Nanorokotteen on havaittu pysäyttävän autoimmuuniprosessit diabetesta sairastavilla hiirillä. Rokote vahvistaa immuunipuolustuksesta huolehtivien "heikkojen T-solujen" toimintaa.
Counterintuitive Cure: A Nanovaccine That Stops Autoimmune Disease by Boosting the Immune System
http://www.scientificamerican.com/artic ... ne-disease
by Katie Moisse
The human body's immune system can quickly track down and kill cells that don't belong. Take certain kinds of bacteria: molecules on their surfaces flag them as foreign invaders, alerting the body's defenders to the breach and drawing a full-fledged attack on anything waving that molecular flag. But sometimes the system mistakenly attacks the body's own cells. The result is autoimmune disease, such as type 1 diabetes, in which the insulin-producing beta cells of the pancreas are attacked and destroyed by T cells.
Scientists have struggled to find ways to treat autoimmune disease without compromising overall immunity. Therapies that suppress the immune system carry the risk of letting infections and even tumors go unchecked. But researchers in Canada have found a way to prevent type 1 diabetes in mice by doing just the opposite?vaccinating to boost the immune system.
The approach, published April 8 in Immunity, exploits the immune system's built-in safety mechanism?a group of regulatory T cells whose job is to squelch overactive immune responses.
"Essentially, there is an internal tug-of-war between aggressive T cells that want to cause [an autoimmune response] and weaker T cells that want to stop it from occurring," says study senior author Pere Santamaria from the Julia McFarlane Diabetes Research Center at the University of Calgary in Alberta. Although they have seemingly opposite effects, these different classes of T cells are "musicians in the same orchestra," Santamaria explains. And they take directions from the same conductor?the antigen-presenting cell (APC).
APCs are specialized white blood cells that grab tiny bits of protein off the surfaces of other cells (like invaders or, in the case of diabetes, beta cells), chop them into pieces (antigens) and present them to T cells to instigate the immune response. "T cells have to be fed," Santamaria says. "If there is no antigen-presenting cell, there is no immune response."
When the aggressive, autoimmune disease-causing T cells are presented with antigens from dying beta cells, they keep attacking and killing the beta cells. But when the weak T cells that want to stop the disease are presented with those same antigens, they kill the APC. "A single weak T cell can blunt the problem by killing the orchestra leader," Santamaria says. And unlike aggressive T cells that die shortly after killing their targets, weak T cells proliferate. "They become long-living cells that attempt to regulate the disease," Santamaria says.
Santamaria designed a "vaccine" to boost the activity of the weak T cells. He used nanoparticles?spheres thousands of times smaller than a single cell?that were coated with beta cell antigens. In doing so, he created an APC doppelganger that could repeatedly activate the weak T cells, causing them to proliferate and kill the real APCs. The nanoparticles shield the antigens from degradation, meaning they stay in the system much longer, so they can be delivered at fewer intervals and at lower doses.
The nanovaccine prevented diabetes in a prediabetic mouse model and restored normal blood sugar levels in diabetic mice. Santamaria hopes to translate his exciting finding into human clinical trials. "We know what we want the compound to look like for use in humans?it's not a pie in the sky," he says. "But launching a clinical trial is not a trivial task. It requires that we do our homework properly."
Over 23 million people in the U.S. have diabetes, according to the most recent report jointly produced by the U.S. Centers for Disease Control, the National Institutes of Health (NIH) and the American Diabetes Association, although only 5 to 10 percent of those cases are thought to be autoimmune (type 1 diabetes). Type 1 diabetics have to carefully monitor their blood glucose levels and routinely administer insulin to keep them down. They have a heightened risk for kidney failure, heart and eye problems, and nerve disease.
Autoimmune disease affects up to 23.5 million Americans, according to the NIH, and it is one of the top 10 leading causes of death in female children and women in all age groups up to 64 years. Santamaria plans to test his approach in models of other autoimmune diseases, such as multiple sclerosis and rheumatoid arthritis. "We're trying to extend this paradigm to see if it applies to other autoimmune disorders, as well. We think it will but that remains to be seen. That?s our hope and dream."
The Scientist: Gut bacteria are what we eat - The Scientist - Magazine of the Life Sciences http://www.the-scientist.com/blog/displ ... z0kbntjTB2 Page 1 of 2
Gut microbes, which help humans degrade otherwise indigestible plant material, acquire some crucial digestive enzyme genes from the bacteria in the food we eat, according to a study published this week in Nature. This new finding provides an example of horizontal gene transfer by which diet can influence the genetic diversity and functionality of the human gut microbiome.
"It's a fascinating story," said microbiologist Jeffrey Gordon of Washington University School of Medicine in St. Louis, who did not participate in the study. "It shows that there's a dimension to human evolution that's occurring at the level of our gut microbiome."
"This is an exciting development," agreed microbiologist Justin Sonnenburg of Stanford University School of Medicine, who also was not involved in the research. "I think we're at the tip of the iceberg here. Human diet is so diverse, I think that we're just getting an initial glimpse of what's likely to be really huge area of variation that differentiates populations of humans."
The human digestive tract harbors trillions of bacteria, many of which establish lifetime, symbiotic relationships with their hosts. The food we eat nourishes our gut flora, and those bacteria feed us with the products and byproducts of their own digestive activities. Consequently, the gut microbiome has evolved to encode a variety of digestive enzymes, for example, those that break down hard-to-digest polysaccharides in food plants, such as celery, broccoli, and other vegetables.
As a PhD student at the Station Biologique de Roscoff in France, biochemist and co-author on the Nature paper Jan-Hendrik Hehemann was interested in a different type of enzymes -- bacterial catalysts that break down polysaccharides in marine algae, which contain sulfates not found in typical food plants. Hehemann and his colleagues identified several genes that they suspected to code for those specialized enzymes in a recently sequenced marine bacteria genome and tested their activity on red algae extracts. Their results revealed that the enzymes encoded by two of the genes represent a whole new class of carbohydrate-digesting proteins, capable of degrading porphyrans -- a unique component of marine plant polysaccharides.
Mining the databases for other marine bacteria that might also contain these so-called porphyranases, Hehemann instead stumbled upon a gut bacterium found in human populations inhabiting Japan (but not North America). The similarities between the genomes of the two bacteria suggested that gut microbe had somehow obtained those genes directly from the marine species. "I was really blown away by this result," he recalled.
Japanese people regularly consume sushi wrapped in seaweed, which carries with it marine bacteria that produce porphyranases. "It was directly obvious for us that this was horizontal gene transfer from the ocean to the Japanese gut," Hehemann said. "As far as I know, there has not before been an example of horizontal gene transfer between different ecosystems."
In a commentary accompanying the study, Sonnenburg compared the gene transfer event to giving human gut bacteria a "new set of utensils" -- likely providing them the ability to digest specific foods prevalent in different regional diets. "I think there's a good bet that you'll see diet match microbiota functionality over and over and over again," he said. "That's exactly what we see in this study."
But the food purification and sterilization techniques commonly used throughout the industrialized world might affect the environmental tuning of the human gut biome function suggested by the study, Sonnenburg added. Removing many harmful bacteria from foods has dramatically reduced food-borne diseases in recent decades, he said, "but I think there's a likely cost -- the loss of microbes that are not harmful." Such microbes may transfer seemingly beneficial genes to the gut biome, increasing its ability to adapt to changes in diet, as well as fine-tune the immune system, such that "if you begin to eradicate microbes with which we have coevolved, that has the potential [to disrupt] homeostasis," Sonnenburg said.
"It shows how we rely on biodiversity that is surrounding us," Hehemann agreed. "Maybe that's the natural way -- that there is a frequent update of our gut microbiome [through] gene transfer to increase gene diversity. Obviously when we eat these highly processed foods, that's not going to happen."
How exactly this gene transfer helps the host, however, is still unclear, said Hehemann, who is currently looking into the benefits porphyranase genes provide gut bacteria in his new lab at the University of Victoria in British Columbia, Canada. It's possible that when the bacteria break down marine algae polysaccharides, it benefits the host through the production of short chain fatty acids, the end product of bacterial metabolism, which can be taken up by the host in the form of calories, Sonnenburg said. "Those are calories that, in the absence of this capability, go totally unrealized."
Antipsychotic Drugs May Boost Pneumonia Risk in Elderly Outpatients
April 6, 2010 ? Older individuals residing in the community who are taking antipsychotic drugs appear to be at increased risk for community-acquired pneumonia, new research suggests.
The data are drawn from a nested case-control study of elderly outpatients who were new users of antipsychotic drugs and under the care of a primary care physician.
The study found that the association between psychotic drug use and community-acquired pneumonia was dose dependent and occurred with both atypical and typical antipsychotics. Also, the risk appeared to be most pronounced during the first week of treatment.
"We believe that clinicians should carefully monitor elderly patients who are starting treatment with atypical and typical antipsychotics because of the potential risk of community-acquired pneumonia, and monitoring is especially important during the first week of treatment and when a high dose is prescribed," Gianluca Trifiro, MD, PhD, assistant professor of medical informatics at Erasmus University Medical Center, Rotterdam, the Netherlands, told Medscape Psychiatry.
Physicians need to pay close attention to the first signs and symptoms of pneumonia, such as dyspnea and fever, and consider stopping antipsychotic treatment if these symptoms develop, he added.
"I am not saying that antipsychotics should not be prescribed to older patients but rather that clinicians should rigorously assess the benefit-risk profile of these medications when treating older patients, particularly those who are home-bound," he said. "Indeed, in these patients, the risk of community-acquired infection may be higher."
An antihistaminergic hypothesis provides the most likely explanation for the development of antipsychotic-induced pneumonia, Dr. Trifiro speculated.
"We noticed that those antipsychotics with the highest affinity to H1-histaminergic receptor (atypicals and phenothiazines) are associated with a higher risk of pneumonia than those with a lower affinity to this receptor (butyrophenones)," he noted. "Sedation as a result of H1-histaminergic receptor blocking in the central nervous system is a well-known cause of swallowing problems, which could facilitate aspiration pneumonia."
The study, by a team from the Netherlands, Italy, and Spain, was published in the April 5 issue of the Annals of Internal Medicine.
Puzzling Mortality Increase in Older Patients
Both atypical and typical antipsychotic drugs are frequently used to treat psychiatric disorders in older patients, including dementia. Both types are approved by the Food and Drug Administration (FDA) for the treatment of bipolar disorder, mania, and schizophrenia.
Although antipsychotic drugs have not been approved for use in patients with dementia or dementia-related psychosis in these settings, they are sometimes prescribed for these problems. Several recent studies have suggested that the use of antipsychotics can increase the risk for diabetes, stroke, pneumonia, and death in older patients with dementia. Pneumonia is often implicated as the primary cause for the mortality increase; however, epidemiologic data have been limited. Also, studies that have examined the risk for pneumonia have included primarily patients hospitalized for pneumonia.
Dr. Trifiro and his colleagues searched an electronic database that maintains medical records for more than 300 general practices in the Netherlands. Medical records in the Netherlands usually include patients' primary care visits, hospital admissions, and visits to outpatient clinics.
Cases in the study included community-dwelling patients 65 years or older who had received a first antipsychotic drug prescription between 1996 and 2006 and had a diagnosis of pneumonia. In most cases, the antipsychotic had been prescribed for the treatment of behavioral and psychological disorders of dementia or other acute psychoses. Only 5% of patients were taking an antipsychotic for schizophrenia.
Up to 20 control participants without pneumonia were matched to each case on the basis of age, sex, and date of onset.
The analysis included 258 case patients and 1686 control patients.
Compared with the past use of any antipsychotic drugs, current use of atypical (odds ratio [OR], 2.61; 95% confidence interval [CI], 1.48 ? 4.61) or typical (OR, 1.76; 95% CI, 1.22 ? 2.53) antipsychotic drugs was associated with a dose-dependent increased risk for pneumonia.
"I was surprised by the finding that typical antipsychotics did not confer a higher mortality risk than atypicals," Dr. Trifiro explained in an interview. "Based on the a priori hypothesis that typicals may induce aspiration pneumonia as a result of extrapyramidal adverse events such as akinesia, I would have expected a higher risk of pneumonia for typicals compared to atypicals, while there is no difference in risk between the 2 classes."
...I would have expected a higher risk of pneumonia for typicals compared to atypicals, while there is no difference in risk...
The study also found that the use of atypical antipsychotic drugs was associated with fatal pneumonia (OR, 5.97; 95% CI, 1.49 ? 23.98 ).
In their article, the study authors emphasized that because the study was conducted in an outpatient setting, the results do not necessarily apply to elderly patients with dementia who reside in other settings, such as a nursing home or long-term care facility.
Possible Role for COPD?
Asked for comment on these findings, D. P. Devanand, MD, chief of geriatric psychiatry at the New York State Psychiatric Institute and professor of clinical psychiatry and neurology at the College of Physicians and Surgeons at Columbia University in New York City, said they are in line with other data on this connection.
"While the finding of an increased rate of pneumonia, and increased mortality risk due to pneumonia, in elderly patients who are prescribed antipsychotics is consistent with other recent studies, antipsychotic medications are not known to directly affect the lungs and the mechanism underlying this association is not clear," Dr. Devanand told Medscape Psychiatry.
"In this study, patients who received antipsychotic medications were more likely to have prior chronic obstructive pulmonary disease (COPD), as well as heart failure and diabetes, compared to the group of patients who did not receive antipsychotic medications," he said. "Since COPD patients are at increased risk of developing pneumonia, it is possible that the increased rate of pneumonia was due to COPD and not necessarily due to the use of antipsychotic medications."
He emphasized that additional studies are needed to clarify the causes of increased rates of pneumonia in elderly patients treated with antipsychotic medications.
Antipsychotics in Geriatric Psychiatry
"Antipsychotic medications for older adults can be an extremely helpful treatment for those elderly with memory/cognitive problems (dementia, like Alzheimer's) who develop paranoia, sundowning (dementia-related insomnia), and agitation," John J. Wernert, MD, MHA, an adult and geriatric psychiatrist and chief medical officer at MDwise Inc in Indianapolis, Indiana, explained to Medscape Psychiatry in an emailed comment. Dr. Wernert was also not involved in the study.
"For many of these mild to moderately demented patients, these medications are the difference between staying at home (managed by family and in-home caregivers) and needing secure placement in a locked Alzheimer's unit or nursing facility," Dr. Wernert noted. "Families are often desperate to have the help these medicines provide so they can care for their loved ones at home."
Antipsychotic medications have beneficial effects but are also sedating, and any medication that has a sedating effect can increase the likelihood of lowering respiratory drive and predisposing the patient to pneumonia, he added. These common medicines include common cold remedies, urinary and bowel medicines, and heart medications. "Many elderly are on multiple medications, so can be at risk of cumulative effects," he added.
Readers should digest the information and conclusions with great care.
"The bottom line is that antipsychotics, like many therapeutic classes of FDA-approved medications, should be prescribed carefully by an experienced physician or practitioner," Dr. Wernert cautioned. "Unfortunately, there is frequently no specialist available, and antipsychotics are prescribed by nurses or family physicians. Combinations of medications and polypharmacy are common problems."
"Concluding that taking an antipsychotic alone will predispose an elderly patient to developing pneumonia is a dangerous and misguided conclusion of this study," he added. "Readers should digest the information and conclusions with great care."
Dr. Trifiro, Dr. Devanand, and Dr. Wernert have disclosed no relevant financial relationships.
Ann Intern Med. 2010;152:418-425.
Suom.huom. IDSA on aiemmin sanonut että borreliabakteeri on helposti hoidettavissa lyhyellä antibioottihoidolla.
http://www.cnn.com/2009/HEALTH/dailydos ... index.html
February 20, 2009
Gram-negative bacteria are drug-resistant superbugs to watch out for
* Gram-negative bacteria are extremely drug-resistant, increasingly seen
* These superbugs are nearly impossible to treat, say experts
* Infectious disease specialists compare gram-negative bacteria to MRSA
* Although not as dangerous or as prevalent as MRSA, gram-negative bacteria are a current threat that may become as big a health problem
A new crop of drug-resistant superbugs is in our midst, and experts believe that they could rival the deadly superbug MRSA.
A new report from the Infectious Diseases Society of America says these superbugs are creeping onto the radar in hospitals across the country, and our ability to fight them is next to none.
Questions and answers
Are these new superbugs poised to be the next MRSA?
Dr. Sanjay Gupta, CNN Chief Medical News Correspondent: They just may be, according to that new report by the Infectious Diseases Society of America, but we can't say that just yet. MRSA is still a much bigger problem.
First, let's define what these superbugs are. They're called "gram-negative" bacteria. They are extremely drug-resistant; they have long, complicated names like "acinetobacter baumanii" and "klebsiella pneumoniae." Two important issues related to these bacteria: They are increasingly cropping up in hospitals, and they are nearly impossible to treat. Dr. Gupta's Blog: Here's why you should be scared of superbugs
Is this related to the Brazilian model who recently died from a bacterial infection?
Gupta: Yes. A gram-negative bacterial infection killed Brazilian model Mariana Bridi da Costa last month. She had her hands and feet amputated and kidneys removed to try to stem the infection's spread before she died. Gram-negative bacteria are also responsible for a spate of infections among returning Iraq war vets.
We've talked a lot about MRSA -- methicillin-resistant Staphlyococcus aureus -- and the core issue there is that very few antibiotics can treat it. The biggest concern with gram-negative bacteria is, there are virtually no drugs to effectively treat them. One drug, Colistin, is the only option that sometimes works, but it is incredibly toxic -- can cause kidney damage.
So how do these infections spread?
Gupta: Gram-negative infections are spread almost exclusively in hospitals, whereas MRSA has escaped the hospital confines and can now be found in the community. But keep in mind that MRSA started in hospitals.
Doctors see gram-negative infections among patients who are already very ill. Might be babies in the NICU, very old patients, patients who've just had surgery, burn patients in the ICU, for example. Gram-negative bacteria can enter the body by way of catheters, IVs, ventilators or wounds.
How common are gram-negative infections?
Gupta: The exact number of gram-negative-related infections or deaths is hard to pin down, because these infections are not reported routinely to the CDC. But doctors we spoke with say that the numbers could one day rival MRSA numbers, and that's really raising eyebrows among infectious-disease experts.
If there are virtually no drugs to treat gram-negative bacteria, then what are the options to stem the spread of these infections?
Gupta: Hospitals have to practice infection control: handwashing between patients; patient families also washing hands. Sometimes isolating patients in a different room if they are found to have an infection. Like with MRSA, not overprescribing antibiotics; that's how these bacteria learn how to adapt and become less treatable. And finally, more research into treatment.
We spoke to Dr. Helene Boucher, director of the Infectious Diseases Fellowship Program at Tufts Medical Center and lead author for the Infectious Diseases Society of America report on gram-negative bacteria. Here are some notes:
CNN: Give us an overview.
Dr. Helene Boucher: The big reason that we wrote report at this time is to make a point and try to get some interest in a big problem that we're facing: infections due to gram-negative organisms. MRSA, which most everyone knows about now, is gram-positive. We know about MRSA, but there has been an increase in infections caused by gram-negative bacteria, and they are resistant to many, or sometimes all, drugs. Another point: There has been a decrease in investment in antibiotics to treat these infections, for which we have limited or no treatment options. There is no antibiotic drug in Phase II or beyond, in patients.
CNN: Where is this cropping up? Mostly in hospitals?
Boucher: We see these infections a lot in hospital settings. Acinetobacter is seen in servicemen, Iraq war vets. Vets often have wound infections. There is difficulty with treating them, deformities that they leave. Some people at risk: ICU patients; very young or old patients; people with a lot of other health problems who are already immunocompromised. Some patients who have had a transplant, a burn or some other thing happen to them. We also worry about infection control problems. We saw this in Brooklyn. A lot of infections spread.
CNN: How does this spread in hospitals? Same way as with MRSA?
Boucher: All infections are thus far in hospitals. Most commonly, it spreads from not washing hands when going between patients. We really emphasize hand hygiene. Sometimes doctors call for private rooms for patients who are infected.
CNN: Do you fear that this will become another MRSA? Or worse?
Boucher: It has borne out in Brooklyn, infection gone from rehab centers to nursing homes to hospitals. Patients move around faster: They go to rehab, go home, go to the dialysis center, etc. That's a lot to worry about, where these bugs tend to be moving. The concern is, this could be as bad as, if not worse than, MRSA. At least with MRSA, we have some drugs to treat it.
CNN: What would it take for this to become more like MRSA, to spread into the community?
Boucher: That's a hard question. It takes a bug being strong enough over time. It takes some change that makes it more transmissible. It takes a breakdown in infection control: not washing hands, not paying attention, etc. This bug gets a little "better" over time. With MRSA, it took football players who took whirlpools in same tub, sharing the same towels. Men having sex with men. If you put people factors and bug factors together, then you see the spread. It depends on how "fit" the bug is, how able it is to grow and replicate when gets resistant to antibiotics.
A lot of people are trying to understand this. Some people -- John Bartlett at Johns Hopkins is one scientist -- have predicted a linear increase over time in these infections. We can predict that in several years, we will get a lot worse off. We can't predict whether or when it would end up being something we see in healthy adults, kids, etc.
One thing we have seen is a number of urinary tract infections in women caused by one of these bad bugs; the key is that the women have never been in the hospital, not gotten antibiotics.
CNN: Why haven't we heard about this much until now?
Boucher: Depends on whom you ask: We infectious disease experts have been talking about it. War victims have gotten some press, but this is not a sexy story. The is not always a community interest, unless there's a famous patient/victim, like the Brazilian model.
CNN: The "double membrane" makes it harder to fight these infections; why? Why are they so tough to fight?
Boucher: There are difficult challenges to developing drugs for gram-negative infections. These infections produce a lot of toxins that make people sick fast. Basically, these gram-negative infections make enzymes that chew up antibiotics. Some make enzymes that chew up penicillin or chew up other antibiotics. So you don't have to get an antibiotic that fights one enzyme but multiple enzymes.
Now, these gram-negatives have become resistant to carbapenems; these are the "smartest" antibiotics. It's not likely we're going to find one drug that overcomes every enzyme; it will be more likely a variety of approaches and drugs.
CNN: Are antibiotic drugs hard to get into a clinical study?
Boucher: It's definitely harder than getting drugs for diabetes or obesity, something you take your whole life. Also, there are regulatory hurdles for people trying to make antibiotics. We're trying to make paths more clear for developing new antibiotics. We hope that encourages investment back in this area.
[The National Institutes of Health] this week signaled interest in sponsoring some studies in this area. The NIH hasn't traditionally been into antibiotic development, so that's promising. Government agencies and industry are banding together to get this done. I see that as good news.
CNN: Is this a big public health problem now or on the horizon?
Boucher: This is a public health problem now. The problem is here and now. Doctors have had people in their hospital succumb to these infections. Maybe there is one, and sometimes no, option for treatment.
CNN: Bottom line?
Boucher: We at IDSA advocate a three-pronged strategy for fighting these gram negative infections:
1) Infection control: prevent people from getting an infection in first place.
2) Prudent use of antibiotics: not overusing antibiotics.
3) Developing new antibiotics: generating interest at NIH, CDC, private industry. Get all key stakeholders more involved with developing effective antibiotics to stem infections.
Reported by CNN Medical Producer Stephanie Smith.