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Archive for November, 2006

Painkillers May Threaten Power Of Vaccines

Posted by tumicrobiology on November 29, 2006

With flu-shot season in full swing and widespread anticipation of the HPV vaccine to prevent cervical cancer, a new University of Rochester study suggests that using common painkillers around the time of vaccination might not be a good idea
Researchers showed that certain nonsteroidal anti-inflammatory drugs (NSAIDs), also known as cyclooxygenase inhibitors, react with the immune system in such a way that might reduce the effectiveness of vaccines.

The research has widespread implications: study authors report that an estimated 50 to 70 percent of Americans use NSAIDs for relief from pain and inflammation, even though NSAIDs blunt the body’s natural response to infection and may prolong it.

“For years we have known that elderly people are poor responders to the influenza vaccine and vaccines in general,” said principal investigator Richard P. Phipps, Ph.D., a professor of Environmental Medicine, and of Microbiology and Immunology, Oncology and Pediatrics. “And we also know that elderly people tend to be heavy users of inhibitors of cyclooxygenase such as Advil, aspirin, or Celebrex. This study could help explain the immune response problem.”

The study is available online in the Dec. 1, 2006, Journal of Immunology, and was funded in part by the National Institutes of Health.

When a person is vaccinated, the goal is to produce as many antibodies as possible to effectively neutralize the infection. To do this, white blood cells called B-lymphocytes, or B cells, spring into action to produce those antibodies. B cells also serve as the immune system’s memory for future protection against the illness.

But Phipps and colleagues discovered that human B cells also highly express the cyclooxygenase-2 (cox-2) enzyme, which is not intrinsically bad unless it is overproduced, causing pain and fever. So, when a person takes a drug to block the cox-2 enzyme — and thereby reduce pain and fever — the drug also reduces the ability of B cells to make antibodies.

“The next step is to figure out the worst time to take drugs that inhibit cox-2 in the context of getting vaccinated. Is it the day before, the day of, or the day after” The timing is likely to be very important,” Phipps said. “But meanwhile, we believe that when you reach for the medicine cabinet to reduce pain at the injection site, that is probably the wrong thing to do.”

The findings are based on laboratory studies of blood samples from people who participated in early clinical trials for the HPV vaccine, and on studies of mice.

For the animal portion of the study, researchers vaccinated normal mice and mice engineered to be cox-2 deficient with a component form of the HPV vaccine. They analyzed the amount of antibodies the animals produced, focusing on the critical virus-neutralizing antibodies. The cox-2 deficient mice made 50 to 70 percent less of these key antibodies.

The same experiment was done on preserved blood samples from people who had been vaccinated against HPV-16, the strain linked to cervical cancer. Scientists reactivated the B cells in the blood samples and watched them churn out antibodies, as expected. But when researchers treated the B cells with a cox-2 inhibiting drug, the cells significantly diminished their production of antibodies — showing that cox-2 is essential for an optimal immune response against HPV 16.

This study is not questioning the effectiveness of the newly marketed HPV vaccine, the Rochester scientists said. They pointed out that in many clinical trials involving thousands of women, the vaccine offered complete protection against the development of cervical cancer. And presumably some of these women were taking NSAIDs at the time.

“There’s no doubt the HPV vaccine showed 100 percent efficacy. Still, our data does suggest that it might be wise to limit the use of NSAIDs when you receive any vaccine,” said co-author Robert Rose, Ph.D., associate professor of Medicine and Microbiology and Immunology at the University of Rochester, and one of the virologists whose work led to the development of the new cancer vaccine.

Scientists do not completely understand the mechanism by which cox-2 influences the immune response in humans. They do believe the response may depend upon the dose and frequency of NSAID use.

The negative effects of blocking cox-2 could be more pronounced in people with compromised immune systems, such as AIDS or cancer patients, the study noted. Moreover, if a vaccine is in short supply and needs to be given in lower-than-optimal doses, taking an NSAID could hamper the immune response even more.

In addition to Phipps and Rose, graduate student Elizabeth Ryan was a co-author on the study, with assistance from students Matt Bernard and Christine Malboef.

Source: University of Rochester Medical Center

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Causes Of Global Death And Disease In The Next 25 Years

Posted by tumicrobiology on November 29, 2006

In 1993, the World Bank sponsored the 1990 Global Burden of Disease study carried out by researchers at Harvard University and the World Health Organization (WHO). This study provided the first comprehensive global estimates of death and illness by age, sex, and region. It also provided projections of the global burden of disease and mortality up to 2020. The study and its projections have been crucial in national and international health policy planning. Colin Mathers and Dejan Locar (from the World Health Organization, Geneva) have now updated the projections based on 2002 data on mortality and burden of disease and published their results in the international open-access journal PLoS Medicine.

As for the earlier report, the researchers used projections of socio-economic development to model future patterns of mortality and illness for three different scenarios: a baseline scenario, a pessimistic scenario that assumes a slower rate of socio-economic development, and an optimistic scenario that assumes a faster rate of growth.

They predict that between 2002 and 2030 under all three scenarios life expectancy will increase around the world, fewer children under the age of 5 years will die, and the proportion of people dying from non-communicable diseases such as heart disease and cancer will increase. Although deaths from infectious diseases will decrease overall, HIV/AIDS deaths will continue to increase. Despite this increase, 50% more people are predicted to die of tobacco-related disease than of HIV/AIDS in 2015. By 2030, the three leading causes of illness will be HIV/AIDS, depression, and ischemic heart disease in the baseline and pessimistic scenarios. In the optimistic scenario, road-traffic accidents (which increase with socioeconomic development) will replace heart disease as the number 3 killer.

In an accompanying editorial, the PLoS Medicine editors ask whether they are publishing “the right stuff”, i.e. research and commentary whose goal it is to reduce mortality and suffering from the most relevant conditions–and whether research funding and health expenditure are consistent with these results.

Citation: Mathers CD, Loncar D (2006) Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med 3(11): e442. (http://dx.doi.org/10.1371/journal.pmed.0030442)

Source: Public Library of Science

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Mass Extinction 250 Million Years Ago Sparked Dramatic Shift To Complex Marine Ecosystems

Posted by tumicrobiology on November 29, 2006

The earth experienced its biggest mass extinction about 250 million years ago, an event that wiped out an estimated 95% of marine species and 70% of land species. New research shows that this mass extinction did more than eliminate species: it fundamentally changed the basic ecology of the world’s oceans.

Ecologically simple marine communities were largely displaced by complex communities. Furthermore, this apparently abrupt shift set a new pattern that has continued ever since. It reflects the current dominance of higher-metabolism, mobile organisms (such as snails, clams and crabs) that actually go out and find their own food and the decreased diversity of older groups of low-metabolism, stationary organisms (such as lamp shells and sea lilies) that filter nutrients from the water.

So says research published in Science on November 24, 2006. An accompanying article suggests that this striking change escaped detection until now because previous research relied on single numbers–such as the number of species alive at one particular time or the distribution of species in a local community–to track the diversity of marine life. In the new research, however, scientists examined the relative abundance of marine life forms in communities over the past 540 million years.

One reason they were able to do this is because they tapped the new Paleobiology Database (http://www.pbdb.org), a huge repository of fossil occurrence data. The result is the first broad objective measurement of changes in the complexity of marine ecology over the Phanerozoic.

“We were able to combine a huge data set with new quantitative analyses,” says Peter J. Wagner, Associate Curator of Fossil Invertebrates at The Field Museum and lead author of the study. “We think these are the first analyses of this type at this large scale. They show that the end-Permian mass extinction permanently altered not just taxonomic diversity but also the prevailing marine ecosystem structure.”

Specifically, the data and analyses concern models of relative abundance found in fossil communities throughout the Phanerozoic. The ecological implications are striking. Simple marine ecosystems suggest that bottom-dwelling organisms partitioned their resources similarly. Complex marine ecosystems suggest that interactions among different species, as well as a greater variety of ways of life, affected abundance distributions. Prior to the end-Permian mass extinction, both types of marine ecosystems (complex and simple) were equally common. After the mass extinction, however, the complex communities outnumbered the simple communities nearly 3:1.

The other authors are Scott Lidgard, Associate Curator of Fossil Invertebrates at The Field Museum, and Matthew A. Kosnik, from the School of Marine and Tropical Biology at the James Cook University in Townsville, Queensland, Australia.

“Tracing how marine communities became more complex over hundreds of millions of years is important because it shows us that there was not an inexorable trend towards modern ecosystems,” Wagner said. “If not for this one enormous extinction event at the end of the Permian, then marine ecosystems today might still be like they were 250 million years ago.”

These results also might provide a wake-up call, Wagner added: “Studies by modern marine ecologists suggest that humans are reducing certain marine ecosystems to something reminiscent of 550 million years ago, prior to the explosion of animal diversity. The asteroid that wiped out the dinosaurs couldn’t manage that.”

Lidgard added, “When Pete walked into my office with his preliminary results, I simply couldn’t believe them. Paleontologists had long recognized that ecosystems had become more complex, from the origin of single-celled bacteria to the present day. But we had little idea of just how profoundly this one mass extinction–but not the others like it–changed the marine world.”

Source: Field Museum

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Evolution Of Typhoid Bacteria: Researchers Warn Of Increased Spread Of Resistant Strains

Posted by tumicrobiology on November 29, 2006

In a study published in the latest issue of Science (24 November, 2006), an international consortium from the Max-Planck Society, Wellcome Trust Institutes in Britain and Vietnam, and the Institut Pasteur in France have elucidated the evolutionary history of Salmonella Typhi. Typhi is the cause of typhoid fever, a disease that sickens 21 million people and kills 200,000 worldwide every year. The results indicate that asymptomatic carriers played an essential role in the evolution and global transmission of Typhi. The rediscovered importance of the carrier state predicts that treatment of acute disease, including vaccination, will not suffice to eradicate this malady. The results also illuminate patterns leading to antibiotic resistance after the indiscriminate use of antibiotics. Fluoroquinolone treatment in southern Asia over two decades has resulted in the emergence of multiple, independent nalidixic acid-resistant mutants, of which one group, H58, has multiplied dramatically and spread globally. The prevalence of these bacteria hampers medical cure of clinical disease via antibiotics.

Typhoid fever remains a major health problem in the developing world and continues to cause disease in Europe and on the american continent. The evolutionary history and population structure of Typhi were poorly understood, partly because these bacteria show little genetic diversity. Now a team led by Mark Achtman and Philippe Roumagnac from the Max Planck Institute for Infection Biology, Berlin, has applied population genetic experience from prior work with Yersinia pestis, Escherichia coli, Helicobacter pylori and Neisseria meningitidis to provide novel insights into the evolution of this pathogen. The team combined its resources to assemble for the first time a globally representative collection of 105 strains of Typhi and investigated the sequence diversity within 90,000 base pairs per strain. Eighty-eight informative sequence differences were detected, showing that the population structure has evolved over the last 10,000 to 43,000 years. Amazingly, the ancestral strain continues to exist today, as do many of its direct descendents, indicating a neutral population structure, whereas normally selective forces lead to extinction of intermediate genotypes. Furthermore, these bacteria are distributed globally, demonstrating that Typhi has spread inter-continentally on multiple occasions.

The authors propose that the unusual population structure of Typhi reflects long-term carriage by asymptomatic carriers, who reached public notoriety at the beginning of the 20th century with “Mr. N the milker” in England and Typhoid Mary (Mary Mallon) in the U.S.A. These individuals infected 100s of people over the decades while they worked in the food production industry. Healthy carriers may have allowed Typhi to survive in hunter-gatherer populations prior to the Neolithic expansion of city states and facilitated its intercontinental spread. Healthy carriers are also consistent with the observation that individual genotypes of Typhi persist for many decades within each country.

Increasing resistance to antibiotics in recent decades has hampered efforts of clinicians to cure typhoid fever. The indiscriminate use of fluoroquinolones, which is a cost-effective, standard treatment for typhoid fever, has been accompanied by a frightening increase in the numbers of resistant Typhi. Investigations of a large strain collection from southern Asia revealed that many different genotypes independently acquired resistance to nalidixic acid, a quinolone. One of these genotypes, H58, has become predominant throughout southern Asia and has even spread to Africa. In Vietnam, up to 95% of Typhi are now resistant to nalidixic acid and many other antibiotics. Although these cases can still be treated with newer antibiotics, those antibiotics are much more expensive than standard fluoroquinolones, which raises the cost of medical treatment. Furthermore, it is likely that Typhi will develop resistance to these antibiotics as well.

The combination of these investigations raises problems for public health measures. Indiscriminate antibiotic usage results in real-time evolution of bacteria that resist treatment. Furthermore, the healthy carrier state provides a safe reservoir for these bacteria which allows them to evade short-term antibiotic treatment and vaccination, indicating that typhoid fever will remain a major health problem for the foreseeable future.

The research was carried out collaboratively by the Max Planck Institute for Infection Biology in Berlin, the Wellcome Trust Sanger Institute, Hinxton Hall, the Institut Pasteur, Paris, and the Oxford University Clinical Research Unit, Ho Chi Minh City, with assistance from hospitals in Ho Chi Minh City and Hanoi and the International Vaccine Institute in Seoul. Financial support was by the Wellcome Trust, UK.

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Nepal Microbiology Discussion Forum (NMDF)

Posted by tumicrobiology on November 22, 2006

Now from TUMDF we have been NMDF. You will get a lot of things from us. Just wait.

Posted in Gaffer's | 38 Comments »

Scientists Explore Function Of ‘Junk DNA’

Posted by tumicrobiology on November 22, 2006

University of Iowa scientists have made a discovery that broadens understanding of a rapidly developing area of biology known as functional genomics and sheds more light on the mysterious, so-called “junk DNA” that makes up the majority of the human genome.

The team, led by Beverly Davidson, Ph.D., a Roy J. Carver Biomedical Research Chair in Internal Medicine and UI professor of internal medicine, physiology and biophysics, and neurology, have discovered a new mechanism for the expression of microRNAs — short segments of RNA that do not give rise to a protein, but do play a role in regulating protein production. In their study, Davidson and colleagues not only discovered that microRNAs could be expressed in a different way than previously known, they also found that some of the junk DNA is not junk at all, but instead consists of sequences that can generate microRNAs.

Davidson and her colleagues, including Glen Borchert, a graduate student in her lab, investigated how a set of microRNAs in the human genome is turned on, or expressed. In contrast to original assertions, they discovered that the molecular machinery used to express these microRNAs is different than that used to express RNA that encodes proteins. Expression of the microRNAs required an enzyme called RNA Polymerase III (Pol III) rather than the RNA Polymerase II (Pol II), which mediates expression of RNA that encode proteins. The study is published in Nature Structural and Molecular Biology Advance Online Publication (AOP) on Nov. 12.

“MicroRNAs are being shown to play roles in cancer and in normal development, so learning how these microRNAs are expressed may give us insight into these critical biological processes,” said Borchert, who is lead author of the study. “Up to now it’s been understood that one enzyme controls their expression, and we now show that in some cases it’s a completely different one.”

Genes that code for proteins make up only a tiny fraction of the human genome. The function of the remaining non-coding sequence is just beginning to be unraveled. In fact, until very recently, much of the non-coding sequence was dismissed as junk DNA. In 1998, scientists discovered that some DNA produced small pieces of non-coding RNA that could turn off, or silence, genes. This discovery won Andrew Fire and Craig Mello the 2006 Nobel Prize for medicine or physiology. Since their discovery, the field has exploded and small, non-coding RNAs have been shown to play an important role in development and disease in ways that scientists are only just beginning to understand.

“Not so many years ago our understanding was that DNA was transcribed to RNA, which was then translated to protein. Now we know that the levels of control are much more varied and that many RNAs don’t make protein, but instead regulate the expression of proteins,” Davidson explained. “Non-coding RNA like microRNAs represent a set of refined control switches, and understanding how microRNAs work and how they are themselves controlled is likely to be very important in many areas of biology and medicine.”

Over 450 microRNAs have been identified in the human genome. Learning how they are turned on and in what cells and what they do, may allow scientists to turn that knowledge to their advantage as a medical tool.

In addition to Davidson and Borchert, William Lanier, a graduate student in the UI Department of Biological Sciences, was also part of the research team. The study was funded in part by the National Institutes of Health.

Source: University of Iowa
Date: November 21, 2006

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