune systems. The Pharmacyclics product disables B cells in the same way as they are in people with XLA.

Their press release implies that their product is superior to Rituxan--the only B cell depletion therapy on the market. Rituxan use can lead to the resurrection of dormant viruses that cause the death of the patient. The most notorious virus is PML--progressive multifocal leucoencephelopathy.

Phamacyclics researchers think that their product does its work without harming the immune system because T cells are unaffected. I would guess that it is likely superior to Rituxan because it leaves the B cells alive, unlike Rituxan. I would also guess that the B cells disabled by Pharmacyclics product still allow some crucial B cell function. Perhaps that is why folks with XLA can have healthy immune systems without antibodies produced by B cells. (I wonder if patients with XLA can develop natural immunity from having diseases like measles and mumps or induced immune via vaccine to these diseases. If they can then this product by Pharmacyclics could be very revolutionary indeed.)

It is still too early to know but if this product works without causing problems with re-activated dormant viruses or other infections, it could be a major breakthrough.

Here is the key quote form the article:

Patients with XLA are devoid of mature B-lymphocytes and immunoglobulins in the bloodstream, but are otherwise healthy. XLA thus provides strong clinical rationale for development of a novel therapeutic drug targeting Btk for safe inhibition of B-cell mediated diseases. In preclinical studies, PCI-32765 has the remarkable ability to selectively inhibit human B-cell activation without effecting T cells

Read more:
http://www.pharmacyclics.com/

Type I Diabetes linked to a childhood virus

2009-03-14T11:56:00.000-07:00

Many researchers and others believe there is a specific trigger for the onset of autoimmune disease. Most believe that trigger to be a virus. The hunt for that viral trigger has been going on for more than two decades. Many candidate viruses have been suggested. Here is another:

Common infant virus may trigger type 1 diabetes
Published 25.11.2008 , updated: 09.12.2008, 11:01

Human parechovirus is a harmless virus which is encountered by most infants and displays few symptoms. Suspected of triggering type 1 diabetes in susceptible people, research methods need to take this “silent” virus into consideration. This comes from findings in a study from the Norwegian Institute of Public Health.

This study was part of a long-term project at the Norwegian Institute of Public Health to investigate if environmental risk factors affect type 1 diabetes. Faecal samples and questionnaires about the health of 102 children were sent in monthly by their parents for closer study. Researchers wanted to see how common human parechovirus infections were among Norwegian infants. Existing research indicates that a related virus which only affects rodents, Ljungan virus, has been linked to the development of rodent diabetes.

Common virus

By studying stool samples from 102 infants and comparing feedback from parents about their child’s health over three years, no significant link could be found between infection episodes and typical symptoms such as coughing, sneezing, vomiting, diarrhoea or fever.

By the age of two, 86 percent of the infants had evidence of parechovirus in their faeces, and 94 percent by the age of three. Human parechovirus 1 was the most prevalent type (76 percent) followed by human parechoviruses 3 and 6 (13 percent and 9 percent respectively).

The researchers also noticed an increase in parechovirus infection between the ages of 6 and 18 months. This could be due to the loss of maternal antibodies by 6 months of age or the exposure to nursery/play groups that often begins at this age in Norway.

Most infections occurred during September to December. The 102 infants were recruited from babies born in 2004, with half from the high risk group for diabetes type 1 and the rest from a low risk group.

The “high-risk” group included babies who had been identified at birth to carry the HLA genotype conferring the highest known risk for type 1 diabetes.

The group not carrying the high-risk genotype included babies born at the same time and in the same area to the high risk babies.

The researchers conclude that most infants are infected by human parechovirus without displaying symptoms and so the total number of previous infections should be considered when looking for triggers for type 1 diabetes among those who are genetically at risk. Perhaps too few infections or infection at a too late time point could be important.

Reference

Tapia G., Cinek O., Witsø E., Kulich M., Rasmussen T., Grinde B., Rønningen K.S. Longitudinal observation of parechovirus in stool samples from Norwegian infants.(2008) J. Med. Virol. 80: 1835-1842

For cures now, needed changes Psoriasis Action Network

2009-03-10T21:28:00.000-07:00

Today in my email in box I received an email from Psoriasis Action Network, a fine organization I presume. I decided to write back with what I saw as the greatest need for action in the autoimmune community. The email below speaks for itself

Dear Alyssa Brown of Psoriasis Action Network

My son has P, PsA and AS. All are related inflammatory diseases. RA, Crohn's, diabetes type I are also related and in some of our relatives on both my wife's and my side. Similar meds and research innovation that stop immune system inflammation can help these and other autoimmune inflammatory conditions.

(1) Why don't advocacy groups work together? Wouldn't our voices be more powerful?

(2) Revolutionary therapies and medication are being delayed for decades by the current FDA clinical trial process. I have read that it cost more than a billion dollars for a single drug to go through trials for a single disease. Insane! In addition it takes a decade or more from research discovery to patient bedside. Double insane!! We need research centers, perhaps twenty or so, spread across US where new research can immediately be tried on patients hero volunteers--lawsuit free with IRBs who think first of patient and LAST about protecting their institution and jobs.

(3) There are over 80 named autoimmune diseases. The FDA requires each new therapy to be tested SEPARATELY on each of the named diseases. There are many underlying similarities in these diseases, why not a clinical trial with patients from many if not all autoimmune named conditions?

(4) The expense and lengthy time requirements to bring revolutionary cures to market mean that Big Pharma wins. They get to keep peddling less effective but very profitable 'blockbuster" drugs longer before better more effective therapies come and take away their market. The time and expense also forces small companies with innovative research to sell that research to Big Pharma or enter into onerous contracts in order to bring the research to market. Imagine if the electronics industry were forced to work that way. Today we would still be using crank handle phones!

(5) Only the suffering and deaths of a tiny handful of volunteers in clinical trial count when FDA makes a call on allowing medications to market. The massive scale of suffering and death by those who get no chance at these meds is not counted.

My son has been in wheel chair for four years. He cannot get his own food or water.

Ustekinumab was shown to have "stunning results" in clinical trials TWO YEARS AGO. It still is not approved today by the FDA rhymes with DELAY. My wife and I have gone through the Abigail Alliance and contacted Centocor senior executives asking for and being repeatedly DENIED ACCESS. Under current FDA compassionate use provisions Centocor is given the final and only say. There is NO APPEAL!

The Jacob Gunvalson court case means even the federal courts refuse to help alleviate the suffering and death of helpless patients. Do something! Why aren’t we blocking traffic and marching in the streets until treatment advances are released for patient use like the AIDS folks did in the eighties. It worked for them.

Why are we such wusses? Why don’t we fight and scream and riot? We are like abused spouses who sit passively back and re- take the abuse over and over and do nothing because they are “helpless” to change the situation. No we are not helpless. AND The situation needs changing now!

Ustekinumab beat Enbrel head to head clinical trials announced last September--still no approval. Do not accept FDA DELAY. Fight the monster. My son's suffering should count. His two brushes with death should count. Patients like him should not have to beg for access that is routinely denied.

(6) Stem cell research--Prochymal is a REVOLUTIONARY advance in treatment of ALL blood and immune cell conditions. The Osiris company has found the "magical" hematopoietic stem cells that can be infused into any human being, no matter blood or MHC type, without the stem cells attacking the patient (graft versus host) or the patient's immune system attacking the stem cells. Think what that means. If healthy immune cells that give rise to healthy immune regulatory cells, virtually all patients with all immune dysfunctions could be cured. All my son needs are healthy regulatory cells to bring balance to his immune system.

Prochymal is stuck in the FDA one named disease at a time nightmare. First they used it on GvHD and stopped it!!!! GVHD kills something like 50% of all patients who experience it in less than a year of onset. Prochymal stops it.

GvHD is like having every autoimmune disease at once so if it can be stopped autoimmune disease can be stopped. Osiris tried it first on Crohn's. It stopped ALL Crohn's symptoms in as little as two weeks. Now they are trying it on diabetes type I but it should be tried for ALL AUTOIMMUNE DISEASE NOW not decades from now.

What is wrong with FDA bureaucrats who cannot understand that if we can get working regulatory cells in our bodies then these cells can with exquisite precision control our immune dysfunctions. The control will be far better and far more targeted than the massive intermediate doses of monoclonal antibodies blocking one inflammatory cytokine at a time.. First too much blocked than as time goes on too little. Exquisite LIVING control is SO MUCH BETTER!

(7) Vaccines for autoimmune, where are they. Anti-TNF alpha, anti-maladapted dendritic and T effector vaccines--lets get them approved! Let HEROES volunteer in research centers today. Stop denying access. There are also vaccines that instead of alerting body to destroy maladapted cytokines and auto-immune cells instead promote tolerance of the proteins under autoimmune attack. These vaccines act like allergy shots. An MS vaccine along these lines has shown promise. Why aren't we finding the proteins being attacked for P, and PsA and creating these tolerance vaccines?

(8) B cell depletion therapies show tremendous promise. Why is the old mouse protein, Rituxan, still the only B cell therapy on the market? Why aren’t we getting HuMax CD 20 et al approved? What is wrong with the FDA? and what is wrong with NIH and research grants to find better B cell therapies that are more targeted to only kill the active autoimmune antibody producing B cells? instead of the "good guy" B cells that stand ready to protect us from various infective illnesses that we are immune to?

I have watched my son go from the editor of his college newspaper with a huge circle of friends to a hunched over, pain wracked, helpless disabled person. These past five years have been Hell for him.

When he first exhibited symptoms of his first autoimmune disease in his senior year of college in fall of 2003, I started reading on line everything I could. I found tremendous hope there that autoimmune disease could be cured and were being cured in the lab. We expected these cures to be immediately expedited and translated into patient cures. We waited eagerly. Then we waited some more and more and more.

Still we wait even for the simplest band-aid “bridge to future” treatment like Ustekinumab. It is should have been approved in summer of 2007 on some special provisional approval that allowed access for the sickest and those willing to give up legal rights to sue. Why wasn't it? Why do we wait?

Ustekinumab is a PRIMITIVE band aid to a problem that is could soon be curable with stem cell research. But it is a very helpful band aid, so lets get approved!

Sorry to ramble. Please forward this email to anyone you think can help get my son and other patients gain faster ACCESS to revolutionary cures currently in research labs and clinical trials.

Sincerely,

Diabetes Type I linked to a viral infection

2009-03-06T21:55:00.000-08:00

Here is the article:

The Peninsula College of Medicine and Dentistry
New study of human pancreases links virus to cause of type 1 diabetes
Key to success is unique availability of relevant organs for research
A team of researchers from the Peninsula Medical School in the South West of England, the University of Brighton and the Department of Pathology at Glasgow Royal Infirmary, has found that a common family of viruses (enteroviruses) may play an important role in triggering the development of diabetes, particularly in children. These viruses usually cause symptoms similar to the common cold, or vomiting and diarrhoea. However, the team has now provided clear evidence that they are also found frequently in the pancreas of people who develop diabetes.

The research, which was carried out at Peninsula Medical School and funded by Juvenile Diabetes Research Foundation (JDRF), is published today, 6th March 2009, in the leading European diabetes journal, Diabetologia. It involved the detailed study of a unique collection of pancreases from 72 young people who died less than a year after the diagnosis of type 1 diabetes.

Type 1 diabetes usually starts in young people and results from the destruction of the insulin-producing beta cells in the pancreas. Patients who develop type 1 diabetes have to take multiple daily injections of insulin for the rest of their lives, and the condition affects around 300,000 people in the UK , including 20,000 children under the age of 15. There are a further estimated 440,000 cases of type 1 diabetes in children worldwide, with more than a fifth living in Europe.

It is accepted that children who develop type 1 diabetes inherit a genetic susceptibility to the disease, but studies of identical twins have shown that when one twin has the disease, the other twin will only have approximately a 40 per cent chance of developing diabetes – suggesting that factors additional to inheritance are also involved.

It has long been speculated that viruses might play a role in causing type 1 diabetes by infecting the beta cells of the pancreas. This new research, which has made use of unique source material collected in Glasgow, is the first to provide evidence supporting this theory in such a large number of pancreases from young people recently diagnosed with the disease. It has revealed that more than 60 per cent of the organs contained evidence of enteroviral infection of the beta cells. By contrast, infected beta cells were hardly ever seen in tissue samples from 50 children without the condition.

The new research suggests that enteroviral infection of the beta cells in children with a genetic disposition to type 1 diabetes may initiate a process whereby the body's immune system identifies beta cells as 'foreign' and rejects them, as it would a transplanted organ.

An extension of the study to adults with type 2 diabetes showed that a large proportion (40 per cent) of these patients also had enteroviral infection in their beta cells. This compared with only 13 percent of non-diabetic adults of the same age group. Unlike type 1 diabetes, type 2 diabetes usually starts in adults and is associated with obesity. The beta cells are not destroyed in this disease but their ability to make insulin is compromised. The way that enteroviruses might contribute to the development of type 2 diabetes has not been established but it is known from laboratory studies that an enteroviral infection of beta cells reduces their ability to release insulin. It is possible that in people who are obese (where there is a greatly increased demand for insulin secretion) a reduction of beta cell function, secondary to enteroviral infection, may be sufficient to trigger type 2 diabetes – although more research is required to confirm this.

Overall, the findings of this new study suggest that vaccination in childhood to prevent enteroviral infections of beta cells might be an attractive means to reduce the incidence of both common forms of diabetes. However, there are up to 100 different strains of enterovirus and more research will be needed to identify which particular enteroviruses are associated with the development of diabetes, and whether vaccines could be developed to prevent their spread.

Professor Noel Morgan from the Peninsula Medical School commented: "We are genuinely excited by the findings of our study. This is the first time that scientists have been able to provide such extensive evidence for the relationship between enteroviral infection of the beta cells and the development of type 1 diabetes. This is due in large part to the unique availability of such a large number of pancreases from young people who had died of type 1 diabetes soon after becoming ill. Not only did this give us access to extremely important research material, but it also underlines the importance of continued organ donation to the development of medical research in the UK. "

He added: "The next stages of research – to identify which enteroviruses are involved, how the beta-cells are changed by infection and the ultimate goal to develop an effective vaccine – will lead to findings which we hope will drastically reduce the number of people around the world who develop type 1 diabetes, and potentially type 2 diabetes as well."

Professor Adrian Bone from the University of Brighton said: "It is a real privilege to be part of this work which sheds light on how targeted beta-cell destruction may be triggered in individuals at risk of developing diabetes. Whilst experimental studies from many laboratories, including my own, have been able to document the "natural history" of the disease processes culminating in overt diabetes, the role of viral infections in initiating these events is still unproven and controversial.

"Indeed," he added, "viruses have been shown to be capable of both inducing and preventing the development of diabetes. The true importance of our present study lies in the translation of these earlier experimental findings into meaningful observations in children and young people with diabetes."

Pathologist, Dr Alan Foulis of the Royal Infirmary in Glasgow, observed: "It is 25 years since I started assembling this collection of pancreases from patients with recent onset type 1 diabetes, with the express purpose of looking for the presence of enterovirus. It is only very recently that techniques of sufficient sensitivity to detect the virus in such specimens have been developed. The success of this study is largely down to the excellent scientific collaboration we have enjoyed".

Karen Addington, Chief Executive of JDRF, said: "Type 1 diabetes is a life- threatening condition that requires a life-time of painful finger prick blood testing and insulin injections. Incidences are increasing by four per cent each year and there is currently no way to prevent it. We are proud to have funded this crucial piece of research, which helps shed light on the causes of this serious condition. JDRF passionately believes that research such as this brings us a step closer to improving treatment and eventually curing this condition."

Autoimmune process prematurely ages immune cells

2009-03-06T21:12:00.000-08:00

Below is an article indicating that in rheumatoid arthritis, T cells age too quickly. I would think this has to do with the damage done to the immune system by being constantly switched to "overdrive". The aging can be seen in the telomere caps at the ends of the chromosomes. Researchers are looking for a way to reverse the damage to the telomere caps without causing cancer.

I think they would be better off looking for a way to stop the out of control autoimmune response as quickly as possible before the telomere damage is done.

There are four sure ways to stop autoimmune disease today and a couple other possible methods.
(1) full bone marrow transplant (gives patient new immune system but many patients die)
(2)B cell depletion--Rituxan only FDA approved medication but chance of death, however less than bone marrow transplant but autoimmune condition can recur in weeks or months
(3)bone marrow re-boot--some of patients bone marrow taken out frozen, rest of bone marrow killed, patient's frozen marrow thawed re-infused--risk of death from infection in between but no risk of gruesome death by GvHD as there is for full bone marrow transplant, also risk that frozen bone marrow may re-introduce the same autoimmune disease. No good way to separate healthy disease free patient bone marrow from autoimmune producing bone marrow.
(4)Prochymal-mixture of bone marrow pre-cursor cells from many many donors, somehow stops both GvHD and stops autoimmune disease. My belief this is the greatest hope for lifetime cures for most autoimmune patients.
Other possibilities
(5)parasites--see previous blog
(6)pregnancy--stops autoimmune for duration of pregnancy and few months after usually not always.

Here is the article about aging immune cells in Rheumatoid Arthritis patients:

Emory University
Immune cells from patients with rheumatoid arthritis have prematurely aged chromosomes

Telomeres, structures that cap the ends of cells' chromosomes, grow shorter with each round of cell division unless a specialized enzyme replenishes them. Maintaining telomeres is thought to be important for healthy aging and cancer prevention.

By this measure, T cells, or white blood cells, from patients with the autoimmune disease rheumatoid arthritis are worn out and prematurely aged, scientists at Emory University School of Medicine have discovered.

Compared with cells from healthy people, T cells from patients with rheumatoid arthritis have trouble turning on the enzyme that replenishes telomeres, they found. Reversing this defect could possibly help people prone to the disease maintain a balanced immune system.

The results are published online this week in Proceedings of the National Academy of Sciences.

In rheumatoid arthritis, T cells are chronically over-stimulated, invading the tissue of the joints and causing painful inflammation. This derangement can be seen as a result of the loss of the immune system's ability to discriminate friend from foe, says senior author Cornelia Weyand, MD, PhD, co-director of the Kathleen B. and Mason I. Lowance Center for Human Immunology at Emory University.

In childhood, new T cells are continually produced in the thymus, she says. But after about age 40, the thymus "involutes" – or shrinks and ceases to function. After that, the immune system has to make do with the pool of T cells it already has.
"What we see in rheumatoid arthritis is an aged and more restricted T cell repertoire," she says. "This biases the immune system toward autoimmunity."

Weyand, postdoctoral fellow Hiroshi Fujii, MD, PhD, and their colleagues were interested in mechanisms of T cells' premature aging, because scientists had previously observed that in rheumatoid arthritis, T cells tend to shift the molecules on their surface and function differently.

They found the answer in telomerase, the enzyme that renews telomeres and is necessary to prevent loss of genetic information after repeated cell division.
Telomerase adds short repeated DNA sequences to the ends of chromosomes to protect them. The enzyme is active in embryonic development but is usually switched off in adult cells. Many cancer cells reactivate it to enable runaway growth.

T cells are some of the very few cells in adults that can turn on telomerase when stimulated, probably because they have to divide many times and stay alive for decades.

Weyand and Fujii found that T cells from patients with rheumatoid arthritis make 40 percent less telomerase enzyme when stimulated. The cells came from 69 patients, 92 percent female, with an average age of 50, and were compared with cells from healthy people with similar demographics.

Shutting off a gene encoding part of the enzyme made normal T cells vulnerable to programmed cell death, and transferring telomerase into patients' T cells rescued them from dying.

The finding suggests that restoring defective telomerase to T cells could possibly help "reset" the immune system in rheumatoid arthritis, Weyand says.

Pharmaceutical industry researchers have been looking for drugs that could elevate or depress telomerase activity, with the goal of either prolonging life or treating cancer. However, turning on telomerase indiscriminately could lead to cancer, so any treatment would have to be targeted to the right cells, she says.
###
The research was funded by the National Institutes of Health and the Diane Wolf Discovery Fund.

Fujii is now an assistant professor of hematology and rheumatology at Tohoku University School of Medicine in Japan.

Reference: H. Fujii, L. Shao, I. Colmegna, J. Goronzy and C.M. Weyand. Telomerase insufficiency in rheumatoid arthritis. www.pnas.org/cgi/doi/10.1073/pnas.0811332106

The Robert W. Woodruff Health Sciences Center of Emory University is an academic health science and service center focused on missions of teaching, research, health care and public service. Its components include schools of medicine, nursing and public health; the Yerkes National Primate Research Center; the Emory Winship Cancer Institute; and Emory Healthcare, the largest, most comprehensive health system in Georgia. The Woodruff Health Sciences Center has a $2.3 billion budget, 17,000 employees, 2,300 full-time and 1,900 affiliated faculty, 4,300 students and trainees, and a $4.9 billion economic impact on metro Atlanta.

Worm Cure for Multiple Sclerosis other autoimmune

2009-03-06T12:39:00.000-08:00

There has been a lot of research into parasitic worms as a cure for autoimmune and allergic disorders. The idea is that the worms have evolved to survive in its host by calming the host's immune system. The chemicals released by the worms mimic cytokines that push our immune systems toward tolerance. One of those cytokines is IL-10 some secretions of the worms may mimic it.

Many researchers further believe that because all humans were universally infected with these parasites from birth that some humans have lost the ability to calm down their own immune systems without the help of these parasites. Thus we see the greatly increasing rates of autoimmune conditions, asthma, and allergy in "developed" countries where most of the population no longer carries these worms but the same is not true of "third world" countries where the rate of allergy, asthma and autoimmune is stable and few in the population suffer from these conditions and all or most people in the population are infected with worms.

There is a clinic in Tijuana, Mexico, a city just a few miles south of San Diego, California, where for a few thousand dollars anyone can be infected with "clean" parasites. In this case, hookworm larva are put on the patient's arm where they burrow through the skin (slight itching sensation) enter the blood stream and eventually end up in the intestines. Many claim that their symptoms of allergy, asthma and autoimmune are greatly lessened in a couple of weeks. I cannot recommend the clinic at this time, but if you are interested here is a link to its website:
http://autoimmunetherapies.com/

Below is a link plus the article about research in the UK to try to determine if parasitic worms can indeed turn off an autoimmune disease, in this case multiple sclerosis. Previously Dr. Joel Weinstock of formerly of the University of Iowa had successfully used pig whipworms (also an intestinal parasite) in humans as a treatment for Crohn's.

http://www.nottingham.ac.uk/

Parasitic worms may lead to treatment for multiple sclerosis

Scientists from The University of Nottingham will study the potential health benefits of parasitic worms as part of a study investigating treatments for people with the autoimmune condition multiple sclerosis (MS).

It is thought that hookworms may play a role in damping down the immune system, which is overactive in people with MS, the most disabling neurological condition in young adults.

The £400,000, three-year project funded by the MS Society, aims to determine whether infection with a small and harmless number of the worms can lead to an improvement on the severity of MS over a 12 month period.

If the trial is successful, the worms have the potential to provide a simple, cheap, natural and controllable treatment for MS.

The WIRMS (Worms for Immune Regulation in MS) study is led by Professor Cris Constantinescu and Professor David Pritchard and is a randomised, placebo controlled, phase 2 study in people with relapsing remitting MS and will be carried out at multiple centres up and down the country.

The 25 worms are microscopic and are introduced painlessly through a patch in the arm. They are then flushed out after nine months.

Professor Constantinescu, said: "People are really interested in this form of potential therapy because it's a natural treatment. It's been tested for safety and we now need to study the potential benefits and any side effects."

Jayne Spink, Director of Research at the MS Society said: "It sounds like science fiction, but it has been shown in a previous small study that people with MS who also had gut parasite infections had fewer relapses.

"Over time, parasitic worms have evolved to be able to survive an immune system attack and have been linked to a reduction in the severity of the symptoms of MS, which can be debilitating.

"If the theories can be shown to be accurate, using hookworms as a future treatment option may prove to be science fact."

MS affects more than 85,000 people in the UK and several million worldwide. Symptoms range from loss of sight and mobility, fatigue, depression and cognitive problems that often come on as attack - or relapses. There is no cure and few effective treatments.

Dorothy Sutton, 58, from Awsworth, has lived with MS for 32 years and is a Helpline volunteer for the MS Society. She said that although the treatment sounded unusual, anything that could potentially to help alleviate the symptoms of MS is a positive step.

"We have to explore every avenue of research to find treatments for MS. As long as it's safe and effective in helping the horrible symptoms, I don't think people mind where it comes from."

The Division of Clinical Neurology at The University of Nottingham's Medical School is a strong research-led unit which draws heavily on its close relationship with people with MS to inform its work.

Led by Professor Cris Constantinescu, the department features two academic and one NHS Neurology Consultants that are affiliated with the Neuroscience Directorate of Nottingham University Hospitals (NUH) NHS Trusts.

Health care reform is coming!

2009-03-02T21:40:00.000-08:00

Health care reform is coming! Thank God! Finally! Hallelujah!

Our family pays every more every year out of pocket costs for health care for our son--over ten thousand dollars a year and rising.

Only my wife works. I am on disability retirement due to my immune dysfunction. I have no health care coverage not even Medicare because as a California teacher of a certain age no money was taken from my salary for medicared.

The money issue is a big worry. Even worse for my wife, she worries if she at age 55 has a health problem and cannot work, we will not be able to get health care for our son. Pretty evil system here in the US.

My wife and I never drank, never did drugs, never partied. Always were on the deans list and honor rolls of every education institution we attended. We did everything right. We worked all our lives including while attending college. We graduated from college in four years with outstanding grades.

I was an athlete on school teams from junior high, to high school to college. I took very good care of my health.

All the good things and good living we did were for naught, as we ended up both carrying "genetic time bombs" through no fault of our own. Now all the our good deeds do not mean that we will have health care for our son.

Good deeds: I have intervened to save three lives-- a choking victim with Heimlich, a drowning victim in a pool not my own and a victim of a violent attack by a mentally deranged stranger. My wife and I were constant volunteers at church--Church Board member, Sunday School teachers, Christian scouting directors, volunteers at church work days. We were community organizers for school bonds.

Yet good deeds do not guarantee good health. Nor do good deeds guarantee health care when you get sick. What a rotten system!

Below is a summary of our possible new health care system. Enjoy.

http://www.latimes.com/features/health/la-he-healthreform2-2009mar02,0,1696038.story
From the Los Angeles Times
A national healthcare reform primer
The many issues confronting President Obama as he tries to achieve insurance coverage for all Americans.
By Bob Rosenblatt

March 2, 2009

Most people with health insurance say they like what they have. They trust their doctors, and they are fearful of any change in their policy.

Many of the 47 million uninsured people in this country don't go to the doctor even if they need to because they figure they can't afford it. They skimp on medications or skip them entirely.

President Obama has said that he and Congress will make both groups happy by cutting costs for those who have coverage and by bringing quality care to those who currently have no insurance.

It's a tremendous challenge. And the goal, if accomplished, will affect every American.

On Thursday, Obama's push to expand healthcare coverage began in earnest, with the announcement of his plan to create a $634-billion fund to do just that. The amount was described as a down payment over 10 years; the final price tag would be even larger, perhaps $2 trillion or more.

The president's strategy is starkly different from the approach by the Clinton administration in 1993, when it corralled hundreds of experts and staff people to produce a detailed plan more than 1,000 pages long. The Clinton effort failed, despite Democratic majorities in both houses of Congress. Obama's approach is this: Give me a bunch of money, and we'll figure out the details later how we are going to manage this thing.

Now the wrangling truly begins -- with the administration trying to push its vision through Congress, with Democrats and Republicans trying to shape the effort to their liking and with special interests trying to affect the final outcome, whatever it may be.

The cost of covering the uninsured ultimately will depend on the number of people included, the specific benefits they receive, and the amount of financial help the taxpayers would provide. The only agreement among economists who study the issue is that the tab would be a big one:

* $200 billion to $250 billion a year, says Joe Antos of the conservative American Enterprise Institute.

* $150 billion to $175 billion a year, says Len M. Nichols of the liberal New America Foundation.

The debate over this first proposal and related, still-to-come proposals will boil down to a discussion about the powers and size of the federal government. Do we want the government to have the power to make us buy health insurance, as individuals or businesses? How much power should the government have to control costs? How much do we want to spend to provide health insurance to our fellow citizens who don't have it?

Here is a primer on the big issues to watch as the healthcare debate unfolds:

Regardless of what happens, will I be able to keep the insurance I have now?

Almost certainly. The big lesson from President Clinton's ill-fated attempt at healthcare reform in 1993 and 1994 was that people are terrified of change. They like their doctors, although they don't like insurance companies. An oft-uttered reassurance in the 2008 residential campaign was: If you like what you have, you can keep it. This will likely be a key plank in any plan offered by the Obama administration.

Further, most people get their coverage at work, and this would continue. Despite rising costs, business managers still place high value on insurance as an attractive benefit. The share of the workforce with coverage remains around 70%.

If I don't have health insurance, would I have to buy it if an agreement on reform is reached?

This is the tricky mandate issue. Advocates say you can't cover everyone unless you make everyone buy a policy.

Although nobody from the administration is using the "M" word these days -- a mandate would represent a big expansion of government authority -- many believe it is the logical way to go. So do Democratic leaders in Congress.

Before such a mandate could become law, however, Congress would have to decide the amount of financial subsidies to help people pay for their coverage. Most people without health insurance work full-time and earn less than $30,000 a year. Meanwhile, the average policy for a family of four under job-based coverage cost $12,680 last year, with the employer paying $9,325, according to figures compiled by the Kaiser Family Foundation. Coverage for an individual through work cost $4,704, with the employer paying $3,983.

A decision on a mandate would also involve intense negotiations between the government and the insurance industry over the terms and details of coverage. The industry has indicated it's willing to deliver "guaranteed issue" (nobody gets turned down) in return for a law requiring mandatory purchase of insurance.

The National Assn of Insurance Commissioners has proposed a model act for the states as a way to control costs. It says that the highest rates for any age group should be no more than 400% of the lowest rate charged to any group. This would be reduced to 300% two years after the law is passed, then to 200% after five years. That would mean a 63-year-old living in San Diego, for example, could not be charged more than double the rate paid by a 25-year-old in Santa Monica.

Price differences and subsidies are crucial. It would be meaningless to have the guaranteed right to buy health insurance if you make $30,000 a year, have high blood pressure and diabetes, and a policy would cost you $10,000.

If I have a business, would I have to buy coverage for my workers?

The answer to this question may determine the success or failure of health reform efforts.

This is the "pay or play" issue in health policy language. A company "plays" by offering coverage to its employees, or "pays" into a public fund to help cover the uninsured.

During his campaign, Obama said he favored a mandate for business. But, like the idea of a mandate for individuals, any discussion of a mandate for business was conspicuously absent from the budget document, and was never mentioned by administration officials in their briefings Thursday. They repeated over and over that the president wants every American covered by health insurance, and that he welcomes all ideas from Congress about how best to achieve the ambitious goal.

Big questions remain. If there is a mandate, which businesses should be exempt? Those with 25 or fewer workers? 10 or fewer? And what share of payroll should businesses have to contribute if they don't offer coverage?

Big companies already offer coverage and likely would continue to do so. They might favor the mandate because it levels the playing field, with all firms now in the game.

Small businesses, vociferous opponents of the Clinton plan in 1993, would be hard to persuade now to accept a mandate as they struggle with the biggest economic slump since the Great Depression.

Would there be some help for older workers who don't have coverage on the job and can't afford an individual policy?

Perhaps. One of the ideas circulating on Capitol Hill would allow people to buy into the Medicare program at age 55 or 60. (Medicare eligibility begins at 65.) Early entry would protect people who may have taken early retirement, or been laid off in their late 50s. They are old enough to have developed medical problems that make it hard to get an affordable policy. (How about Medicare for all?)

The question that would need to be resolved is how much would the government charge as a premium. Most of the cost of Medicare is borne by the taxpayers, with the beneficiaries paying only a small share. Since Medicare faces long-term financial problems, Congress might want to charge the full cost of Medicare to these new enrollees. This could range from $500 to $700 a month. (Still cheaper than what my wife and I pay out of pocket each year)

Might there be a public health insurance plan?

This idea, backed by the president, would create for the first time a public insurance plan to compete with the myriad plans offered by private-industry insurers. The plan would be designed to provide a benchmark for quality coverage, with a basic package of comprehensive benefits. The Obama health plan issued during the presidential election campaign envisioned that millions of the 47 million uninsured would move into a public plan.

How can the country pay for a reworking of its health insurance system?

There's the rub. The only thing certain is that it would cost a lot, and the debate will be vigorous over where that money should come from.

Obama has proposed a down payment of $630 billion. Most of the money would come from an increase in federal income taxes by limiting deductions for people making more than $250,000 a year.

He also wants to cut payments to Medicare HMOs, saving about $175 billion over 10 years, according to the budget plan issued Thursday. This program, known as Medicare Advantage, requires enrollees to get their hospital and doctor care within a network of providers. In return, they get extra benefits, such as dental care, which are not included in the regular Medicare program. Under regular Medicare, called fee-for-service, the beneficiary can see any doctor or hospital where Medicare payments are accepted.

Other ways to find revenue, mentioned by administration officials but not endorsed in any way, include:

* Capping the federal income tax deduction for health insurance.

Workers do not currently pay taxes on the total value of their coverage. Suppose Sarah Jones has a policy at work with premiums of $10,000 a year. She pays $2,000 and her employer pays $8,000 on her behalf. That $8,000 is not counted as income for Sarah Jones. And her employer can deduct the $8,000 as a business expense.

If this deduction were limited, the government could collect lots of money to pay for the uninsured. But it would mean higher taxes for workers who have the most expensive policies, and they won't greet that very warmly. Also, this would be a flip-flop politically for the president, since he spent millions of dollars on TV commercials during the campaign attacking the Republican presidential candidate, Sen. John McCain of Arizona, for making exactly the same proposal.

* Creating a special tax dedicated for healthcare.

This could be a special value-added tax on all goods, a kind of tax common in Europe. New taxes, however, are never popular, and especially not during a severe recession.

* Finding ways to make the system more efficient.

The president said in his budget that "healthcare costs could be reduced by a stunning 30% -- or about $700 billion a year -- without harming quality if we moved as a nation toward the proven and successful practices adopted by the lower-cost areas and hospitals."

A study of Medicare spending, for example, shows that if hospitals in L.A. used the same methods of care as hospitals in Sacramento, Medicare would have saved $468 million in 2005 on inpatient care. The Medicare patients in L.A. spent more days in hospitals, more time in the intensive care unit and were seen by more specialists. Yet despite the higher spending, patients in L.A. didn't live any longer and the quality of care was not better than in Sacramento, according to a study by the Dartmouth Institute for Health Policy and Clinical Practice.

Efficiency is one of the most popular ideas in Washington because it looks pain-free politically. After all, everybody is against waste. Except of course, when that "waste" is money you get -- or want -- for a service or product.

Currently, for example, if Drug A and Drug B are safe and effective in treating an illness, the Food and Drug Administration approves the sale of both drugs -- and Medicare and Medicaid pay for these drugs. But the House version of the stimulus bill would've allowed government programs to consider cost in deciding which drug to pay for, allowing programs to pick the cheaper one.

This was alarming to drug manufacturers and disease-specific patient-advocacy groups. Drug B might cost a lot more than Drug A, but it also might relieve pain more effectively and make life more bearable for a specific subset of the population. Neither drug makers nor these groups want the government to limit the ability of insurers and Medicare to pay for Drug B.

The Senate heard these concerns, and the final version of the stimulus bill included the word "clinical" as the standard of effectiveness that should be pursued. In other words, the programs can also emphasize how a drug works, not simply how much it costs.

What happened in the stimulus bill shows how hard it will be to create economic efficiency that slows the growth in healthcare spending.

::

Even in this deep recession, healthcare spending is expected to rise 5% this year, while the nation's output of goods and services (the gross domestic product) shrinks by 0.2%, according to government forecasts issued just last week.

Health reform means trying to bring insurance to those who don't have it without making the federal budget deficit even deeper, controlling the growth in health spending without denying patients what they think they need, limiting unnecessary procedures without hampering the autonomy of doctors to do what they think is best.

If Obama can figure out a way to persuade Congress to expand coverage to millions of uninsured people, while keeping those with coverage happy, it will be a feat of political magic that has eluded presidents for decades.

health@latimes.com or bobblatt@aol.com

Mono associated with Multiple Sclerosis

2009-03-02T21:27:00.000-08:00

High levels of Epstein Barr viral antibodies in the blood are associated with multiple sclerosis, again!

I had a really bad case of mono in college. The only time in my life that I remember the horizon seeming to move up and down as I walked. I think the effect was caused by the very high fever. My neck was swollen up like I had the mumps.

Weird that, my now wifeof thirty three years and then fiancee did not catch mono even though she was heavily exposed. I guess not all people can get it.

Also the immune problems I have (throat and extremity swelling, flushing, syncope, anaphylaxis) were already present before the mono and seem to be no worse after the mono.

Not everyone who gets mono gets an autoimmune disease.

Not everyone who gets autoimmune has mono first. My son, who has three autoimmune diseases (psoriasis, PsA, AS) that came on suddenly in his senior year of college, never had mono.

The article linking MS to mono is below:

Epstein-Barr Virus May Be Associated with Progression of MS
Release Date: March 2, 2009

BUFFALO, N.Y. -- Epstein-Barr virus (EBV), the pathogen that causes mononucleosis, appears to play a role in the neurodegeneration that occurs in persons with multiple sclerosis, researchers at the University at Buffalo and the University of Trieste, Italy, have shown.
Multiple sclerosis (MS) is an autoimmune disease that can cause major disability. There currently is no cure.

"This study is one of the first to provide evidence that a viral agent may be related to the severity of MS disease process, as measured by MRI," said Robert Zivadinov, M.D., Ph.D., associate professor of neurology in UB's Jacobs Neurological Institute (JNI) and first author on the study.

The research appears in the Online First section of the Journal of Neurology, Neurosurgery and Psychiatry and is available at http://jnnp.bmj.com/cgi/rapidpdf/jnnp.2008.154906v1.
"A growing body of experimental evidence indicates that past infection with EBV may play a role in MS," said Zivadinov, "but the relationship of EBV and the brain damage that can be seen on MRI scans had not been explored."

The study involved 135 consecutive patients diagnosed with MS at the Multiple Sclerosis Center of the University of Trieste. Evaluations of the MRI scans were carried out at the University of Trieste and at the JNI's Buffalo Neuroimaging Analysis Center (BNAC), which Zivadinov directs.
The Buffalo researchers measured total brain volume, as well as the decrease in gray matter, at baseline and three years later.

Results showed that higher levels of anti-EBV antibody measured at the beginning of the study were associated with an increased loss of gray matter and total brain volume over the three-year follow-up.

The researchers now are carrying out prospective longitudinal studies in patients who experienced a condition called "clinically isolated syndrome," a first neurologic episode that lasts at least 24 hours, and is caused by inflammation/demyelination in one or more sites in the central nervous system. If a second episode occurs, the patient is diagnosed with MS.
The study will investigate the relationship of anti-EBV antibody levels to development of gray matter atrophy, neurocognitive function and disability progression over time.

UB and Trieste researchers also are investigating interactions between environment, certain genes and EBV antibodies and the association with MRI injury in MS. A paper on this work is "in press" in the Journal of Neuroimmunology.

Marino Zorzon, M.D., from the University of Trieste, is second author on the Journal of Neurology, Neurosurgery and Psychiatry study. Murali Ramanathan, Ph.D., from the UB School of Pharmacy and Pharmaceutical Sciences and the JNI, is co-corresponding author with Zivadinov. The BNAC and JNI are located in Kaleida Health's Buffalo General Hospital.
Additional contributors to the study are Bianca Weinstock-Guttman, M.D., from UB; Maurizia Serafin, M.D., from Cattinara Hospital in Trieste; and Antonio Bosco, M.D., Ph.D., Alessio Bratina, M.D., Cosimo Maggiore, M.D., Attilio Grop, Maria Antonietta Tommasi, M.D., all from the University of Trieste, and Bhooma Srinivasaraghavan, from the BNAC.

The study was supported in part by the Consortium for International Development of the University of Trieste, Italy. The researchers also gratefully acknowledge additional support from the National Multiple Sclerosis Society and a Pediatric MS Center of Excellence Center Grant.

The University at Buffalo is a premier research-intensive public university, a flagship institution in the State University of New York system and its largest and most comprehensive campus. The School of Medicine and Biomedical Sciences is one of five schools that constitute UB's Academic Health Center. UB's more than 28,000 students pursue their academic interests through more than 300 undergraduate, graduate and professional degree programs. Founded in 1846, the University at Buffalo is a member of the Association of American Universities.

Suicide, a topic worth some discussion

2009-03-02T20:27:00.000-08:00

Our FDA friends refuse to allow us access to life changing and life saving research developments. We live in pain and discomfort every day. What happens to us is of no importance to those in power. So depression is a normal part of the equation, especially as our end gets near. Having an "out" if things get too bad is a kind of security, a safety net, that our 'immune normal' friends cannot understand especially those who consider themselves to be religious.

I have been dead, suffocated.

I can tell you step by step how it feels. The desperate need for air does not end at any stage only gets worse and then added to by a horrible sharp pain in the center of the brain that becomes all encompassing. This pain feels like something is squeezing your brain in a giant vice. At this point you are completely deaf and blind. There is not enough oxygen for those senses to work. No part of your body is under voluntary control. More surprisingly the sense of body also disappears. There is no sensory feedback from your arms, legs or skin even on the outside of your head. You feel like you are floating someone where in the center of your brain with no connection to a body at all. Time slows down. The experience seems to last for hours and hours not the minutes it actually takes.

Suffocation is so fun, NOT.

I can assure my conservative friends that think that lethal injection of criminals is too easy because the criminals deserve worse. Our con friends do not see a twitching body or hear screams that it is a form of suffocation. They think it is a peaceful death. It is not. It is suffocation and suffocation is not fun. The screams of the criminals who die are silent but the horror and pain of the death is real.

Depression caused by our constant pain and limitations can lead to thoughts of suicide. No question. I do not recommend any method that involves suffocation. I do not recommend it at all as usually a day later things do not look so black. But having a choice of the possibility of suicide is a right we all deserve.

At the very worst times of pain, the thought that we could have an out is liberating and actually makes the pain less and the episode easier to get through. The loss of control of our lives is already so great. Why some "normal immune" folks want to deny us this, I do not understand.

February 28, 2009
THE SATURDAY PROFILE
Preparing to End Her Life, While Protecting Another
By SARAH LYALL
BRADFORD, England

MULTIPLE sclerosis came into Debbie Purdy’s life about the same time as her husband, a Cuban jazz violinist named Omar Puente. “He didn’t speak English, and I didn’t speak Spanish,” she recalled. “What we had was jazz, and a dictionary.” When she received her diagnosis, one of her first thoughts was: “How do you say ‘multiple sclerosis’ in Spanish?”

That was 1995. Somehow, the couple have adjusted together to the changes in Ms. Purdy’s deteriorating body. They have adjusted as she has gone from walking with a cane to using a manual wheelchair to using an electric one. They have traded water glasses for plastic cups, installed a panic button at home in case she falls and put up a hoist to help her get in and out of bed.

But there may be a limit to the Purdy-Puente partnership, so close it feels almost symbiotic. The possibility exists that Ms. Purdy, 45, will get so sick that she no longer wants to live. Should that happen, she says, she plans to travel to an assisted suicide clinic in Switzerland and drink a lethal cocktail of drugs. As things now stand, she would have to go without her husband, she says, because helping someone die — even, say, by pushing a wheelchair onto the airplane — is illegal in Britain.

It is her choice alone, Ms. Purdy said.

“Omar’s being prepared to go to jail because he loves me and respects my choices is the same reason I wouldn’t want him to go to jail: because I love him,” she said. “I’m not even prepared to let him be interviewed by the police.”

Ms. Purdy has taken her private struggle and turned herself into the latest public face of an anguished, longstanding debate about assisted suicide in Britain. She has sued the government in an effort to force officials to provide assurance that if Mr. Puente did help her die in Switzerland, he would not be prosecuted.

Last week, her latest appeal failed when three Court of Appeal judges ruled that although they sympathized with Ms. Purdy, only Parliament could change the law. She is now considering whether to pursue the case further in the courts or to lobby for a new law.

Assisted suicide is legal in Switzerland. In recent years, about 90 Britons have killed themselves in the clinic, which is in Zurich. So far, no one back home has been prosecuted for helping them, but that does not mean it will not happen. “Many have faced police questioning and agonizing months waiting for the final decision not to prosecute,” said Ms. Purdy’s lawyer, Saimo Chahal.

Ms. Purdy explained her thinking in a recent conversation in her and Mr. Puente’s tiny house on a sloping street here in Bradford, a down-at-the-heels industrial northern city. If Ms. Purdy had not been in a wheelchair, if her hands had not been shaking, if she had not been speaking matter-of-factly about things like loss of bladder control, the painful swelling in her feet and how hard it was for her to brush her teeth, it would have been difficult to believe that she was ill at all.

She is that joyful.

SHE talked about her happiness that Barack Obama is president. She talked about how strangers actually welcome the chance to help her, because it makes them feel they have done something noble. She talked about the adventurous life she once led.

Ms. Purdy grew up in Brixton, south London, with a father who was a peripatetic inventor and a mother who stayed home to look after her and her four siblings. She went to the University of Birmingham but left when she realized how lucrative her part-time job, selling ads for the Yellow Pages, was. And thus began an era of impetuous traveling to unlikely places, like Oslo and Houston, and then talking her way into unlikely jobs, like dancing in a club in Japan, running a road-safety project for 8- to-12-year-olds in Hong Kong and working as a music journalist and travel brochure writer in Singapore, where she and Mr. Puente met.

She does not want to talk about death, but the fact is always there. She has primary progressive, rather than relaxing-remitting, multiple sclerosis, meaning that her condition is inexorably worsening. Sometimes she chokes when she swallows. She has not been upstairs in her own house in two years. She needs help cooking, cleaning and shopping.

Mr. Puente, 47, who teaches and travels the world playing music, was away but spoke by telephone later. “Debbie was the woman I chose to be my wife,” he said. “I’ve seen the whole process, from when she was a very strong woman with a wonderful big bottom and strong legs, to using a walking stick to a wheelchair. She is still articulate and enthusiastic and full of life. She doesn’t want to die.”

He does not want her to die either, and especially not alone. But, he added: “I love that woman and I don’t want her to suffer badly. Apart from everything else, she wants to control her life and make her own decisions.”

Mr. Puente is a big bear of a man, and he has a jazz musician’s sense of improvisation and possibility, a way of grasping happiness in the present. He often tells Ms. Purdy that, as her husband, it is his job to make sure her life is not unbearable.

Fifteen years ago, she lost control of her bowels for the first time. “I wanted to die,” she recalled. “I was in floods of tears and Omar sat down and said, ‘What’s wrong?’ and he laughed. And I said, ‘How can you laugh at me?’ And he said: ‘It’s your choice, either I’ll cry with you or laugh at you.’ ”

Not long ago, a team of nurses came in to install the hoist that helps Ms. Purdy in and out of bed.

“He was laughing,” Ms. Purdy said. “The nurses threw him out of the room when we were trying it out, because he was acting like it was a sex toy.”

BUT when you have a progressive disease, time moves in the wrong direction. If Ms. Purdy exhausts her options and cannot get the assurance she needs from the government, she is prepared to go to Switzerland alone, she said. But she would have to do it while she is still physically able, which would be long before she is ready to die, she said.

She has worked out all the logistics, including how to get the $6,000 the trip would cost. That does not mean she will do it; she just wants the choice.

“I don’t want to kill myself,” she said. “I don’t want to go to Switzerland and end my life early. But this is a security blanket.”

She thinks often about what she can withstand. At what point does a life slip from manageable to untenable?

“When I was 20 and jumping out of airplanes, I thought being in a wheelchair would be unbearable,” Ms. Purdy said. “But it’s not. I thought asking people for help would be horrible and unbearable.

“But what I consider dignity has changed, and what I consider unbearable and horrible has changed,” she said. “Having a stranger pick me up off my bathroom floor, that’s not undignified. What is undignified is having a stranger say that I have no control over my own life.”

TNF blocker pills, creams? Yes!

2009-02-26T22:49:00.000-08:00

Remicade in a pill? Oral Enbrel? Humira as a cream? TNF alpha blocker eye drops to stop Behcet's? Yes, all of that is coming. As soon as the FDA gets out of the way and lets it happen.

Research and Markets: TNF Antagonists: Most Successful with Plenty of Competition in the Pipeline
DUBLIN, Ireland--(BUSINESS WIRE)--
Feb 24, 2009 - Research and Markets

(http://www.researchandmarkets.com/research/6015b3/competitor_analysi) has announced the addition of the "Competitor Analysis: TNF Antagonists & Agonists" report to their offering.
The present Competitive Intelligence Report about Tumor Necrosis Factor (TNF) and TNF receptor antagonists and agonists used to treat TNF-mediated inflammatory diseases such as rheumatoid arthritis or to treat cancer, respectively, provides a competitor evaluation in the field of R&D projects with TNF Antagonists & Agonists as of February 2009.

TNF blockers are the commercially most successful single-target group of biologic therapies. 2008 sales of the four approved brands were US$16.35 bln with double digit growth rates due to indication expansion and new market entrants. Abbott's fully human antibody Humira recorded 2008 sales growth of 48% over the previous year which may explain why competitors with the established brands Enbrel and Remicade also have fully human anti-TNF antibodies in their pipeline. Forthcoming patent expiries also may have encouraged to develop next generation anti-TNF antibodies. Clinical indications approved for therapy with TNF blockers include rheumatoid arthritis (RA) and juvenile RA, ankylosing spondylitis, psoriatic arthritis, psoriasis in adults and in children, Crohn's disease and pediatric Crohn's disease, and ulcerative colitis.

As in other cases, a clinically validated target with commercial success attracts companies to exploit and leverage their new technologies. Next generations of TNF blockers may bring orally bioavailable versions, locally applied TNF blockers, antagonists with higher binding affinities or better tissue penetration due to smaller size. At least 15 clinical stage and 19 preclinical stage are under evaluation in various indications including ophthalmic use, osteoarthritis, Behcet's disease, organ transplantation, cutaneous sarcoidosis, oral mucositis, atopical dermatitis and sepsis.

The report includes a compilation of marketed products and their sales in 2008 and current active projects in research and development of TNF antagonists and agonists. In addition, the report lists company-specific product portfolios and R&D pipelines of TNF antagonists and agonists.

Competitor projects are listed in a tabular format providing information on:

Drug Codes,
Target / Mechanism of Action,
Class of Compound,
Company,
Product Category/Therapeutic Area,
Indication,
R&D Stage and
additional comments with a hyperlink leading to the source of information.
Competitor Analysis: TNF Antagonists & Agonists
Sales of TNF Antagonists in 2008

More B cell news

2009-02-26T22:43:00.000-08:00

B cells as targets for asthma as well as autoimmune? Turning off select B cell clones and turning off allergy? or autoimmune disease? All is becoming possible. Rituxan is good first step in B cell depletion, but much better is coming. Read below.

Contact: Tom Rickey
tom_rickey@urmc.rochester.edu
585-275-7954
University of Rochester Medical Center
A worm-and-mouse tale: B cells deserve more respect

By studying how mice fight off infection by intestinal worms – a condition that affects more than 1 billion people worldwide – scientists have discovered that the immune system is more versatile than has long been thought. The work with worms is opening a new avenue of exploration in the search for treatments against autoimmune diseases like diabetes and asthma, where the body mistakenly attacks its own tissues.

The findings, reported by scientists who performed the work at the Trudeau Institute in Saranac Lake, N.Y., and who are now at the University of Rochester Medical Center, appear in the March issue of the journal Immunity. The article was published online Feb. 26.

The research focuses mainly on B cells, one of many types of immune cells that the body maintains to fight off invaders like bacteria, viruses, and parasites. Besides B cells, there are T cells, macrophages, neutrophils, monocytes, mast cells and others, all working in concert to keep an organism healthy. The cells cruise our bodies, looking to eliminate infectious threats before they become a serious risk to our health.

For many years, scientists believed that the major job of B cells was to identify foreign invaders and tag them with antibodies, marking the microbe for destruction by the immune system. But scientists are discovering that B cells do much more, resulting in new information about our immune system that could be useful for developing more effective vaccines and better treatments for many types of disease.

In the past few years, Frances Lund, Ph.D., professor of Medicine in the Division of Allergy/Immunology and Rheumatology at the University of Rochester Medical Center, has found an array of unexpected functions for B cells. In the laboratory, she has found that B cells produce chemical signaling molecules known as cytokines that spur other immune cells in the body to action. Her team has also shown that B cells are crucial for presenting to T cells snippets of proteins from invaders, so that the T cells can recognize the invader, a crucial step that allows T cells to mature into useful cells which can then fight an infection efficiently.

In the new paper, Lund's team tested how the findings actually translate by watching closely as an organism – in this case, a mouse – actually fights off infection by a parasite. They chose to study the intestinal parasite Heligmosomoides polygyrus, a bright red worm about one-third of an inch long that infects mice.

It's a cousin of the scores of worms that infect more than 1 billion people worldwide. Roundworms, hookworms, pinworms, and others – these and other worms cause fatigue, diarrhea, nausea, and death.

"Nematodes – worms – sicken a lot of people, they can cause severe malnutrition, and they play havoc with the immune system, making many people more vulnerable to other threats, such as malaria," said Lund, whose project was funded by the National Institute of Allergy and Infectious Diseases.

The team not only verified the additional actions of B cells that they've discovered in the laboratory, but, importantly, they showed that these functions are crucial for the organism to fight off infection.

Lund's team showed that the chemical messengers produced by B cells, such as interleukin-2 and tumor necrosis factor, are necessary for the immune system to protect mice against Heligmosomoides polygyrus. The team also showed that B cells must be present in order for T cells to mature and operate properly.

"It's long been dogma that B cells need the help of T cells to make antibody. That's in all the textbooks," said Lund. "Now work from our laboratory and others shows that it's a two-way street, that T cells need the help of B cells also."

B cells' effects on T cells may open a new window on such diseases as lupus, asthma, multiple sclerosis, and diabetes, where doctors know that T cells are active. Maybe manipulating B cells offers a new way to affect the activity and survival of the T cells that cause disease.

The work also brings up the possibility of more targeted treatments than current treatments, which generally affect all B cells. Lund has found that different B cells produce different collections of chemical signaling molecules. Someday, instead of having a drug that simply targets all B cells, it may be possible to target a specific type of cell, cutting down side effects and making a treatment more effective.

"It may be that only certain B cells play a role in damaging immune responses. If we can narrow down the group of cells at the root of the problem, we may be able to find important new targets for improving treatment," said Lund.

###
The paper is dedicated in memory of author Frank Sprague, who was a technical associate at Trudeau and performed many of the experiments.

The first authors of the paper, who share equal credit, are post-doctoral associate Wojciech Wojciechowski, now at Rochester, and former post-doctoral associate David P. Harris, now with Lexicon Genetics. Other authors in addition to Sprague include technicians Betty Mousseau and Kim Kusser, now at Rochester; former technician Melissa Makris; Markus Mohrs and Katja Mohrs of Trudeau; Tasuko Honjo of Kyoto University; and Troy Randall, Ph.D., professor of Medicine at the University of Rochester Medical Center.

Most of the research described in the paper was done by Lund's group at the Trudeau Institute, before the group moved to Rochester last summer.

Contact: Cathleen Genova
cgenova@cell.com
617-397-2802
Cell Press
Busy Bs: Lymphocyte uses multiple mechanisms to shape immune response

New research expands our understanding of how a type of immune cell called a B lymphocyte enables the immune system to mount a successful defense against an intestinal parasite. The study, published by Cell Press online in the journal Immunity on 26 February, provides some intriguing insight into the variety of mechanisms implemented by B cells to protect the host from infection.

B cells are critical cells of the immune system that produce antibodies (Abs) to help rid the body of harmful pathogens. This type of immunity, called "humoral immunity", is complemented by "cellular immunity" which is mediated by T lymphocytes. Research has shown that B cells do not just produce Abs but can regulate the immune response in many other ways as well. B cells produce critical regulatory chemicals called cytokines and there is some evidence that B cells may amplify T cell dependent immune responses.

An earlier study by Dr. Frances E. Lund from the Department of Medicine at the University of Rochester indicated that specific types of B cells may promote the maturation of T cells. To gain insight into the mechanisms used by B cells, Dr. Lund and colleagues performed a series of experiments to examine whether cytokine-producing B cells are required for protection against the intestinal parasite, Heligmosomoides polygyrus (Hp).

The researchers found that B cells were required for protection against Hp and that B cells mediate protection, in part, by producing Abs. In addition, B cells promoted the production and long-term maintenance of an essential type of T cell, called T helper 2 cells (Th2), which are known to be critical for protection from Hp. Importantly, the influence of B cells on the Th2 cells was independent of antibody production.

The researchers went on to show that B cell-derived cytokines interleukin-2 and tumor necrosis factor ? were required both for effective Ab and for Th2 cell responses to Hp. Therefore, in addition to Ab production, B cells also make a critical contribution to the immune response to this pathogen by regulating T cells.

"Our findings fill an important gap as they show for the first time that multiple cytokines made by B cells regulate both humoral and cellular protective immune responses to infectious organisms," says Dr. Lund. "In addition to protective effects, we also suggest that cytokine-producing B cells may play a role in damaging immune responses, such as reactions to allergens and autoantigens. Therefore, B cell subsets may represent future targets for many types of therapeutics to treat allergy, asthma and autoimmunity."
###

The researchers include Wojciech Wojciechowski, Trudeau Institute Inc., Saranac Lake, NY, University of Rochester, Rochester NY; David P. Harris, Trudeau Institute Inc., Saranac Lake, NY, Lexicon Genetics, The Woodlands, TX; Frank Sprague, Trudeau Institute Inc., Saranac Lake, NY, Betty Mousseau, Trudeau Institute Inc., Saranac Lake, NY, University of Rochester, Rochester NY, Melissa Makris, Trudeau Institute Inc., Saranac Lake, NY, Kim Kusser, Trudeau Institute Inc., Saranac Lake, NY, University of Rochester, Rochester NY, Tasuko Honjo, Kyoto University, Yoshida-Konoe, Sakyo-Ku, Kyoto, Japan, Katja Mohrs, Trudeau Institute Inc., Saranac Lake, NY, Markus Mohrs, Trudeau Institute Inc., Saranac Lake, NY, Troy Randall, University of Rochester, Rochester NY, and Frances E. Lund, Trudeau Institute Inc., Saranac Lake, NY, University of Rochester, Rochester NY.

FDA fails to protect us and Americans know it

2009-02-24T20:31:00.000-08:00

The American public now realizes how incompetent the FDA bureaucrats are at protecting our foods. Hopefully soon they will realize that FDA incompetence also is keeping sick Americans from having access to clinical trial cures. FDA bureaucrats, through incompetence or something more sinister, have delayed breakthrough medications and cures for years even decades. Prime example is Ustekinumab. Other examples are HuMax CD-20. The biggest breakthrough since the discovery of Penicillin is the discovery of a universal blood and immune stem cell formulation that allows any patient's immune system, no matter what HLA type, to accept these universal cells (Prochymal by Osiris). Prochymal should be in shot gun try it against everything trials for a hundred different autoimmune and blood disorders. That it is not, indicates complete lack of imagination on part of FDA and complete lack of understanding of the breakthroughs in stem cell technology that are here now.

Here is the article indicating the American public's complete distrust in the FDA:

U of Minnesota study finds confidence in food safety plunges in wake of peanut butter contamination

Fewer than one in four consumers now believe the US food supply is safer than it was a year ago

Fewer than one in four consumers now believe the U.S. food supply is safer than it was a year ago, according to new data from the University of Minnesota's Food Industry Center.

After January's national salmonella outbreak, just 22.5 percent of consumers in the study said they were confident the food supply is safer than a year ago, the lowest reading since the study began in May 2008. Eight people died and more than 500 have become ill in the most recent outbreak, which may have originated in a Georgia peanut plant and spread through peanut-butter products sold nationwide.

The drop in confidence mirrors a similar drop last June, when a salmonella outbreak later traced to jalapeno peppers sickened nearly 1,500 people. The study involves continuously tracking consumer confidence in food supply safety via a weekly online survey of about 175 consumers from across the nation. The consumers are selected each week by a national market research company.

Several measures are being collected on an ongoing basis to monitor consumer concerns, expectations and perceptions of the safety of the food supply from natural/accidental contamination, and the defense of the food supply from deliberate contamination from an act of terrorism. These measures soon will be used to develop a composite food confidence indicator similar to the Consumer Sentiment Index that measures overall consumer confidence.

The indicator is unique because of its continuous tracking feature, said Jean Kinsey, director of the Food Industry Center. Consumers' response to food-borne illnesses and recalls helps inform the design of food safety strategies and regulations, and consumer confidence "is critical to their peace of mind as well as to the economic health of the entire food industry."

The ongoing study is conducted jointly with the Louisiana State University AgCenter and is funded by the National Center for Food Protection and Defense.

FDA delays another breakthrough--increased "workload" extends review

2009-02-21T22:07:00.000-08:00

The lazy FDA bureaucrats have again delayed a new drug for which there is NO alternative on the market today. They say they have "an increased workload" so they have to "extend the review." Poor babies. Sick Americans suffer while FDA bureaucrats take two hour lunches. It is now FIFTY YEARS since the drug was discovered. Let's hear for the heroes at the FDA.

Here is the article:

Hemispherx plays the FDA waiting game
February 20, 2009 — 12:17pm ET By Calisha Myers
http://www.fiercebiotech.com/story/hermiphex-continues-play-waiting-game/2009-02-20

Hemispherx Biopharma says the FDA, citing an increased workload, has extended its review for Ampligen for the treatment of chronic fatigue syndrome. No drug candidate has received FDA approval for the treatment of chronic fatigue syndrome, but supporters remain confident in the drug's potential.

Kim McCleary, president and CEO of the Chronic Fatigue and Immune Dysfunction Syndrome Association of America, tells the Philadelphia Business Journal that the group remains optimistic that the FDA will find Hemispherx's data sufficient for an approval. "If it is approved, it is expected to be quite expensive," McCleary said. "[Ampligen] has shown to be effective in certain subsets of the condition... If they get an approval, we think other companies will follow them in and it will lead to more research."

It has taken Hemispherx some time to get to this stage. The company began as HEM--a Maryland-based contract services company that primarily provided research services for the NIH and NASA. It was reorganized into a drug development company in the 1980s. Since then, the company has fired and rehired its CEO (who co-invented Ampligen), battled with a Wall Street shortseller after going public and avoided an alleged hostile takeover, the Business Journal reports.

The original compound for Ampligen was discovered at Merck in the 1960s. The drug candidate Ampligen has has been under development for over three decades and has been studied as a treatment for a range of diseases, including AIDS, cancer and the avian flu.
As of September 30, Hemispherx had an accumulated deficit of $182.5 million, according to its latest SEC report.