Sunday, March 22, 2015
This morning he laid on the grass on his side resting his head on hand, elbow in the grass reading the Sunday morning comics. What's so special about that? For a decade his back and neck have been frozen in place. He had to sit in a special straight back chair or lie in bed as his only two "activity" centers. He was comfortable no other places. Our family room TV had to be placed at a precise height and angle so he could see it. he could no more twist his head/neck to read comics or lie down in the grass than he could fly to the moon.
He can stand in one place for up to 10 or 20 seconds. He runs again instead of a slow pain filled walk. His inflamed lungs are completely normal. He no longer has to worry about odors spasming them shut. In fact he has had NO ASTHMA since he started Otezla. He can sing again. He can talk freely and at length. For a year and a half, he was without a voice due to inflammation in the tendons of his voice box and lungs. He can whistle again! Last week he whistled along in perfect synchrony to the Andy Griffith theme song he heard on one of those old time TV channels.
He is still disabled. He tires easily. His voice volume is not completely normal. He has more flatulence than before Otezla and he did have nausea for the first couple of weeks after taking the pill in morning and evening. BUT he did NOT lose weight. He actually gained weight and now some muscle mass which for his is good. He has been rail thin for a decade. He was never anything like overweight but within a year or so of the first diagnosis, his once athletic 20 year old body melted away to war orphan thinness, so losing weight on Otezla had been a concern.
Previous to Otezla my son had tried every TNF alpha inhibitor, Enbrel, Humira, Simponi, Remicade, Cimzia. Enbrel reversed his symptoms for a two or three months before it stopped working.
High dose Remicade (seven vials for 120 lb body) infusions every six weeks worked to reverse his symptoms and was the previous best medicine for him. Its effects and benefits continued for about six years before this biologic finally failed him. He took the DMARDS, Imuran and sulfaslazine with the Remicade to help control symptoms and to help prevent neutralizing antibody formation (perhaps why Remicade retained efficacy for those six years). During the infusions he was given solumedrol and tylenol as a preventatives for possible scary adverse reactions. To obtain the infusion he was forced to sit in a cancer clinic for three to four hours while the Remicade slowly dripped into his vains. Then he was on a roller coaster of better and worse symptoms. After the infusion he was good to great for a few weeks until in the last two weeks before the next infusion the pain and symptoms started to return. Our family had to plan any outing for the week or two after infusion.
With Otezla, he takes PILLS. Two per day--12 hours apart. There are no more trips to the cancer clinic. No infusion with risk of site infections or site reactions. No medication he has used so far has been so easy. A pill is what we were all hoping for. That is what we now have.
Otezla's mode of action is to block an enzyme, PDE4, that degrades a "good guy" molecule called cAMP which lowers inflammation cytokines including IL-23( a real bad guy for psoriasis). The more cAMP in our bodies the better for reducing autoimmune symptoms.
After reading about Otezla side effects on line, I expected not much from this medication except a lot of nausea, possible depression etc for a medication that was supposed to be not so effective. Our only hope was that it would be a bridge to get him our son to the time when the FDA finally approved the new anti IL17. But we were desperate. My son's Remicade failed last Spring. His pain, his inflammed lungs, his neck and back were all quickly getting worse. We tried Cimzia in the summer. Not much help. It stopped working at all by late August. By mid September I was in a state of fear again for my son. Without an effective treatment for the inflamation, he not only is in severe constant pain "in his bones" and joints but worse he cannot breathe. He simply cannot pull air into lungs. Within a day or two of starting, his rapid decline stopped--period. No other medication had worked so quickly. Within two or three weeks his symptoms had declined to a point that it took two years for Remicade infusions to match. He has continued to get better and better.
For us Otezla is a true medical miracle. it made not work as well for you or your loved one but it is certainly worth a try.
NOTE 1: Remicade infusions cost our insurance company nearly 70K a year. Otezla is 24K a year. My son was able to stop using Imuran completely--talk about side effects check out Imuran! He still takes sulfasalazine with the Otezla.
NOTE 2: My wife who was diagnosed with PsA last year has not been able to take Otezla yet. Her current insurance company requires her to fail at DMARDS, Enbrel and Humira first. So far DMARDS sulfasalzine (red eyes, exhaustion) and methotrexate (moderate help) have failed to stop her downward spriral. Enbrel only helps but has not reversed her symptoms like Otezla did for my son. This weeks she starts Humira--which did absolutely nothing for our son. She has now been through a year and a half of worsening symptoms and pain, she needed a cane for many months, thanks to Congress allowing insurance companies to force patients to suffer through all cheaper alternatives before insurance fat cats allow patients access to effective meds.
Saturday, June 5, 2010
Suffering human are a "scarce social resource" that must not be jeopardized by allowing clinical trial access to all
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.
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
Tuesday, May 18, 2010
New evidence that incompetent T regs are a root cause of asthma perhaps allergy and autoimmune as well
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.
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]
Monday, May 17, 2010
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
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
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.
Saturday, May 15, 2010
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
But now, a team of researchers, at Genentech Inc.,
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.
Friday, March 26, 2010
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:
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
Tuesday, February 9, 2010
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:
Tuesday, January 12, 2010
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.
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:
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]
Monday, January 4, 2010
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:
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.
Thursday, December 31, 2009
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
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:
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.
Stanford University Medical Center
Wednesday, December 30, 2009
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:
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.”
Monday, December 28, 2009
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.
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