The incidence of allergies in children has increased over the past few decades, especially in the West (Europe). In Sweden, 30 to 40 percent of children have some kind of allergy. A combination of environmental and lifestyle factors during pregnancy and early infancy are thought to be responsible for the sharp rise in allergic diseases.

“Psychosocial factors and the stress hormone cortisol are associated with allergic diseases,” says Dr Fredrik Stenius of the Department of Clinical Research and Education at Stockholm South General Hospital. “Our study found that children with low salivary cortisol levels as infants have a lower prevalence of allergies during the first two years of life, compared to other children.”

The team has previously described a link between a lower prevalence of allergies in school children and an anthroposophic lifestyle.

“And now we’ve found the same link in infants from families that follow anthroposophic lifestyles, and that they have relatively low levels of cortisol,” adds Dr Stenius, who earned his PhD earlier in the year with a thesis on the subject.

The researchers believe that factors related to stress regulation also influence the development of infant allergies and will now monitor the infants from the neonate period and into childhood.

Material adapted from Karolinska Institutet.

Reference / Abstract
Stenius F, Borres M, Bottai M, Lilja G, Lindblad F, Pershagen G, Scheynius A, Swartz J, Theorell T, Alm J. ‘Salivary cortisol levels and allergy in children: The ALADDIN birth cohort.’ Journal of Allergy and Clinical Immunology, epub ahead of print 27 aug 2011, paper issue 2011 Dec;128(6):1335-9.

Claudia Lucchinetti, MD

The new findings will guide researchers as they seek to further understand and treat the disease. The study was published in the December issue of the New England Journal of Medicine.

Researchers do not know precisely what causes MS, but it is thought to be an autoimmune disease in which the body’s immune system attacks and destroys its own myelin. This fatty substance surrounds and protects axons, nerve cell projections that carry information, and its damage slows down or blocks messages between the brain and body, leading to MS symptoms, which can include blindness, numbness, paralysis, and thinking and memory problems.

“Our study shows the cortex is involved early in MS and may even be the initial target of disease,” says Claudia F. Lucchinetti, M.D., co-lead author of the study and Mayo Clinic neurologist. “Inflammation in the cortex must be considered when investigating the causes and progression of MS”, she says.

Study authors say current therapeutic options may not even address issues associated with the cortex. Understanding how the cortex is involved, therefore, is critical to creating new therapies for MS. “Measures of cortical damage will enhance enormously the power of clinical trials to determine if new medications address tissue changes of MS in all regions of the brain,” says co-lead author Richard Ransohoff, M.D., a Cleveland Clinic neurologist.

These measures are important because disease accumulates in the cortex over time, and inflammation in the cortex is a sign the disease has progressed.

The research is distinct because it studied brain tissues from patients in the earliest stages of MS. “What’s unique about the study is, and the reason the National MS Society funded this international team of researchers, is that it offers a rare view of MS early in the disease,” says Timothy Coetzee, Ph.D., Chief Research Officer at the National Multiple Sclerosis Society. “Collaborative studies like this, that deepen our understanding of the sequence of nervous system-damaging events, should offer new opportunities for stopping MS disease progression and improving quality of life for people with MS.”

The findings support the understanding that MS is primarily a disease of inflammation, not neurodegeneration, as some studies have recently suggested. Co-lead authors Drs. Lucchinetti and Ransohoff conclude that it is “overwhelmingly likely” that MS is fundamentally an inflammatory disease, and not a neurodegenerative Alzheimer-like disease.

How They Did It
The research did not at first focus on the ‘outside-in’ question, says Dr. Lucchinetti. Instead, the team initially wondered what tissue changes in the cortex of MS patients gave rise to indicators of cortical damage. For the last several years, researchers knew from MRI studies that the cortex was damaged very early after onset of MS, and they knew from autopsy studies that the cortex was demyelinated, as was white matter. What researchers were unable to determine, until completion of the present study, was whether findings at autopsy (usually after 30 to 50 years of disease) accurately reflected the indicators of cortical damage from MRI images taken after only a few months of disease. In autopsy MS tissues, cortical lesions show demyelination, but without inflammation-raising the possibility that MS cortex degenerates due to intrinsic tissue defects. Such a process would not be treatable by current MS therapies and could not be explained by present concepts of the causes of MS.

Drs. Lucchinetti and Ransohoff determined to see if early-MS cortical lesions were, or were not, inflammatory. To do so, they studied the Mayo resource of white-matter biopsies taken largely from patients with suspected tumors, but eventually proving to have MS. About one-fourth of the biopsies also included tiny fragments of cortex, which formed the focus of study. The primary question was quickly answered: cortical demyelinating lesions of early-MS patients resembled those found at autopsy in every way but one — the early lesions were highly inflammatory. These findings were reassuring because they indicated that treatments targeting inflammation in the disease may ameliorate MS effects on both the cortex as well as the white matter.

While investigating the cortical changes in the biopsies, researchers were struck by the high frequency of cortical demyelinating lesions. Furthermore, in the white matter biopsies, which contained miniscule cortical fragments, about 20% showed inflammatory demyelination was contained entirely in the cortex.

Researchers also noted inflammation was present in the meninges, the protective membranes that cover the surface of the brain and demarcate the subarachnoid space. Meningeal inflammation and cortical demyelination were highly-associated. Looking at implications of their data, Drs. Lucchinetti and Ransohoff could weave together a proposed pathway for lesion initiation, along with known experimental data from MS animal models, and term this pathway the “outside-in” theory. The research findings also lend urgency to efforts to use MRI to “see” more deeply into the cortical lesions of MS, particularly given that cortical damage is an important correlate of progressive disability and cognitive dysfunction in MS.

This study was funded by the National MS Society’s MS Lesion Project, led by Dr. Lucchinetti, as well as the National Institutes of Health.

Other Mayo Clinic study authors include: Bogdan Popescu, M.D.; Reem Bunyan, M.D.; Shanu Roemer, M.D.; Joseph Parisi, M.D.; Bernd Scheithauer, M.D.; Caterina Giannini, M.D.; Stephen Weigand, M.S.; Jay Mandrekar, Ph.D.

Additional authors included Hans Lassmann, M.D. from the Center for Brain Research, Medical University of Vienna, Austria; Wolfgang Bruck, M.D. from the Department of Neuropathology, University Medical Center and Institute for MS Research in Gottingen, Germany; and Natalia Moll, M.D, Ph.D. from the Neuroinflammation Research Center and Department of Neurosciences Lerner Research Institute, Cleveland Clinic.

Material adapted from Mayo Clinic.

In a paper published in the journal PLoS One, the researchers tested their drug against 15 viruses, and found it was effective against all of them — including rhinoviruses that cause the common cold, H1N1 influenza, a stomach virus, a polio virus, dengue fever and several other types of hemorrhagic fever.

The drug works by targeting a type of RNA produced only in cells that have been infected by viruses. “In theory, it should work against all viruses,” says Todd Rider, a senior staff scientist in Lincoln Laboratory’s Chemical, Biological, and Nanoscale Technologies Group who invented the new technology.

Because the technology is so broad-spectrum, it could potentially also be used to combat outbreaks of new viruses, such as the 2003 SARS (severe acute respiratory syndrome) outbreak, Rider says.

Other members of the research team are Lincoln Lab staff members Scott Wick, Christina Zook, Tara Boettcher, Jennifer Pancoast and Benjamin Zusman.

Few antivirals available
Rider had the idea to try developing a broad-spectrum antiviral therapy about 11 years ago, after inventing CANARY (Cellular Analysis and Notification of Antigen Risks and Yields), a biosensor that can rapidly identify pathogens. “If you detect a pathogenic bacterium in the environment, there is probably an antibiotic that could be used to treat someone exposed to that, but I realized there are very few treatments out there for viruses,” he says.

There are a handful of drugs that combat specific viruses, such as the protease inhibitors used to control HIV infection, but these are relatively few in number and susceptible to viral resistance.

Rider drew inspiration for his therapeutic agents, dubbed DRACOs (Double-stranded RNA Activated Caspase Oligomerizers), from living cells’ own defense systems.

When viruses infect a cell, they take over its cellular machinery for their own purpose — that is, creating more copies of the virus. During this process, the viruses create long strings of double-stranded RNA (dsRNA), which is not found in human or other animal cells.

As part of their natural defenses against viral infection, human cells have proteins that latch onto dsRNA, setting off a cascade of reactions that prevents the virus from replicating itself. However, many viruses can outsmart that system by blocking one of the steps further down the cascade.

Rider had the idea to combine a dsRNA-binding protein with another protein that induces cells to undergo apoptosis (programmed cell suicide) — launched, for example, when a cell determines it is en route to becoming cancerous. Therefore, when one end of the DRACO binds to dsRNA, it signals the other end of the DRACO to initiate cell suicide.

The microscope images above show that DRACO successfully treats viral infections. In this set of four photos, dengue hemorrhagic fever virus kills untreated monkey cells (lower left), whereas DRACO has no toxicity in uninfected cells (upper right) and cures an infected cell population (lower right). (click to enlarge)

Each DRACO also includes a “delivery tag,” taken from naturally occurring proteins, that allows it to cross cell membranes and enter any human or animal cell. However, if no dsRNA is present, DRACO leaves the cell unharmed.

Most of the tests reported in this study were done in human and animal cells cultured in the lab, but the researchers also tested DRACO in mice infected with the H1N1 influenza virus. When mice were treated with DRACO, they were completely cured of the infection. The tests also showed that DRACO itself is not toxic to mice.

The researchers are now testing DRACO against more viruses in mice and beginning to get promising results. Rider says he hopes to license the technology for trials in larger animals and for eventual human clinical trials.

This work is funded by a grant from the National Institute of Allergy and Infectious Diseases and the New England Regional Center of Excellence for Biodefense and Emerging Infectious Diseases, with previous funding from the Defense Advanced Research Projects Agency, Defense Threat Reduction Agency, and Director of Defense Research & Engineering (now the Assistant Secretary of Defense for Research and Engineering).

Material adapted from MIT.

“The findings suggest that if young people can get improvements from dietary supplements, then the elderly and people at high risk for certain diseases might benefit even more,” said Janice Kiecolt-Glaser, professor of psychiatry and author of the study, which was published this month in the journal Brain, Behavior and Immunity.

“The more we understand about the complex interplay between inflammation and immunity, the closer we’ll get to figuring out which lifestyle choices and changes have the biggest impact on long term health.”

Omega-3 polyunsaturated fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have long been considered as positive additives to the diet.

Earlier research suggested that the compounds might play a role in reducing the level of cytokines in the body, compounds that promote inflammation, and perhaps even reduce depression. Psychological stress has repeatedly been shown to increase cytokine production so the researchers wondered if increasing omega-3 might mitigate that process, reducing inflammation.

To test their theory, they turned to a familiar group of research subjects – medical students. Some of the earliest work these scientists showed that stress from important medical school tests lowered students’ immune status.

“We hypothesized that giving some students omega-3 supplements would decrease their production of proinflammatory cytokines, compared to other students who only received a placebo,” explained Kiecolt-Glaser. “We thought the omega-3 would reduce the stress-induced increase in cytokines that normally arose from nervousness over the tests.”

The team assembled a field of 68 first- and second-year medical students who volunteered for the clinical trial. Half the students received omega-3 supplements while the other half were given placebo pills. The students were randomly divided into six groups, all of which were interviewed six times during the study.

At each visit, blood samples were drawn from the students who also completed a battery of psychological surveys intended to gauge their levels of stress, anxiety, or depression. The students also completed questionnaires about their diet during the previous weeks.

“The omega-3 supplement the students received was probably about four or five times the amount of fish oil you’d get from a daily serving of salmon,” explained Martha Belury, professor of human nutrition and co-author in the study.

Part of the study, however, didn’t go according to plans.

Changes in the medical curriculum and the distribution of major tests throughout the year, rather than during a tense three-day period as was done in the past, removed much of the stress that medical students had shown in past studies.

“These students were not anxious. They weren’t really stressed. They were actually sleeping well throughout this period, so we didn’t get the stress effect we had expected,” Kiecolt-Glaser said.

But the psychological surveys clearly showed an important change in anxiety among the students: Those receiving the omega-3 showed a 20 percent reduction in anxiety compared to the placebo group. An analysis of the of the blood samples from the medical students showed similar important results.

“We took measurements of the cytokines in the blood serum, as well as measured the productivity of cells that produced two important cytokines, interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα),” said Ron Glaser, professor of molecular virology, immunology & medical genetics and director of the Institute for Behavioral Medicine Research.

“We saw a 14 percent reduction in the amounts of IL-6 among the students receiving the omega-3.” Since the cytokines foster inflammation, “anything we can do to reduce cytokines is a big plus in dealing with the overall health of people at risk for many diseases,” he said.

Inflammation is a natural immune response that helps the body heal, but it also can play a harmful role in a host of diseases ranging from arthritis to heart disease to cancer.
Even though the study showed omega-3 supplements can reduce both anxiety and inflammation – and some of the researchers said that they take omega-3 supplements – the researchers are not ready to recommend that the public start taking them daily.

“It may be too early to recommend a broad use of omega-3 supplements, especially considering the cost and the limited supplies of fish needed to supply the oil,” Belury said. “People should just consider increasing their omega-3 through their diet.”

Also working on the research with Kiecolt-Glaser, Glaser and Belury were William Malarkey, professor emeritus of internal medicine, and Rebecca Andridge, an assistant professor of public health.

Material adapted from Ohio State University Center for Clinical and Translational Science.

“Rats who were given this specific lactic acid bacterium from their time in the uterus up to adult age put on significantly less weight than other rats. Both groups ate the same amount of high-energy food,” explains Karlsson.

Ms. Karlsson also observed that the rats which were given lactobacilli had a richer and better composition of the bacteria which occur naturally in the intestines. A healthy gut flora should contain a large proportion of ‘good bacteria,’ such as lactic acid bacteria, in order to keep the inflammation-causing bacteria in check.

A third group of rats were given the inflammation-causing Escherichia coli bacteria in their drinking water, in addition to the same high-energy food as the other rats. The E. coli supplement led to changes in gut flora and increased body fat.

In another study, Caroline Karlsson has studied the first feces of 79 children born vaginally. A fetus lives in a sterile environment, and therefore has no micro-organisms in its intestines, but during birth the baby swallows the lactobacilli that are naturally present in its mother’s vagina.

“It had not previously been shown that all newborn babies born vaginally have lactobacilli in their gut flora as early as two days after birth. Thanks to the application of a gene-based technique, we have been able to show in our study that this is in fact the case”, says Caroline Karlsson, who also found that babies with high birth weight had more inflammation-causing bacteria, such as E. coli, in their intestines than babies of normal weight.

A healthy gut flora at an early stage appears to play a part in children’s wellbeing later in life. This is a conclusion in a further study, where Caroline Karlsson showed that children with allergic eczema at the age of 18 months had a lower diversity in the gut flora when they were just one week old compared with the children who did not develop allergic eczema.

In the aforementioned study on rats, it emerged that the mother’s diet and bacteria consumption affect the development and health of her young.

“A number of female rats were given food with high energy content during pregnancy and while they were suckling their young. We saw that, at two weeks of age, the young whose mothers were given high-energy food had higher body weight and more fat in their bodies, as well as higher levels of inflammation, than young whose mothers were given a more balanced diet”, explains Caroline Karlsson.

The research was financed by Formas.

Material adapted from Lund University.

Multiple sclerosis is a demyelinating condition affecting the central nervous system. Although the cause for this condition is unknown, patients with MS seem to have genetic vulnerability to certain environmental factors that could trigger this condition.

While other studies have tried to ellucidate whether infection with the Epstein-Barr virus could be considered a risk factor in multiple sclerosis, what University of Granada researchers did was conducting a meta-analysis of observational studies including cases and controls, aimed at establishing such association.

A 151-patient sample
In a sample of 76 healthy individuals and 75 patients with multiple sclerosis, researchers sought a pattern that would show an association between this virus and multiple sclerosis. Thus, they determined the presence of ant¡bodies to Epstein-Barr virus antigens synthetized within the central nervous system. Simultaneously, they identified viral DNA to measure antibody levels to EBV within the central nervous system, and the presence of EBV DNA respectively.

This piece of research was conducted by Olivia del Carmen Santiago Puertas at the Department of Microbiology, University of Granada, and coordinated by professors José Gutiérrez Fernández, Antonio Sorlózano Puerto and Óscar Fernández Fernández.

The researchers found a statistically significant association between viral infection and multiple sclerosis starting from the detection of markers that essentially indicate an infection in the past, while markers that indicate recent infection or reactivation are not relevant.

The researcher Olivia del Carmen Santiago Puertas state that, as the factors triggering this condition are still unknown “studying them is important to try to develop a prevention method”.

This study found an association between MS and some viral infection markers “but, to obtain a definitive conclusion, further research is needed with a significant number of patients that combine different microbiological techniques, where the different viral infection markers are recorded, and assessing patients’ clinical state even years before the onset of the first symptoms of multiple sclerosis”.

Material adapted from University of Granada.

References:
Relation between Epstein-Barr virus and Multiple Sclerosis. Analytic study of scientific production. European Journal of Clinical Microbiology and Infectious Diseases. 2010.

New Strategies and Patent Therapeutics in EBV-Associated Diseases. Mini-Reviews in Medicinal Chemistry. 2010.

Mark Schaller, of the University of British Columbia, who co-authored the article with Justin H. Park from the University of Bristol, suggests that a host of psychological factors combine to detect and avoid potentially infectious things in our immediate environment.  This provides a “crude” first line of defense against infection, and reduces the workload of the “real” immune system.

This affects our interactions with other people. One study reviewed by Schaller and Park found that when people felt more vulnerable to infection, they were less extroverted.  Another study on worldwide personality differences revealed that people are generally less extroverted in countries where infectious diseases have historically been highly prevalent. Many other studies suggest that the threat of disease may contribute to prejudices against people who look or act in ways that seem unusual.

However, the authors are quick to point out that many of these prejudicial responses are erroneous and costly. Blemished skin, for example, may be perceived as infectious when it is not. “This system is designed to identify things that might be infectious, but it relies on imperfect cues,” says author Mark Schaller.  “One consequence is that it may often lead us to avoid things, and people, that pose no risk at all.”

He suggests that research on the behavioral immune system can help scientists uncover the hidden causes of many prejudices and, therefore, be better prepared to intervene and undo those prejudices.

Research on the behavioral immune system may also have health benefits.  According to the review, new research shows that when people see potentially infectious things in their environment, it may lead the “real” immune system to respond more strongly to actual infection.

Material adapted from Association for Psychological Science.

The current study is recognized now as the most comprehensive to date regarding the purported link between chronic fatigue syndrome and XMRV.

The 2009 study linking CFS and XMRV led some CFS patients to take antiretroviral agents in hope of alleviating the symptoms of chronic fatigue syndrome, a debilitating condition of unknown cause. But in light of her new findings, Singh believes the off-label use of antiretrovirals by CFS patients is not appropriate and potentially dangerous.

“Our investigation found no trace of XMRV in any of the blood samples taken from patients we obtained ourselves, or from patients previously tested in the 2009 Science study,” Singh said. “Because of our findings, we believe chronic fatigue syndrome patients should reconsider the merit of taking antiretroviral agents to alleviate their symptoms.”

CFS is a devastating disorder characterized by overwhelming fatigue that is not improved by bed rest and may be exacerbated by physical or mental activity, according to the U.S. Centers for Disease Control and Prevention. It affects millions of people in the United States and worldwide. XMRV (xenotropic murine leukemia virus-related virus), which was first described in 2006, is a retrovirus. Other retroviruses are known to cause AIDS in humans and many kinds of cancer in animals.

In 2009, a researcher at the Whittemore Peterson Institute in Reno, Nev., Judy A. Mikovits, Ph.D., published a study that found XMRV in the blood of 68 percent of CFS patients she sampled. That study, which engendered much controversy, was followed by another one performed by National Institutes of Health and the U.S. Food and Drug Administration researchers that also detected DNA sequences related to XMRV in CFS patients. Since then, however, several other studies in Europe and China found no trace of the retrovirus in CFS samples.

Singh and her colleagues in the U of U departments of anesthesiology and pathology, and ARUP Laboratories analyzed blood samples from 100 CFS patients and 200 healthy controls from the greater Salt Lake City area using molecular, serological, and viral growth assays, including assays used by researchers who previously found XMRV or XMRV-related viruses in CFS patients. CFS patients for the study were provided by the Fatigue Consultation Clinic, headed by Lucinda Bateman, M.D., in Salt Lake City.

In addition, Singh also analyzed samples from individuals from the 2009 study linking XMRV and CFS. Those samples were obtained by a third-party phlebotomy service that collected blood in home visits, de-identified the samples, and sent them to the Singh lab. Thus, the samples were not opened in any other research lab where XMRV might be present, minimizing chances of contamination. All samples were analyzed in a blinded manner.

Singh’s study is more comprehensive and differs from other studies in a number of significant ways:

• It comprises a larger set of patients who fall under well-recognized criteria for CFS
• Patients and controls were from the same geographical area, which was not true for either of the previous studies that showed a correlation between XMRV and CFS
• They analyzed blood samples using multiple, well-defined, sensitive and specific methods, including methods used in the original study
• Unlike many other studies, Singh and her colleagues used blinded methods to evaluate samples
• Singh’s study tested blood samples obtained from individuals tested in the original 2009 study

XMRV is closely related to many mouse retroviruses, and contamination of blood samples or testing reagents with mouse DNA could result in a false-positive test for XMRV. Singh and her colleagues found that some of the positives obtained in other CFS-XMRV studies could be due to the presence of mouse DNA in a reagent used in testing; other positives could be attributed to carry-over of XMRV from positive controls to other samples.

In her own study, Singh initially obtained false positives for XMRV in blood samples. But she determined those false readings were related to robotic equipment that previously had been used for extraction of DNA from XMRV-infected tissue culture cells. Several months later, this equipment led to new samples getting contaminated. When the robotic equipment was abandoned, no more false positives were detected in either CFS patients or healthy patients.

“It’s easy to see how sample extraction and tissue culture processes might be vulnerable to contamination,” Singh said.

Although she found no evidence for XMRV or any related virus in either her study samples or those tested at the Whittemore Peterson Institute, Singh says there is much data to encourage further research into whether other infectious agents are associated with CFS.

“These research efforts must continue,” she says. “Chronic fatigue syndrome is a devastating disease for which a cure needs to be found.”

Material adapted from University of Utah Health Sciences.

Scientists from Ohio State University’s Institute of Behavioral Medicine Research reported their results in the latest issue of the Journal of Neuroscience.

John Sheridan, professor of oral biology, and Jonathan Godbout, an assistant professor of molecular virology, immunology and medical genetics, turned to colonies of mice to make their discoveries.

Groups of mice living together quickly adopt a hierarchy ranging from dominant to subordinate. This vaguely political system controls the interaction among the animals. Once these patterns had been established, the researchers then added an additional, highly aggressive mouse to the mix for a two-hour period each day to disrupt the social hierarchy.

With no place to retreat, the mice were forced into conflicts with the new aggressor. After as few as three episodes with the aggressor, the original mice showed distinct signs of what the researchers considered “anxiety-like behaviors.” This kind of experiment creates a “social disruption” within the group of mice and is widely used to mimic psychological stress.

“These animals can’t flee, so they have to stand and fight,” Sheridan explained. “In doing so, they’re repeatedly defeated, creating a condition called “learned helplessness,” a condition closely linked to depression.

What Sheridan and Godbout saw was that the animals’ anxiety continued for a long time after the termination of the stressful episodes of defeat. “For two weeks or more after we stopped the stressor, we could still see this anxiety-like behavior,” Sheridan said.

The real discoveries came when the researchers analyzed what was happening in the animals’ brains and in their immune response.

“We found that in the stressed animals, a certain type of immune cell (myeloid progenitor cell, or MPC), produced in the bone marrow, entered the circulatory system and migrated to the brain,” explained Godbout.

These MPCs might normally relocate in this way to deal with an infection or an injury in the brain, but in this case, they moved solely because of the response to a social stressor, he said. The experiments showed that the number of these cells more than tripled in the brain following the stress.

Other immune cells called microglia, normally residing in the brain, also triggered an inflammatory response because of the stress. The researchers also noted that the stressor caused a particular activation pattern of neurons, or nerve cells, within the brain.

The response to social stress also caused an increase in the amounts of some inflammatory cytokines in the brain, including interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-a) which are linked to inflammation. These cytokine responses correlated with an insensitivity of MPCs to glucocorticoids, hormones that normally inhibit inflammation in the body.

So the research team saw these and other cellular changes occurring in the brain following the stress, at the same time they were seeing the behavioral changes – the anxiety-like behavior.

The findings are evidence of a two-way communication that’s existing between the body and the brain in times of stress, Sheridan said.

To test that apparent connection, they gave the mice injections of propranolol – a so-called “beta-blocker” drug often used for cardiac conditions – before they encountered the more aggressive mouse. In this case, the researchers saw no increase in IL-1 or TNF-a, no glucocorticoid insensitivity, and no long-lasting anxiety-like behavior in the test animals.

“If we treated the animal with a beta-blocker each night before we put the intruder in, it completely blocked the signal. The anxiety-like behavior never developed,” Godbout said.

“What this basically argues is that we may now have a new target for individuals who have extended anxiety-like behavior,” Sheridan said. “We may have a new target cell to think about in terms of new therapies.

“And since that cell (the MPCs traveling from the bone marrow) is coming from the periphery of the body, we might not need to resort to psychoactive drugs that can have adverse effects on the brain.”

Proving that, however, will take more animal studies and subsequent large studies using humans before this approach could be used clinically, he said.

Working with Sheridan and Godbout on the research were Eric Wohleb, Mark Hanke, Angela Corona, Nicole Powell, LaTonia Stiner, Michael Bailey and Randy Nelson, all of Ohio State.

Material adapted from Ohio State University.

In a study published in the March, 2011 issue of Brain, Behavior, and Immunity, the authors took blood samples from 49 men (24 with PTSD and 25 controls) and 18 women (10 with PTSD and 8 controls). They then used gene microarray technology to determine which genes were activated in the subjects’ monocytes, which are immune cells that regularly cross the barrier between the bloodstream and the brain, and thus give a broad picture of immune reaction in both the body and brain.

“We were looking for evidence of inflammation caused by immune activation,” explained lead author Thomas Neylan, MD, director of the PTSD program at SFVAMC and a professor in residence of psychiatry at UCSF. “We know that people with PTSD have higher rates of cardiovascular disease and arthritis, which are diseases associated chronic inflammation. We also hoped that seeing which genes were expressed in PTSD might show us potential therapeutic approaches that we hadn’t thought of.”

The researchers found no evidence of increased immune activation among the men with PTSD compared to those without PTSD. In contrast, the women with PTSD showed significant evidence of immune activation compared to women without PTSD.

“Previous gene microarray studies on PTSD grouped men and women together, which gave inconclusive results,” said senior investigator Lynn Pulliam, MS, PhD, chief of microbiology at SFVAMC and professor of laboratory medicine and medicine at UCSF.

“This is the first time that it’s been shown that men and women respond differently to PTSD on a very basic biological level.” Neylan characterized the finding as “unexpected.”

The researchers do not know why there seems to be such a marked difference between men and women, said Neylan. However, in a study published in the January, 2011 issue (posted in April, 2011) of the journal Disease Markers, they analyzed data collected from the same subjects to explore one possible explanation: gender differences in cell signaling pathways.

“We know that gene expression patterns are determined by hormones and proteins that are circulating in the body, and we know that some of those hormones and proteins are produced in response to signals from the brain or central nervous system,” explained lead author Aoife O’Donovan, PhD, a researcher in psychiatry at SFVAMC and UCSF. “These signaling pathways are used by the brain and central nervous system to communicate with the immune system and tell immune cells what to do.”

The researchers used sophisticated bioinformatics software to look at three different signaling pathways associated with inflammation: NF-kappa B, glucocorticoid receptor (GR), and CREB/ATF.

In the NF-kappa B and GR pathways in both men and women with PTSD, they found evidence of signaling that could promote inflammation.

In the CREB/ATF pathway, however, they found what O’Donovan called “totally contrasting” effects: men with PTSD had increased signaling, which in turn could possibly lead to less inflammation, while women with PTSD had decreased signaling, which could lead to more inflammation.

“This particular pathway might be a clue to the gender difference in monocyte gene expression in PTSD,” said Pulliam.

“It’s still very early,” cautioned O’Donovan, “but these bioinformatics results are telling us something about how PTSD could increase the risk for autoimmune disorders like arthritis as well as cardiovascular disease, cancer, and other diseases of aging. They also point us in the direction of some potential treatment targets, telling us where future investigative energy might be well spent.”

Neylan emphasized that because of the small sample size, particularly among the women, the results of the two studies are suggestive rather than conclusive. “The next step is to look at larger groups of men and women, and we are working on that,” he said.

Co-authors of the Brain, Behavior, and Immunity study are Bing Sun, MD, PhD, and Hans Rempel, PhD, of SFVAMC; Jessica Ross, MD, MS, of SFVAMC and UCSF; and Maryann Lenoci, MA, of SFVAMC.

Co-authors of the Disease Markers study are Bing Sun, MD, PhD; Steve Cole, PhD, of UCLA; Hans Rempel, PhD; and Maryann Lenoci, MA.

Both studies were supported by grants from the Department of Defense and the Department of Veterans Affairs Sierra Pacific Mental Illness Research & Education Clinical Center. Some of the funds were administered by the Northern California Institute for Research and Education.

Material adapted from University of California – San Francisco.

“MS is more common at higher latitudes, farther away from the equator,” said George C. Ebers, MD, with the University of Oxford in the United Kingdom and a member of the American Academy of Neurology. “Since the disease has been linked to environmental factors, such as low levels of sun exposure and a history of infectious mononucleosis, we wanted to see whether the two together would help explain the variance in the disease across the United Kingdom.”

Infectious mononucleosis is a disease caused by the Epstein-Barr virus, which is a Herpes virus that is extremely common but causes no symptoms in most people. However, when a person contracts the virus as a teenager or adult, it often leads to infectious mononucleosis. The body makes vitamin D when exposed to ultraviolet B (UVB) light.

For the study, researchers looked at all hospital admissions to National Health Service hospitals in England over seven years. Specifically, they identified 56,681 cases of multiple sclerosis and 14,621 cases of infectious mononucleosis. Scientists also looked at NASA data on ultraviolet intensity in England.

The study found that adding the effects of sunlight exposure and mononucleosis together explained 72 percent of the variance in the occurrence of MS across the United Kingdom. Sunlight exposure alone accounted for 61 percent of the variance.

“It’s possible that vitamin D deficiency may lead to an abnormal response to the Epstein-Barr virus,” Ebers said.

He noted that low sunlight exposure in the spring was most strongly associated with MS risk. “Lower levels of UVB in the spring season correspond with peak risk of MS by birth month. More research should be done on whether increasing UVB exposure or using vitamin D supplements and possible treatments or vaccines for the Epstein-Barr virus could lead to fewer cases of MS.”

The study was supported by the Multiple Sclerosis Society of Great Britain and Northern Ireland, the Medical Research Council and the Wellcome Trust.

Material adapted from American Academy of Neurology (AAN).

Current treatments for autoimmunity suppress the patient’s entire immune system, leaving patients vulnerable to a range of adverse side effects. Because the new compound, known as SR1001, only blocks the actions of a specific cell type playing a significant role in autoimmunity, it appears to avoid many of the widespread side effects of current therapies.

“This is a novel drug that works effectively in animal models with few side effects,” said Tom Burris, Ph.D., a professor in the Department of Molecular Therapeutics at Scripps Florida who led the study, which was a multidisciplinary collaboration with scientists including Patrick Griffin, William Roush, and Ted Kamenecka of Scripps Research, and Paul Drew of the University of Arkansas for Medical Sciences. “We have been involved in several discussions with both pharmaceutical and biotechnology firms who are very interested in developing it further.”

A lengthy process of drug development and review is required to ensure a new drug’s safety and efficacy before it can be brought to market.

“This impressive multidisciplinary team has used a combined structural and functional approach to describe a class of molecules that could lead to new medicines for treating autoimmune diseases,” said Charles Edmonds, Ph.D. who oversees structural biology grants at the National Institutes of Health. “Breakthroughs such as this highlight the value of scientists with diverse expertise joining forces to solve important biological problems that have the potential to benefit human health.”

Targeting Specific Receptors
For the past several years, Burris and his colleagues have been investigating small-molecule compounds that affect particular disease-related receptors (structures that bind other molecules, triggering some effect on the cell). In particular, the scientists have been interested in a pair of “orphan nuclear receptors” (receptors with no known natural binding partner) called RORα and RORγ involved in both autoimmune and metabolic diseases.

These particular receptors play a critical role in the development of TH17 cells, a form of T helper cells that make up part of the immune system. A relatively new discovery, TH17 cells have been implicated in the pathology of numerous autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, and lupus. TH17 cells produce Interleukin-17, a natural molecule that can induce inflammation, a characteristic of autoimmunity.

“If you eliminate TH17 cell signals, you basically eliminate the disease in animal models,” Burris said. “Our compound is the first small-molecule orally active drug that targets this specific cell type and shuts it down. Once SR1001 is optimized, chances are it will be far more potent and effective.”

The compound works without affecting other types of T helper cells and without any significant metabolic impact, Burris added.

The first author of the study, “Inhibition of TH17 Differentiation and Suppression of Autoimmunity by a Selective Synthetic ROR Ligand,” is Laura A. Solt of Scripps Research. In addition to Burris, Griffin, Roush, Kamenecka, Drew, and Solt, other authors include Naresh Kumar, Philippe Nuhant, Yongjun Wang, Janelle L. Lauer, Jin Liu, and Monica Istrate of Scripps Research; Dušica Vidović, Stephan C. Schürer of Scripps Research and the Center for Computational Science, University of Miami; and Jihong Xu and Gail Wagoner of the University of Arkansas for Medical Sciences.

Material adapted from The Scripps Research Institute.

Reference / Abstract
Laura A. Solt, Naresh Kumar, Philippe Nuhant, Yongjun Wang, Janelle L. Lauer, Jin Liu, Monica A. Istrate, Theodore M. Kamenecka, William R. Roush, Dušica Vidović, Stephan C. Schürer, Jihong Xu, Gail Wagoner, Paul D. Drew, Patrick R. Griffin & Thomas P. Burris. (2011). “Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand.” Nature (DOI: 10.1038/nature10075).

“If you or someone you love has had to deal with sneezing, itchy eyes, breathlessness, rashes, and other symptoms this time of year, unbalanced eating habits may be to blame,” Dr. Pescatore says. “Proper nutrition can make a dramatic difference. With insights into diet that I have compiled over the years, I have been able to rid or reduce many of my patients’ use of multiple medications for asthma and allergy. There’s no need for anyone to stay indoors or feel miserable for an entire season due to these conditions.”

Whether you suffer from allergies or asthma, says Dr. Pescatore, the cure is the same: You must reduce inflammation in your body. So, for example, if you have yeast or mold allergies, consider a low-yeast diet. Avoid fermented foods, aged cheeses, and mushrooms. During grass season, limit consumption of milk products to avoid congestion, as well as all grains including corn, wheat, oats, rye, and rice.

“Refined sugars, flours, and processed food all trigger inflammation so steer clear of them,” Dr. Pescatore says. “Additionally, avoiding specific foods that cross-react with environmental allergens can reduce your overall ‘allergy burden,’ which can allow your body to better handle your inhaled allergens.”

Tree allergy season, he notes, peaks in April and extends in June so during this period it is best to avoid celery, carrots, apples, potatoes, peaches, nuts, and spices belonging to the apiaceae family (i.e., anise, caraway, coriander, cumin, fennel, parsley and parsnip).

In addition to modifying your diet, Dr. Pescatore has found that certain nutritional supplements can help allergy and asthma sufferers. Specifically, Vitamin D3 can decrease inflammation, Vitamin C helps combat the added stress to our bodies caused by allergies, and Vitamin A helps rid the body of mucus. Additionally, Vitamin B12 stabilizes the imbalance of bacteria that occurs in the gut of most allergy sufferers, Pantethine works as a natural steroid that produces a helpful enzyme, quercetin is one of nature’s best antihistamines, and magnesium helps your body rid itself of the toxins we consume and face daily while helping us breathe more easily.

There are more allergy-preventive measures you can take. “Closing your windows at night prevents allergens from coming into your home, and having an air purifier can reduce airborne allergens, including mold,” says Dr. Pescatore. Taking your shoes off before going inside will prevent some allergens from entering with you, and you should vacuum your car’s interior where pollen hide. Even rubbing olive oil on your hair at night is recommended — because it will keep pollen from getting on your bedding.

“Following these simple steps,” concludes Dr. Pescatore, “could mean the difference between an enjoyable spring and a typically unpleasant one for the millions of Americans who suffer from allergies and asthma.”

Material adapted from Dr. Fred Pescatore, MD.

The developers of the technology at the University of Rochester Medical Center dub it the “Pacman strategy” because it hinges upon molecular machines produced in abundance by tumors to chew through and gobble up particular chains of molecules.

The key feature of the work is a new type of fusion molecule with three parts: a potent immune cell activator; a second molecule to keep that molecule quiescent until it’s needed; and a link between the two that gives scientists control over how the two interact.

The overall fusion molecule acts like a tiny anti-cancer grenade: The portion designed to arouse the immune system to attack cancer is inactive until it’s freed, an act that occurs when the link between it and its inhibitory counterpart is cleaved by specialized tumor proteins that chew up such molecules.

The work, led by graduate student John Puskas and Professor John Frelinger, Ph.D., was published online recently in the journal Immunology. Puskas, who is defending his doctoral thesis today, is first author of the paper.

A protease is designed to destroy the link between IL-2 and its inhibitor, freeing IL-2 near tumors.

“One reason we chose IL-2 is that it’s approved and used to treat patients today. If we’re able to reduce the toxicity associated with it, perhaps it could be used more broadly,” said Frelinger, professor of Microbiology and Immunology.

In experiments using the technology in the lab, the activity of IL-2 in the fusion protein was weak but became 10 to 50 times more biologically active after cleavage. Importantly, in experiments in mice with cancer, tumor growth was inhibited in mice where IL-2 was turned on using the technology compared to mice in which it was not. In many of the treated mice, tumor cells could not be detected after one week.

A key to the technology is the molecular link between IL-2 and its inhibitor. Puskas and Frelinger built that link out of a chain of amino acids – building blocks of proteins. Such chains are broken or cleaved constantly in the body by enzymes known as proteases. In these experiments, when the link is broken, IL-2 breaks free from its inhibitor and is suddenly available to activate other immune cells.

Puskas and Frelinger created links that are cleaved by molecules found much more commonly in cancer cells than other cells. For instance, in one set of experiments, they created a link that is broken only by prostate specific antigen, a protease that is found in prostate cancer cells. They also created links that are cleaved by proteases known as MMP2 and MMP9 – both examples of matrix metalloproteinases commonly overactive in many types of tumors.

The approach is designed to turn on the immune system powerfully right in the neighborhood of cancer cells, to destroy those cells, but to avoid a system-wide immune response that could cause severe side effects.

Frelinger points out that the new work is quite different from other experimental anti-cancer efforts that have involved fusion proteins. In other fusion protein approaches, the molecules are active throughout the body. In the new work, the cytokine is designed to be active only near tumor cells, an approach designed to reduce unwanted side effects.

“The beauty of this approach is that you can change any part of the molecule you want,” said Frelinger, who also has an appointment in the University’s James P. Wilmot Cancer Center. “If you want to target a specific type of cancer, you change the protease sequence to tailor it to particular types of tumors. If you want to change the part of the immune system activated, you change the cytokine.

“Our hope is that an approach like this might someday be coupled with other types of therapy, so that the body could initiate and maintain a vigorous immune response to kill tumors.”

Other authors besides Puskas and Frelinger include graduate students Denise Skrombolas and Abigail Sedlacek, and faculty members Edith Lord, Ph.D., and Mark Sullivan, Ph.D. The work was supported by the National Institutes of Allergy and Infectious Diseases as well as by Steven and Alison Krausz and F.C. Blodgett.

“John was very brave for taking on this project,” said Frelinger. “It really was something that hadn’t been attempted before. He did an outstanding job.”

Material adapted from University of Rochester Medical Center.

Scientists have known for many years that pancreatitis, a painfully inflamed pancreas, is a common risk factor for pancreatic cancer – along with things like smoking and diet. But nobody knew exactly why.

Now the UCSF team, led by Matthias Hebrok, PhD, has discovered at least part of the connection. In an article appearing in the journal Cancer Cell this week, they show that two molecular “signals” produced abundantly in the pancreas during inflammation – a protein named Stat3 – helps initiate the early stages of pancreatic cancer, while another protein, called MMP7, appears to affect metastasis.

In laboratory experiments, Hebrok and his colleagues showed that blocking these proteins in mice shrunk the number of lesions that can lead to cancer and reduced the extent of cancer metastasis. They also showed that one of these molecules, MMP7, may be a clinical indicator of cancer stage, possibly making it useful as a marker for more aggressive disease. The research could also help identify new ways to target pancreatic cancer with drugs.

“If you are able to down-regulate inflammatory signals at an early stage of the disease, you may be able to curb the formation of early lesions,” said Hebrok, who directs the UCSF Diabetes Center and is the Hurlbut-Johnson Distinguished Professor in Diabetes Research.

Inflammation And Pancreatic Cancer
Pancreatic cancer in the United States is all too common and far too deadly. According to the National Cancer Institute, there were some 43,140 new cases of pancreatic cancer diagnosed in the United States in 2010 and 36,800 deaths from the disease last year. Overall, fewer than one in 20 people diagnosed with pancreatic cancer this year will be alive five years from now.

One of the problems with the disease is that there are no reliable, sensitive screens that allow doctors to catch it early. By the time it is detected, the cancer often is so advanced it cannot be surgically removed or easily treated.

Like many scientists who study diabetes, Hebrok is very familiar with pancreatic cancer, because diabetes onset often precedes the cancer diagnosis and may be one of the warning signs. Part of his research in the past few years has involved looking at the microscopic changes that take place in the pancreatic organ when cancer emerges.

The pancreas is a 6-inch-long gland sandwiched between the stomach and the backbone. Inside are tiny cavities called “acini” in which enzymes are produced that drain through ducts into the stomach to help digest food. Pancreatic cancer may start in these cavities or in the ducts when the cells lining them undergo transformations and begin multiplying, forming cancerous lesions – a process often kick-started by inflammation.

Hebrok and his colleagues have discovered that the molecule Stat3 is a key player in this process. It is produced in the pancreas and induces the cells of the pancreas to proliferate as part of a normal healing process in response to inflammation. Sometimes this process goes awry, however, and leads to the transformation of normal cells into cancerous ones. Stat3 also increases the amount of MMP7, which contributes to cancer metastasis.

The UCSF team showed that blocking MMP7 in mice blocks metastasis and reduces the size of cancer tumors. Collaborating with a group at the University of Utah, they examined blood samples taken from people with pancreatic cancer, and they found that those with more MMP7 in their blood were more likely to be at an advanced stage of cancer.

This suggests that MMP7 might be a useful marker to guide treatment for people with pancreatic cancer. And the new insight into the overall process of how inflammation is linked to pancreatic cancer might help scientists identify new targets for cancer therapy – if ways of interfering in the process can be found and if those approaches prove effective in clinical trials

“As with many things, timing is critical,” Hebrok said. “We will need to understand in more detail during which stage of the disease therapeutic targets are activated to efficiently inhibit their function and thus cancer formation and progression.”

Material adapted from UCSF.

The research group, led by Ohio State University scientists, has described studies in mice suggesting that chronic exposure to very fine particulate matter triggers events that allow white blood cells to escape from bone marrow and work their way into the bloodstream. Their presence in and around blood vessels alters the integrity of vessel walls and they also collect in fat tissue, where they release chemicals that cause inflammation.

The cellular activity resembles an immune response that has spiraled out of control. A normal immune response to a pathogen or other foreign body requires some inflammation, but when inflammation is excessive and has no protective or healing role, the condition can lead to an increased risk for cardiovascular diseases, diabetes and obesity, as well as other disorders.

Though many questions about the beginning of this process remain unanswered, the scientists predict that the damage may originate in fluid that lines the lung. Tiny molecules in this fluid change structure after being exposed to polluted air, and that change appears to set off this cascade of damaging white blood cell behavior by activating a receptor called “toll-like receptor 4.”

The job of toll-like receptor 4, or TLR4, is to recognize specific characteristics of pathogens and then send out signals to activate other players in the immune system. Mice that lack this molecule do not produce as much inflammation after exposure to pollution as do normal mice, suggesting that TLR4 has a prominent role in the body’s response to chronic exposure to particulate matter.

“Our main hypothesis is that particulate matter stimulates inflammation in the lung, and products of that inflammation spill over into the body’s circulation, traveling to fat tissue to promote inflammation and causing vascular dysfunction,” said Sanjay Rajagopalan, professor of cardiovascular medicine at Ohio State and senior author of the study. “We haven’t identified the entire mechanism, but we have evidence now that activation of TLR4 influences this response.”

The research is published in a recent issue of the journalCirculation Research.

Many of these researchers already have documented the link between chronic exposure to polluted air and high blood pressure, diabetes and obesity. They now aim to pinpoint how and where the earliest damage occurs.

For this study, the scientists exposed different groups of mice to either filtered air or air containing between eight and 10 times more fine particulates than the ambient air in an urban environment – an average of approximately 111 micrograms per cubic meter. The mice were exposed for six hours per day for five days per week for at least 20 weeks.

The polluted air contained fine particulates that are so tiny – 2.5 micrometers or smaller in diameter, or about 1/30th of the average width of a human hair – that they can reach deep areas of the lungs and other organs in the body.

For most of the experiments, the effects of exposure to pollution were compared in normal mice and mice deficient in TLR4.

After exposure to polluted air, the normal mice showed higher levels of white blood cells known as inflammatory monocytes in their spleens and circulating in their bloodstream than did mice breathing filtered air. Deficiency of TLR4 diminished this effect in mice breathing dirty air. That suggested that if the receptor is not active, the monocytes will not be released.

Other findings implicated yet another potential compound involved in the damage. The increase in monocytes was accompanied by an increase in superoxides in the blood vessels. These compounds are designed to kill pathogens, but they are toxic if they have no bug to fight. They are produced by an enzyme called NADPH oxidase – and NADPH oxidase is found inside monocytes.

In an experiment comparing normal mice and mice lacking a component of the NADPH oxidase enzyme, the mice without the enzyme produced fewer oxygen free radicals in response to polluted air than did normal mice.

“The free radicals can have a high impact on vascular function,” explained Thomas Kampfrath, a postdoctoral researcher in Ohio State’s Davis Heart and Lung Research Institute and first author of the study. Indeed, an examination of the aortas of these mice showed that vessels in animals exposed to polluted air exhibited exaggerated responsiveness to stressors – a sign of incipient hypertension, or high blood pressure, Kampfrath said.

Yet another model of mice genetically altered so their monocytes express yellow fluorescent protein allowed the researchers to observe exactly where the monocytes traveled in segments of mouse muscles and fat tissue. In mice breathing polluted air, the monocytes began to stick to blood vessel walls and fat cells.

“This is a sign that the monocytes are responding to inflammatory stimuli – which in our case is particulate matter – and then in turn they can cause more inflammation because they release inflammatory factors,” said Rajagopalan, who is also the associate director for vascular research at the Davis Heart and Lung Research Institute.

Those factors include what are called proinflammatory cytokines, including TNFa (tumor necrosis factor alpha), MCP-1 (monocyte chemoattractant protein) and IL-12 (interleukin-12). These are chemical messengers that cause inflammation, most often to fight infection or repair injury. When they circulate without an infection to fight, the body experiences excess inflammation.

Mice breathing polluted air showed higher levels of these cytokines in their blood than did mice breathing filtered air. And the mice deficient in the TLR4 receptor showed dramatically lower levels of the cytokines.

“Most of our experiments initially assessed global inflammation. The monocytes are virtually everywhere in the body,” Rajagopalan said. “And then we asked the question, how does it happen, and where does it come from?”

Kampfrath in particular is focused on the lung’s role in this process. Those same cytokines were also significantly elevated in the lungs of mice that had experienced prolonged exposure to polluted air, and the lack of TLR4 activation lowered this effect.

Protective fluid in the lung contains molecules called phospholipids, and this research showed that those molecules become oxidized – meaning a chemical reaction changes their shape and function – after they are exposed to polluted air. That much is determined.

And a series of experiments in different types of white blood cells demonstrated that when the cells are treated with oxidized phospholipids, they will release those proinflammatory cytokines. The lack of TLR4 in those cells diminishes these effects.

These experiments confirmed that these activities in the lung could trigger inflammation seen throughout the rest of the body in mice exposed to polluted air. The question that remains unanswered, however, is the process by which phospholipids become oxidized after chronic lung exposure to dirty air, Kampfrath said.

“After exposure, there is an increase in oxidized phospholipids in the lung fluid. We know it happens, but we don’t know how,” he said. “What we do know is that the increase in oxidized phospholipids in turn promotes inflammation.”

In an editorial in the same issue of Circulation Research, Daniel Conklin of the University of Louisville wrote, “Is the mystery solved regarding the mechanism how inhaled [fine particulate matter] exposure stimulates vascular inflammation and injury? Well, probably not completely, but the present scenario laid out … connects findings from their study with many disparate human and animal epidemiological/exposure studies into a plausible story.”

Co-authors include Andrei Maiseyeu, Zhekang Ying, Zubair Shah, Jeffrey Deiuliis, Nisharahmed Kherada, Sampath Parthasarathy, Susan Moffatt-Bruce and Qinghua Sun of the Davis Heart and Lung Research Institute; Xiaohua Xu of the Division of Environmental Health Sciences; and Kongara Reddy and Nitin Padture of the Department of Materials Science and Engineering, all at Ohio State; Robert Brook of the University of Michigan; Lung Chi Chen of New York University; and Henning Morawietz of the University of Technology in Dresden, Germany.

Material adapted from Ohio State University.

“We showed there is no association between vaccination and the illnesses these vulnerable children experience,” Morgan said.

The impetus for the study, published this week in the journal Pediatrics, was the case of Hannah Poling, a 2-year-old girl from Athens, Ga. Shortly after receiving several vaccines, Poling fell ill and her behavior regressed. The chatty toddler began exhibiting some classic behavioral signs of autism. A physician’s group for the Department of Health and Human Services determined Hannah’s IEM — in her case a mitochondrial disorder – made her vulnerable to injury from vaccination. The family received more than $1 million in compensation for her injuries.

The case led to widespread concern than special populations of children might be at risk from vaccination.

Morgan’s study examined children with a group of IEM called urea cycle disorders. Through the Urea Cycle Disorders Consortium, 169 children were enrolled and 74 cases were closely examined in which children had experienced both vaccination and an IEM-related illness serious enough to require hospitalization. IEMs are known to trigger serious side effects from stress on the body such as illnesses.

Thomas Morgan, M.D., a clinical geneticist in the Department of Pediatrics at Vanderbilt, examines patient Marieuz Tomas-Francisco, who has an inborn error of metabolism, while her mother, Alicia Francisco Diego holds her. (Photo Credit- Vanderbilt University, Daniel Dubois)

“We looked back from each child’s hospitalization seven and even 21 days before the illness and found no association with vaccinations,” Morgan said.

He points out all children with IEMs are more vulnerable than children without such disorders to the illnesses the vaccines protect against. He hopes this study will help physicians and parents feel more comfortable providing vaccines to children with IEMs.

“I would hope that people who are skeptical about vaccines will see we take the issue seriously enough to actually study it. That’s what science does is provide information without having to rely on opinion,” Morgan said.

Morgan said since Poling has a different type of IEM, vaccine safety should be studied in each of these disorders. He said this is the first study of its kind to show that children with an IEM are not harmed by vaccines.

Other contributors to the article include Cameron Schlegel, a fourth-year School of Medicine student who worked on the study as part of an Emphasis Project. Kathryn Edwards, M.D., director of the Vanderbilt Vaccine Research Program; Teresa Welch-Burke, R.N., B.S.N.; Yuwei Zhu, M.D., M.S.; and Robert Sparks are also contributors. Marshall Summar, M.D., former professor of Pediatrics and Molecular Biophysics at Vanderbilt, who now serves as chief of Genetics and Metabolism at Children’s National Medical Center in Washington, D.C., is senior author.

Material adapted from Vanderbilt University.

Inflammation is part of the body’s natural immune response to tissue damage. However, chronic inflammation is associated with many diseases. In the brain, it is thought to play a role in aging and neurodegenerative diseases, such as Parkinson’s and Alzheimer’s disease. If further research determines that inflammation causes memory decline, anti-inflammatory drugs could prove useful in staving off the damage.

Studies in animals have shown that prolonged brain inflammation impairs function of the hippocampus – a region of the brain involved in storing and generating memory. It does so by disrupting the establishment of memories, a process known as long term potentiation.

The scientists in the study hypothesized that the presence of C-reactive protein (CRP), a marker of chronic low grade inflammation in the brain, would be associated with poorer memory creation and smaller medial-temporal lobes, which include the hippocampus.

They examined 76 women and men (mean age 71.8) with detectible levels of CRP in their blood, and 65 people (mean age 70.8) with undetectable levels. All participants were given a 16-word list learning task to measure verbal recall, and underwent magnetic resonance imaging, MRI to measure volumes of regions of the medial temporal lobes, specifically the hippocampus, entorhinal cortex, and parahippocampal cortex.

The results showed that adults with measureable levels of C reactive protein recalled fewer words and had smaller medial temporal lobes.

Scientists do not know if the inflammation indicated by the C reactive protein is the cause of the memory loss, if it reflects a response to some other disease process or if the two factors are unrelated. But if inflammation causes the cognitive decline, relatively simple treatments could help, said Joel H. Kramer, PsyD, UCSF clinical professor of neuropsychology and the director of the neuropsychology program at the UCSF Memory and Aging Center.

“Anti-inflammatory drugs available today could be used to treat low grade infections in the brain, and could be used more aggressively following surgery, which prompts a large inflammatory response,” he said.

Kramer and his colleagues plan to monitor the participants until the end of their lives and to use additional inflammatory markers – ones that tend to be more sensitive to acute changes than CRP.

“We think such a study will give us a better idea of what’s driving the processes we’ve observed,” he said. “If baseline levels of inflammatory markers predict change over time, we’d consider a clinical trial using anti-inflammatory drugs to treat inflammation.”

Inflammation is just one of several possible factors that might be driving cognitive decline in normally aging adults, said Kramer. He and his colleagues are examining the possible impact of cardiovascular and stroke risk factors, as well. “We’re also just starting to look at exercise, and want to study sleep,” he said.

Material adapted from University of California – San Francisco.

But exactly how stress makes these changes in these bacteria still isn’t quite clear, researchers say.

“Since graduate school, I’ve been interested in how stress affects the bacteria naturally in our bodies,’ explained Michael Bailey, an assistant professor of dentistry and member of the Institute for Behavioral Medicine Research at Ohio State University.

“Even though we’ve known that stress changes these bacteria, we didn’t really understand what that meant or if there was any sort of biological function associated with effects on these bacteria.”

The human digestive tract is a universe filled with microbes. There are probably 100 trillion bacteria in the average human, 90 percent of which live mainly in the intestine. They easily outnumber human cells 10-to-one in each person.

Bailey and colleagues turned to mice to better understand the roles that bacteria play in immune balance. They ran a series of experiments using a common stressor for these animals. For two hours daily for six days, an aggressive mouse was placed in a cage of a group of more docile mice.

At the end of the string of experiments, blood samples were taken from both stressed animals and matched mice from a control group, along with samples of material from inside each animal’s intestine. The blood samples were analyzed to detect the levels of two biomarkers used to gauge stress – a cytokine called interleukin-6 (IL-6) and a protein called MCP-1 that summons macrophages, or scavenger cells, to the site of an infection.

From the intestinal samples, Bailey’s team could determine the relative proportion of at least 30 types of bacteria residing there.

Compared to the control mice, the stressed animals showed two marked differences: The proportion of one important type of bacteria in the gut – Bacteroides – fell by 20 to 25 percent while another type – Clostridium – increased a similar amount. Also, levels of the two biomarkers, IL-6 and MCP-1, jumped 10-fold in the stressed mice, compared to controls.

The researchers then treated stressed mice with broad-spectrum antibiotics that could kill as much as 90 percent of the intestinal bacteria for a short period. When they again looked at the two immune biomarkers in the stressed mice, they saw only a doubling of IL-6 and MCP-1 – an increase only one-fifth as much.

“We know now that if we knock the population of bacteria down with antibiotics, we don’t have the same innate immune response,” Bailey said. “That showed that the bacteria are involved in the ability of stress to prime the innate immune system.”

He said that the research shows that some of the changes in systemic immunity in the body can be influenced by changes in these bacterial colonies, a result that reinforces the idea that they have a broader effect on the immune response.

The next step, the researchers say, is to better understand the roles that the bacteria play in activating the immune system, and to determine if other factors are playing a key role in the process.

Working with Bailey on the project were Jeff Galley, Amy Hufnagle and Rebecca Allen, also from Ohio State; Scot Dowd of the Medical Biofilm Research Institute in Lubbock, TX, and Mark Lyte from Texas Tech University.

Material adapted from Ohio State University.

“There’s a lot more to depression than feeling blue,” said first author Owen Wolkowitz, MD, a professor of psychiatry at UCSF. “As if feeling depressed is not bad enough, we are finding that long-term depression may be associated with damage to cells in the body, and this may predispose patients to certain physical diseases.”

Previously considered a mental illness affecting only the brain, major depressive disorder, or MDD, now is believed to be tied to significant physical damage outside the brain, explained Wolkowitz. For example, depressed individuals are more likely to develop the diseases of advanced age, including diabetes, heart disease, osteoporosis, stroke and dementia.

In probing the links between depression and physical disease, the research team explored aging of the immune system as measured by the shortening of telomeres in immune cells taken from the blood.

Telomeres are tiny units of DNA-protein complexes that seal off and protect the ends of chromosomes and act as a biological clock controlling a cell’s life. Telomere shortening predicts earlier onset of several major age-related diseases and earlier mortality, and may serve as one index of human longevity.

The researchers compared the length of telomeres in 18 individuals with MDD not currently receiving antidepressant medications to the length of telomeres in 17 healthy controls. Overall, telomeres of the depressed group did not differ from those of the healthy group; however, individuals with nine or more years of untreated chronic depression showed significant telomere shortening, even after accounting for chronological age. The degree of shortening in this subset of the depressed group corresponded to about seven years of “accelerated cell aging.”

Telomere shortening also was associated with higher levels of inflammation and oxidative stress in patients, both linked to cell damage and premature aging. Oxidative stress is an imbalance between destructive “free radical” molecules and the body’s ability to neutralize them with antioxidants. The authors suggest that telomere shortening in very chronic depression may reflect an individual’s cumulative exposure to biochemical stressors that promote cell death and increase the likelihood of physical disease.

“While this finding itself might seem depressing, there is yet good news: many lifestyle factors like exercise and aspects of diet have been linked to longer telomeres,” said co-author Elissa Epel, PhD, an associate professor in the UCSF Department of Psychiatry. “So while our personal history matters, it is possible that what we do today may matter even more, in terms of protecting our telomeres.”

Epel and co-author Elizabeth Blackburn, PhD, UCSF professor of biochemistry and biophysics, pioneered research on the impact of psychological stress on several biological markers of cell aging. Blackburn shared the 2009 Nobel Prize in Physiology or Medicine for her telomere research and co-discovery of the cellular enzyme telomerase. Telomerase helps repair and restore telomeres, protecting cells from damage related to premature aging.

In related work, the research team recently reported in the journal Molecular Psychiatry, available here, that individuals with MDD show increased activity of the telomerase enzyme. Depressed individuals with the lowest telomerase activity before antidepressant treatment, and those with the greatest increase in activity during treatment, showed the strongest antidepressant responses. These findings suggest that the seemingly paradoxical increase of telomerase in untreated depressed individuals indicates their bodies are attempting to compensate for the damage to their telomeres. Increases during treatment, on the other hand, may represent true improvement in depression.

“We speculate that telomerase may provide a biological marker for antidepressant responses,” Wolkowitz said. “Once we better understand these systems, we will be in a stronger position to treat depression and possibly prevent some of its associated physical illnesses.”

Additional UCSF co-authors are Synthia Mellon, PhD; Jue Lin, PhD; Victor Reus, MD; Rebecca Rosser; Heather Burke, PhD; Eve Kupferman, PhD; Mariana Compagnone, MD; and J. Craig Nelson, MD. Co-authors from other institutions are Firdaus Dhabhar, PhD, of Stanford and Yali Su, PhD, of Kronos Science Laboratory.

Material adapted from University of California – San Francisco.

Download / Reference
Wolkowitz OM, Mellon SH, Epel ES, Lin J, Dhabhar FS, et al. 2011. Leukocyte Telomere Length in Major Depression: Correlations with Chronicity, Inflammation and Oxidative Stress – Preliminary Findings. PLoS ONE 6(3): e17837. doi:10.1371/journal.pone.0017837

However, new research led by Steven E. Schutzer, MD, of the University of Medicine and Dentistry of New Jersey-New Jersey Medical School, and his colleagues, may be the first to examine the body compartment most involved for neurologic symptoms – the central nervous system and its liquid spinal fluid.

This study did not find XMRV in the spinal fluid and is the latest of several studies that call the 2009 finding into question as a cause. However the other studies only focused on blood, not the central nervous system.

Schutzer and colleagues, in an article published online byAnnals of Neurology, examined the cerebrospinal fluid of 43 individuals with a generally accepted definition of CFS. The team targeted spinal fluid based on the belief that if there is a neurological component to CFS as the symptoms suggest, then spinal fluid might contain a relevant pathogen such as a virus that is associated with the syndrome.

“Spinal fluid is a liquid window to the brain,” said Schutzer. “It is an important area of the body to examine when there is abnormal central nervous system function and an infectious or immunologic cause is suspected.”

The relative separation of the central nervous system from the circulatory system was also an important consideration because the sheer complexity of blood makes cause and effect far harder to decipher when substances are found there.

Schutzer and his team analyzed spinal fluid using specialized Polymerase Chain Reaction (PCR) techniques that amplified nucleic acid present in the fluid, and found no evidence of XMRV. Other common viruses also appeared to be absent.

This latest finding that XMRV does not appear to be in the spinal fluid of patients with Chronic Fatigue Syndrome comes within weeks of another study published by Schutzer and colleagues [PLoS ONE 6(2): e17287. doi:10.1371/journal.pone.0017287] that analyzed the spinal fluid of the same 43 CFS patients and found 738 proteins in those patients’ fluid that appear to be specific to CFS. The earlier paper compared that group of patients with others who either were healthy controls or had been diagnosed with Lyme disease. The two studies, taken in tandem, strongly suggest that while XMRV does not appear to be directly associated with CFS in the central nervous system, other substances found in spinal fluid do have an association.

“This latest study was not designed to address the ongoing controversy over possible XMRV in the blood,” said Schutzer. “It was specifically designed to survey the central nervous system for XMRV and, if found, other viruses. Here, and in general, the detection of a microbe is only a first step. Additional research would be necessary to prove that it is a cause of a condition,” Schutzer emphasized.

The authors urge investigators to search prospectively for microbes and other possible mechanisms of the syndrome, paying particular attention to the central nervous system.

Authors, in addition to Dr. Schutzer, were Megan A. Rounds, David J. Ecker and Mark W. Eshoo of Ibis Biosciences, and Benjamin H. Natelson of University of Medicine and Dentistry of New Jersey, Beth Israel Medical Center and Albert Einstein School of Medicine.

Material adapted from University of Medicine and Dentistry of New Jersey (UMDNJ).

“Herpes infects mucous membranes, such as the lip or eye, and generates viral particles,” submits study Principal Investigator Elaine Bearer, M.D., Ph.D., Harvey Family Professor and Vice Chair for Research, Department of Pathology, UNM School of Medicine. “These viral particles burst out of the cells of the mucous membrane and enter sensory nerve cells where they travel inside the nerve toward the brain. We now can see this cellular transportation system and watch how the newly formed virus engages cellular APP [amyloid precursor protein] on its journey out of the cell.”

Tagging herpes virus inside cells with green fluorescent protein, scientists used live confocal imaging to watch HSV1 particles emerge from infected cells. Newly produced viral particles exit the cell nucleus and then bud into cellular membranes containing amyloid precursor protein (APP). Electron microscopy at HEI detailed the ultrastructural relationship between HSV1 particles and APP.

This dance between viral particles and cellular APP results in changes in cellular architecture and the distribution of APP, the major component of senile plaques found in the brains of Alzheimer’s disease patients. Results from this study indicate that most intracellular HSV1 particles undergo frequent, dynamic interplay with APP, which facilitates viral transport while interfering with normal APP transport and distribution. This dynamic interaction reveals a mechanism by which HSV1 infection leads to Alzheimer’s disease.

In developed countries such as the U.S., approximately 20 percent of children are infected with HSV1 prior to the age of five. By the second and third decades of life, as much as 60 percent of the population is infected, and late-in-life infection rate reaches 85 percent.

Symptoms of primary HSV1 infection include painful blisters of the mouth, lips, or eyes. After infection, HSV1 persists in nerve cells by becoming latent. Upon re-awakening, new viral particles are made in the neuron and then travel back out its pathways to re-infect the mucous membrane. Many infected people experience sporadic episodes of viral outbreaks as the well-known recurrent cold sore.

“Clinicians have seen a link between HSV1 infection and Alzheimer’s disease in patients so we wanted to investigate what might be going on in the body that would account for this,” adds Dr. Shi-Bin Cheng, post-doctoral associate, Department of Pathology and Laboratory Medicine, Alpert Medical School, Brown University. “What we were able to see in the lab strongly suggests a causal link between HSV1 and Alzheimer’s Disease.”

“It’s no longer a matter of determining whether HSV1 is involved in cognitive decline, but rather how significant this involvement is,” Bearer asserts. “We’ll need to investigate anti-viral drugs used for acute herpes treatment to determine their ability to slow or prevent cognitive decline.”

Researchers recommend people treat a cold sore as quickly as possible to minimize the amount of time the virus is actively traveling through a person’s nervous system. The faster a cold sore is treated, the faster the HSV1 returns to a dormant stage.

Material adapted from House Ear Institute.

Download / Reference
Cheng S-B, Ferland P, Webster P, Bearer EL, 2011 Herpes Simplex Virus Dances with Amyloid Precursor Protein while Exiting the Cell. PLoS ONE 6(3): e17966. (doi:10.1371/journal.pone.0017966).

“These bacteria affect immune function, and may help explain why stress dysregulates the immune response,” said lead researcher Michael Bailey.

“These changes can have profound implications for physiological function,” explained Dr Bailey. “When we reduced the number of bacteria in the intestines using antibiotics, we found that some of the effects of stress on the immune system were prevented”, he added. “This suggests that not only does stress change the bacteria levels in the gut, but that these alterations can, in turn, impact our immunity.”

“This is the first evidence that the gut microorganisms may play a role in innate immunological stress responses,” said Monika Fleshner, Professor of Integrative Physiology at the University of Colorado, Boulder. “The study reveals the dynamic interactions between multiple physiological systems including the intestinal microbiota and the immune system.”

Because gut bacteria have been linked to diseases like inflammatory bowel disease, and even to asthma, a future goal of the study is to determine whether alterations of gut bacteria is the reason why these diseases tend to be worse during periods of pressure.

The research was conducted with colleagues from the Texas Tech University Health Sciences Center and the Research and Testing Laboratories, and was funded by the National Institute of Health.

Material adapted from Elsevier.

Reference / Abstract
“Exposure to a social stressor alters the structure of the intestinal microbiota: Implications for stressor-induced immunomodulation” by Michael T. Bailey, Scot E. Dowd, Jeffrey D. Galley, Amy R. Hufnagle, Rebecca G. Allen and Mark Lytee; and the brief commentary on it is “The gut microbiota: A new player in the innate immune stress response?” by Monika Fleshner. Please see the articles for the authors’ affiliations and disclosures of financial and conflicts of interest. The article appears in Brain, Behavior, and Immunity, Volume 25, Number 3 (March 2011), published by Elsevier

While roughly 20 percent of ALS cases appear to have a genetic cause, the vast majority of cases appear to arise sporadically, with no known trigger. Research groups searching for a cause of this so-called sporadic form had previously spotted a protein known as reverse transcriptase, a product of retroviruses such as HIV, in ALS patients’ serum samples, suggesting that a retrovirus might play a role in the disease. However, these groups weren’t able to trace this reverse transcriptase to a specific retrovirus, leaving some scientists in doubt whether retroviruses are involved in ALS.

Seeking to verify whether a culprit retrovirus indeed exists, Avindra Nath, M.D., a professor of neurology at the Johns Hopkins University School of Medicine, and colleagues examined brain samples from 62 people: 28 who died from ALS, 12 who died from chronic, systemic diseases such as cancer, 10 who died from accidental causes and 12 who had another neurodegenerative disease, Parkinson’s disease, at the time of their deaths. Using a technique known as polymerase chain reaction, the researchers searched for messenger RNA (mRNA) transcripts from retroviruses, a chemical signature that retroviruses were active in these patients.

In samples from the ALS and chronic disease patients, the search turned up mRNA transcripts that came from human endogenous retrovirus K (HERV-K). This retrovirus is one of thousands that became a part of the human genome after infecting our ancestors long ago. Nowadays, these retroviruses are no longer contagious, but are instead passed along through inheritance in part of the genome that scientists consider “junk” DNA.

When Nath and his colleagues took a closer look at the mRNA, they saw that the transcripts seemed to originate from different parts of the genome in the samples from ALS and systemic disease patients. The transcripts also came from different tissues in the brain. While patients with ALS tended to have HERV-K transcripts present in areas surrounding the motor cortex of the brain – the area affected by the disease – the other patients’ transcripts were spread more diffusely through the brain.

Although the researchers express caution, the findings, reported in the January Annals of Neurology, suggest that HERV-K might be the ALS retrovirus that researchers have been looking for.

“This paper doesn’t establish causation beyond the level of doubt, but it does provide some promising links between HERV-K and ALS,” Nath says. “We’ve never found a putative retrovirus for this disease before, so this opens up a whole new area.”

He and his colleagues plan to study whether HERV-K might cause neuronal damage, a step closer to linking this retrovirus to ALS. They also plan to study what factors may cause HERV-K to reactivate in some people and lead to ALS symptoms. Researchers might eventually be able to fight ALS, Nath adds, using antiretroviral drugs specific to HERV-K.

Material adapted from Johns Hopkins Medicine.

In their study, the authors compare the occurrence of infections and allergies in vaccinated and unvaccinated children and adolescents. These include bronchitis, eczema, colds, and gastrointestinal infections. The researchers’ data are based on the results of the German Health Interview and Examination Survey for Children and Adolescents (KiGGS).

The evaluation showed that unvaccinated children and adolescents differ from their vaccinated peers merely in terms of the frequency of vaccine preventable diseases. These include pertussis, mumps, or measles. As expected, the risk of contracting these diseases is substantially lower in vaccinated children and adolescents.

Material adapted from Deutsches Aerzteblatt International.

Reference
Schmitz R, Poethko-Müller C, Reiter S, & Schlaud M. Vaccination status and health in children and adolescents – findings of the German health interview and examination survey for children and adolescents (KiGGS). Dtsch Arztebl Int 2011; 108(7): 99–104.

Researchers looked at the serum vitamin D levels in blood collected in 2005-2006 from a nationally representative sample of more than 3,100 children and adolescents and 3,400 adults. The samples are derived from the National Health and Nutrition Examination Survey (NHANES) – a program of studies designed to assess the health and nutritional status of adults and children in the United States. The survey is unique in that it combines interviews, physical examinations, and laboratory studies. One of the blood tests assessed was sensitivity to 17 different allergens by measuring levels of Immunoglobulin E (IgE) – a protein made when the immune system responds to allergens.

When the resulting data was analyzed by Einstein researchers, no association between vitamin D levels and allergies was observed in adults. But for children and adolescents, low vitamin D levels correlated with sensitivity to 11 of the 17 allergens tested, including both environmental allergens (e.g., ragweed, oak, dog, cockroach) and food allergens (e.g., peanuts).

For example, children who had vitamin D deficiency (defined as less than 15 nanograms of vitamin D per milliliter of blood) were 2.4 times as likely to have a peanut allergy than were children with sufficient levels of vitamin D (more than 30 nanograms of vitamin D per milliliter of blood).

The research shows only an association and does not prove that vitamin D deficiency causes allergies in children, cautioned Michal Melamed, M.D., M.H.S., assistant professor of medicine and of epidemiology & population health at Einstein and senior author of the study.

Nevertheless, she said, children should certainly consume adequate amounts of the vitamin. “The latest dietary recommendations calling for children to take in 600 IU of vitamin D daily should keep them from becoming vitamin-D deficient,” she said.

The title of the paper is “Vitamin D levels and food and environmental allergies in the United States: Results from NHANES 2005-2006.”

Material adapted from Albert Einstein College of Medicine of Yeshiva University.

In their analysis of 93 older adults, the researchers screened for gene function among different types of immune cells and found that genes originating from two particular cell types — plasmacytoid dendritic cells and monocytes — were overexpressed in chronically lonely individuals, compared with the remainder of the sample. These cell types produce an inflammatory response to tissue damage, and are part of the immune system’s first line of defense, which produces an immediate inflammatory response to tissue damage.

It is this same inflammatory response that over the long-term can promote cardiovascular disease, cancer, and neurodegeneration.

The report provides further evidence of how lifestyle and social environments can impact human health. In addition, the researchers suggest that evolutionarily ancient immune system cells may have developed a molecular sensitivity to our social environment in order to help defend us against socially transmitted pathogens.

The research appears in the Feb. 7-11 issue of the journalProceedings of the National Academy of Sciences. Other authors were Lewis C. Hawkley and Jesusa M. Arevalo of UCLA, and John T. Cacioppo of the University of Chicago.

The research was funded by the National Institutes of Health, the John D. and Catherine T. MacArthur Foundation, the Norman Cousins Center at UCLA, the John Templeton Foundation, and the James B. Pendleton Charitable Trust.

Material adapted from University of California, Los Angeles (UCLA), Health Sciences.

Research has demonstrated that inflammatory processes also have other roles to play as inflammatory substances produced by the body influence mechanisms in the brain involving learning and memory.

Inflammatory substances produced in moderate quantities in the brain can be beneficial during the formation of new brain cells, for example. However, an increase in the levels of these substances, as is the case during illness, can result in damage to the brain.

“Previous studies have shown that individuals suffering from various mental illnesses have an increased peripheral inflammation, but the reason behind this increase is not known,” says Petra Suchankova Karlsson, who wrote the thesis. “It has been suggested that the stress that goes with mental illness activates the body’s immune system, but it is also possible that inflammation in the body affects the brain, which in turn results in mental illness.”

Previous studies have focused on how environmental and psychological factors affect the immune system’s impact on the brain. Suchankova’s thesis presents for the first time results that suggest that several different genes linked to the immune system are associated with healthy people’s personality traits. It also demonstrates that some of these genes are associated with an increased risk of developing schizophrenia or suicidal behaviour.

“One of the things we studied was a gene variant that increases impulsiveness in people who carry it,” says Suchankova. “We already knew that the risk of attempting suicide is higher in impulsive people and therefore analysed this gene variant in a group of patients who had attempted to take their life. We found that these patients more often carried the particular gene variant when compared to the general population which meant that this variant was not only associated with increased impulsiveness in healthy individuals but also with increased risk of suicidal behaviour.”

The change in the levels of inflammatory substances in the blood of patients suffering from a mental illness as previously noted may have been caused by inflammation-related genes affecting the risk of mental illness, rather than the illness itself leading to a change in levels, as is traditionally believed.

“It could well be that some variants of the genes play a role in the development of mental illness by controlling how the brain is formed, perhaps during the embryonic stage, or by affecting the transfer of signal substances,” says Suchankova.

The results of this thesis support the proposed role of the immune system in mental illness, and could be used as a basis for further studies that, it is hoped, will lead to the development of new treatment methods.

The thesis has been successfully defended.

Material adapted from University of Gothenburg.

Reference / Abstract
Petra Suchankova, Fariba Baghaei, Roland Rosmond, Göran Holm, Henrik Anckarsäter, & Agneta Ekman. (article in press). Genetic variability within the S100B gene influences the personality trait self-directedness. Psychoneuroendocrinology 2010. doi:10.1016/j.psyneuen.2010.10.017

Cells of the immune system called macrophages can either stimulate inflammation or suppress it by releasing chemical signals that alter the behaviour of other cells. The new study, by scientists from Imperial College London, has shown that a protein called IRF5 acts as a molecular switch that controls whether macrophages promote or inhibit inflammation.

The results suggest that blocking the production of IRF5 in macrophages might be an effective way of treating a wide range of autoimmune diseases, such as rheumatoid arthritis, inflammatory bowel disease, lupus, and multiple sclerosis. In addition, boosting IRF5 levels might help to treat people whose immune systems are compromised.

Researchers from Imperial College London previously developed anti-TNF treatments, a class of drug that is widely used as a treatment for rheumatoid arthritis. The drugs target TNF, an important signalling chemical released by immune cells to stimulate inflammatory responses. However, about 30 per cent of patients do not respond to anti-TNF drugs so there is a serious need to develop more widely effective therapies.

Dr. Irina Udalova from the Kennedy Institute of Rheumatology at Imperial College London, the senior researcher on the study, said, “Diseases can affect which genes are switched on and off in particular types of cells. Understanding how this switching is regulated is crucial for designing targeted strategies to suppress unwanted cell responses.

“Our results show that IRF5 is the master switch in a key set of immune cells which determines the profile of genes that get turned on in those cells. This is really exciting because it means that if we can design molecules that interfere with IRF5 function, it could give us new anti-inflammatory treatments for a wide variety of conditions.”

Gene association studies have linked variations in the gene that encodes IRF5 with an increased risk of autoimmune diseases. This led Dr Udalova and a PhD student in her lab, Mr. Thomas Krausgruber, to investigate what role the protein plays in controlling inflammation.

They used engineered viruses to introduce extra copies of the IRF5 gene in human macrophages grown in the laboratory, which makes the cells produce more IRF5. When they did this to macrophages with anti-inflammatory characteristics, it made them switch to promoting inflammation. When they blocked IRF5 in pro-inflammatory macrophages using synthetic molecules, this reduced the cells’ production of signals that promote inflammation.

The researchers also studied genetically modified mice that were unable to produce IRF5. These mice produced lower levels of chemical signals that stimulate inflammation.

IRF5 seems to work by switching on genes that stimulate inflammatory responses and dampening genes that inhibit them. It can either do this by interacting with DNA directly, or by interacting with other proteins that themselves control which genes are switched on. Dr Udalova’s group are now studying how IRF5 works at a molecular level and which other proteins it interacts with so that they can design ways to block its effects.

The study was funded by the Medical Research Council, the European Community, and Arthritis Research UK.

Material adapted from Imperial College London.

The initial study, which was designed to define the dose range of such a therapy in a group of 13 patients, could lead to a daily pill to boost immunity in the elderly, the researchers said. Data will appear in the January issue of the journal Clinical Immunology.

The identification of a drug to reverse the immunological decline in aging, known as immunosenescence, is the culmination of years of research by Edward J. Goetzl, MD, at UCSF and the National Institute on Aging, into how cytokine levels change as people age, how that varies by gender, and which changes dictate whether someone will be healthy into their 90s or begin a downward cycle of decline starting in middle age.

“No one’s really talking about longevity and lifespan now, but about ‘health span,’” said Goetzl, director of UCSF Allergy and Immunology Research, which focuses on developing new diagnostics and treatments for allergic and immunological diseases.

“If, at age 50, your cytokine levels are the same as they were at 25, you’ll probably stay healthy as you age,” he said. “But if they’re heading downhill, we need to do something about it. If you could take a low-dosage pill with no side effects, wouldn’t you do it?”

In 2009, Goetzl had studied a group of 50 elderly adults through the National Institute on Aging, examining their levels of key cytokines – Interleukin (IL)-2, IFN-gamma and IL-17 – and discovered that truly healthy 70-80 year old women had the same levels of those as did healthy 20 year olds.

However, elderly men and frail women who showed increased levels of inflammatory diseases and weakened defenses against infections tended to have lower levels of the first two cytokines, which are protective, and higher levels of IL-17, which is linked to inflammation. That imbalance, the researchers found, began in late middle age.

They then set out to find a drug that could raise IL-2 and IFN-gamma and either have no effect on IL-17 or lower it.

“We now had a profile – in humans – that we could take to test tubes to say, ‘Does this drug have a desirable effect?’” Goetzl said. “Our job was to find a therapy that not only works, but does so at a dose range with no side effects.”

The team focused on three classes of drugs, among them the one that includes lenalidomide – a derivative of thalidomide – which is undergoing a renaissance, Goetzl said.

First introduced in the late 1950s as a sedative, thalidomide was never approved in the United States, but was withdrawn from the world market in 1961 after causing severe birth defects in infants whose mothers took the drug to reduce nausea during pregnancy.

In recent years, however, lenalidomide has been found to be an effective co-therapy for some cancers, particularly multiple myeloma and kidney tumors, as well as leprosy, at doses of 5 mg to 20 mg per day. Those cancers are tied to a drop in IL-2, the main cytokine that Goetzl’s team had linked to declines in aging immune systems.

In this study, the team tested the drug in healthy seniors, each of whom were matched in race, gender, and national origin to a healthy young adult participant. They found that extremely low levels of lenalidomide – 0.1 μM – optimally stimulated IL-2 production in the young people (21-40 years) roughly sevenfold, but stimulated IL-2 production in patients over age 65 by 120-fold, restoring them to youthful levels for up to five days. At that dosage, the drug also increased IFN-gamma up to six fold in the elderly patients, without suppressing IL-17 generation.

The researchers also found that lenalidomide had many other beneficial effects on the elderly participants’ T cells, including better migration throughout the body, more efficient patrolling activity, and longer survival after defending the body against an infection.

The team plans to begin larger-scale clinical trials in 2011 to test the drug’s effectiveness and hopes for broader availability within a few years.

Material adapted from University of California – San Francisco.

As time passes, however, this specific immunity can wear off. That is because not all memory T cells live long enough to foster long-term immunity.

MIT biologists have now demonstrated the conditions that favor development of long-term memory T cells over short-term memory T cells, which can respond quickly but do not stick around for very long after the initial infection. That discovery could help vaccine designers better tailor their formulas to elicit long-term memory immunity, says Jianzhu Chen, MIT professor of biology and member of the David H. Koch Institute for Integrative Cancer Research.

Chen and Herman Eisen, emeritus professor of biology, are senior authors of a paper on the work that appeared in theProceedings of the National Academy of Sciences the week of Dec. 13.

In the PNAS study, the MIT team looked at mice infected with influenza. In mice, as in humans, influenza virus stimulates T cells, whose job is to kill infected cells. Every T cell is programmed to recognize different foreign proteins (also called antigens) located on the surfaces of infected cells. When a T cell binds to the antigen, the T cell becomes activated and starts rapidly reproducing, creating an army of cells that can identify and destroy the invader.

Once the infection is eliminated, most of the activated T cells die off, but a few of them stick around, in case the virus comes back. These are short-term memory T cells. Because they have already battled the virus and reproduced many times, they survive only weeks or months after the initial infection. (T cells can only divide a certain number of times before they die.)

A set of long-term memory T cells also develops during infection. These cells are programmed differently, so they can persist for decades. Recipients of the smallpox vaccine, for example, have been shown to still have T cells against the virus up to 70 years later, says Eisen.

Until now, it has been unclear how these different cell types develop. In their new study, Eisen and Chen investigated the role three factors: T-cell location, the amount of antigen exposure, and length of exposure.

Scientists already knew that T cell contact with a large amount of virus provokes development of short-term memory T cells, says Eisen. Chen and colleagues discovered that large amounts of antigen also suppress development of long-term memory T cells. Those cells only develop when exposed to a small amount of the antigen for a short period of time.

For example, if you have an infection in the respiratory tract, nearby T cells will be exposed to many viruses and become short-term memory cells. Those cells hang around the respiratory tract, ready to pounce quickly if the same virus re-infects you, but they eventually die off.

In more distant parts of the body, T cells are exposed to only small amounts of the virus, and some of those cells become long-term memory T cells specific to that virus. These maintain a low level of constant vigilance in case the virus ever returns.

Ulrich von Andrian, professor of immunopathology at Harvard, says the new study’s major contribution is its experimental support of existing theories. “It builds on ideas that have been around for a while, that were not rigorously tested by experiments, for the most part,” says von Andrian, who was not part of the research team.

When developing vaccines, the goal is usually to generate a stable population of long-term memory T cells. This study suggests that the best way to do that is to give a small amount of antigen, and, for vaccines that require multiple injections, not to give them too frequently.

“The general rule of thumb is that you don’t want to give a large amount of antigen on a short-term basis,” says Chen. He adds that the amount of antigen for inducing a long-term memory T cells likely varies depending on the route of immunization and the form of antigen, and so the dosage for each vaccine will have to be determined through experiments.

He says the findings will likely not impact flu-vaccine design because existing dosages have already been optimized over many decades. However, the findings should be applicable to vaccines now under development for other diseases, such as HIV, tuberculosis and dengue fever, says Chen.

Material adapted from MIT.

Abstract / Reference
“Antigen-bearing dendritic cells regulate the diverse pattern of memory CD8 T-cell development in different tissues,” by Ching-Hung Shen, Oezcan Talay, Vinay S. Mahajan, Ilya B. Leskov, Herman N. Eisen, and Jianzhu Chen. Proceedings of the National Academy of Sciences, 13 December, 2010

The team based in the Institute for Lung Health at the University of Leicester and Glenfield Hospital examined the impact on asthmatics of a common environmental mold, Aspergillus fumigates (A. fumigatus), usually found in soil and compost heaps.

Professor Andy Wardlaw from the University of Leicester said: “Asthma is a very common condition where the breathing tubes (bronchi) can go into spasm making it difficult to breathe. Around a fifth of adults with severe asthma, which they have had for a long time, get permanent (fixed) narrowing of their bronchi. It is known that A. fumigatus can grow in the lungs of some people with asthma and mold allergy, which can cause severe lung damage.

“This problem is thought to only affect a very small number of people with asthma; however, about half of people with severe asthma have evidence of allergy to molds like A. fumigatus.”

Researchers in the Institute for Lung Health at the University of Leicester and Glenfield Hospital, Leicester, carried out a study funded by the Midlands Asthma and Allergy Research Association (MAARA, a Midlands based charity funding research into asthma and allergy research. www.maara.org) and the European Regional Development Fund (ERDF), to determine whether the problem of A. fumigatus growing in the lungs is more common than previously thought, and whether this could explain the fixed narrowing of the airways that occurs in some people with asthma.

Professor Wardlaw added: “Our study showed that 6 out of 10 people with asthma who were allergic to A. fumigatus grew the mold from their sputum. We also found that if you were allergic to A. fumigatus you had more narrowing of the airways than if you were not allergic, and this was worse in patients from whom A. fumigatus was grown.

“Our research concluded that it is possible that fixed narrowing of breathing tubes in many people with asthma could be caused by A. fumigatus growing in their lungs.

“Treating individuals from whom A. fumigatus is detected with antibiotics against the mold may prevent fixed narrowing of the airways.”

Material adapted from University of Leicester.

Reference
Abbie Fairs, Joshua Agbetile, Beverley Hargadon, Michelle Bourne, William R. Monteiro, Christopher E. Brightling, Peter Bradding, Ruth H. Green, Kugathasan Mutalithas, Dhananjay Desai, Ian D. Pavord1, Andrew J. Wardlaw and Catherine H. Pashley. IgE Sensitization to Aspergillus fumigatus Is Associated with Reduced Lung Function in Asthma. December 2010 issue of the American Journal of Respiratory and Critical Care Medicine.

In an article published in the December issue of Archives of General Psychiatry, Emory neuroscientist Charles Raison, MD, and colleagues say there is mounting evidence that disruptions in ancient relationships with microorganisms in soil, food, and the gut may contribute to the increasing rates of depression.

According to the authors, the modern world has become so clean, we are deprived of the bacteria our immune systems came to rely on over long ages to keep inflammation at bay.

“We have known for a long time that people with depression, even those who are not sick, have higher levels of inflammation,” explains Raison.

“Since ancient times benign microorganisms, some times referred to as ‘old friends,’ have taught the immune system how to tolerate other harmless microorganisms, and in the process, reduce inflammatory responses that have been linked to the development of most modern illnesses, from cancer to depression.”

Experiments are currently being conducted to test the efficacy of treatments that use properties of these “old friends” to improve emotional tolerance. “If the exposure to administration of the ‘old friends’ improves depression,” the authors conclude, “the important question of whether we should encourage measured re-exposure to benign environmental microorganisms will not be far behind.”

Dr. Raison is associate professor in the Department of Psychiatry and Behavioral Sciences at Emory University School of Medicine. Co-authors include Christopher A. Lowry, PhD, Department of Integrative Physiology and Center for Neuroscience, University of Colorado, and Graham A. W. Rook, BA, MB, BChir, MD, FSB, Department of Infection, Windeyer Institute for Medical Sciences, University College London.

Material adapted from Emory University.

“Superantigens have a real talent for disrupting the body’s immune system,” says Karin Lindkvist from the University of Gothenburg’s Department of Cell- and Molecular Biology, one of the authors of the article. “If you’re infected with bacteria that secrete superantigens, your immune system will respond so strongly that it’ll make you ill. Our study shows that superantigens activate the immune system in more ways than previously thought.”

We are all exposed daily to various types of foreign organism that can harm us. The human body has therefore developed cells whose role it is to “kill” and remove all foreign invaders that find their way in – the immune system.

Antibiotic-resistant bacteria have become increasingly common with the more widespread use of different types of antibiotics. Yellow staphylococci (Staphylococcus aureus) are one of the most common bacteria in the world around us, with most children and adults carrying them at some point. One strain, MRSA (methicillin-resistant Staphylococcus aureus), has developed resistance to penicillin and other penicillin-like antibiotics that are normally used to treat infections caused by staphylococci. Staphylococci can cause a variety of conditions such as long-term wound infections and abscesses, and can also lead to food poisoning.

Karin Lindkvist and Maria Saline are two of the researchers who have studied how superantigens activate the immune system. Photograph: University of Gothenburg.

The toxins produced by staphylococci are also known as superantigens. A normal viral infection will trigger the activation of around 0.0001% of the body’s natural killer cells (T cells), which is enough to destroy the virus. However, contracting bacteria that secrete superantigens leads to the activation of 5-20% of the body’s T cells. Such a strong immune response will often result in illness, which generally involves fever and extreme nausea. Superantigens are also well-known for causing toxic symptoms, as in toxic shock syndrome. There is also some speculation as to whether superantigens can cause autoimmune disorders, such as rheumatoid arthritis.

“By investigating how superantigens activate the immune system via its T cells, we’ve been able to show that they bind to more than one part of the T cell receptor,” says Lindkvist. “This is an important discovery for our understanding of superantigens’ biological function, and for the future development of a vaccine against superantigens. We haven’t yet looked at whether other superantigens can activate T cells in the same complex way, but it’s reasonable to assume that they can.”

In addition to Karin Lindkvist, the research team behind the discovery comprises Maria Saline, Karin Rödström, Gerhard Fischer, Vladislav Orekhov and Göran Karlsson, all from the University of Gothenburg.

The study The structure of superantigen complexed with TCR and MHC reveals novel insights into superantigenic T cell activation has been published in the scientific journal Nature Communications.

Material adapted from University of Gothenburg.

Reference
Journal: Nature Communications 1, (1 November 2010)
Title: The structure of superantigen complexed with TCR and MHC reveals novel insights into superantigenic T cell activation.
Authors: Maria Saline, Karin E. J. Rödström , Gerhard Fischer, Vladislav Yu. Orekhov, B. Göran Karlsson & Karin Lindkvist-Petersson

Dr. Daniel Lindqvist from the Psychoimmunology Unit at Lund University is presenting these results in his PhD thesis. He is part of a research group led by Dr Lena Brundin, which sees inflammation in the brain as a strong contributory factor to depression. This is a new theory that challenges the prevalent view that depression is only due to a lack of the substances serotonin and noradrenaline.

“However, current serotonin-based medication cures far from all of the patients treated. We believe that inflammation is the first step in the development of depression and that this in turn affects serotonin and noradrenaline”, says Daniel Lindqvist.

One of the articles in his thesis shows that suicidal patients had unusually high levels of inflammation-related substances (cytokines) in their spinal fluid. The levels were highest in patients who had been diagnosed with major depression or who had made violent suicide attempts, e.g. attempting to hang themselves.

The research group at the Division of Psychiatry in Lund is now getting ready to conduct a treatment study based on its theory. Depressed patients will be treated with anti-inflammatory medication in the hope that their symptoms will be reduced.

The researchers believe that the cause of the inflammation that sets off the process could vary. It could be serious influenza, or an auto-immune disease, such as rheumatism, or a serious allergy that leads to inflammation in the body. A certain genetic vulnerability is probably also required, i.e. certain gene variants that make some people more sensitive than others.

Other studies in Daniel Lindqvist’s thesis show that patients with depression and a serious intention of committing suicide had low levels of the stress hormone cortisol in their blood. The cortisol levels were also low in saliva samples from individuals several years after a suicide attempt. This has been interpreted to mean that the depressed patients’ mental suffering led to a sort of ‘breakdown’ in the stress system, resulting in low levels of stress hormones.

“It is easy to take and analyse blood and saliva samples. Cortisol and inflammation substances could therefore be used as markers for suicide risk and depth of depression”, says Daniel Lindqvist.

Material adapted from Lund University.

The team, led by Dr Prakash Nagarkatti from the University of South Carolina, focused their research on cannabinoids, a group of compounds found inside the cannabis plant, including THC (delta-9 tetahydrocannabinol) which is already used for medical purposes, such as pain relief.

“Cannabis is one of the most widely used drugs of abuse worldwide and it is already believed to suppress immune functions making the user more susceptible to infections and some types of cancer,” said Dr Nagarkatti. “We believe the key to this suppression is a unique type of immune cell, which has only recently been identified by immunologists, called myeloid-derived suppressor cells, MDSCs.”

While most immune cells fight against infections and cancers to protect the host, MDSCs actively suppress the immune system. The presence of these cells is known to increase in cancer patients and it is believed that MDSCs may suppress the immune system against cancer therapy, actually promoting cancer growth.

Dr. Nagarkatti’s team demonstrated that cannabinoids can trigger a massive number of MDSCs through activation of cannabinoid receptors. This research reveals, for the first time, that marijuana cannabinoids may suppress the immune system by activating these unique cells.

“These results raise interesting questions on whether increased susceptibility to certain types of cancers or infections caused from smoking marijuana results from induction of MDSCs,” said Nagarkatti. “MDSCs seem to be unique and important cells that may be triggered by inappropriate production of certain growth factors by cancer cells or other chemical agents such as cannabinoids, which lead to a suppression of the immune system’s response.”

In a related study, also published in the European journal of Immunology, Dr. Christian Vosshenrich from the Institut Pasteur in Paris, reveals that when cancer cells grow they produce a molecule called interleukin-1 β (IL-1β), which also triggers MDSCs. This study identifies how MDSCs produced during cancer growth also weaken the ability of immune cells to kill cancer cells.

“Marijuana cannabinoids present us with a double edged sword,” concluded Dr Nagarkatti. “On one hand, due to their immunosuppressive nature, they can cause increased susceptibility to cancer and infections. However, further research of these compounds could provide opportunities to treat a large number of clinical disorders where suppressing the immune response is actually beneficial.”

Material adapted from Wiley-Blackwell.

References
Elkabets. M, Ostrand-Rosenberg. S, Di Santo. J, Apte. R, Vosshenrich. C, “IL-1β regulates a novel myeloid-derived suppressor cell subset that impairs NK cell development and function”, European Journal of Immunology, Wiley-Blackwell, November 2010, DOI: 10.1002/eji.201041037

Hedge. V, Nargarkatti. M, Nargarkatti. P, “Cannabinoid receptor activation leads to massive mobilization of myeloid-derived suppressor cells with potent immunosuppressive properties” European Journal of Immunology, Wiley-Blackwell, November 2010 DOI: 10.1002/eji.201040667

The finding catapults the humble microglia cell from its well-recognized duty of protecting the brain to direct involvement in creating the cellular networks at the core of brain behavior. Its apparent role as an architect of synapses – junctions between brain cells called neurons – comes as a surprise to researchers long accustomed to thinking of microglia as cells focused exclusively on keeping the brain safe from threats.

“When scientists talk about microglia, the talk is almost always about disease. Our work suggests that microglia may actively contribute to learning and memory in the healthy brain, which is something that no one expected,” said Ania Majewska, Ph.D., the neuroscientist at the University of Rochester Medical Center who led the work.

Researchers Marie-Ève Tremblay, Ph.D., and Ania Majewska, Ph.D.

First author Marie-Ève Tremblay, Ph.D., a post-doctoral associate in Majewska’s lab, used two sophisticated imaging techniques to get an unprecedented look at microglia in the brain. She used immunoelectron microscopy and two-photon microscopy to look at how microglia interact with synapses in the brains of healthy mice as their environment changed. In the experiments, the scientists looked into the brain while the mice were on a normal cycle of light and dark; while the mice were in the dark for several days; and again when the mice went back to a normal light/dark cycle.

This two-photon image shows dynamic interaction between a microglial cell (yellow) and a neuron’s dendritic spines (green points) in the living brain. The spines with white arrows are being touched by the microglia; the red arrow points to a spine that had been touched by the microglia just five minutes earlier.

“Why are microglia so dynamic? What are they contacting, and why, even when there is no injury?” asked Tremblay. “The idea that immune cells are always active in our brain, contributing to the ongoing process of learning and memory, really challenges current views of the brain.”

Most notably, the scientists found that microglia changed their activity in response to the environment. When the lights were off, microglia contacted more synapses, were more likely to reach toward a particular type of synapse, tended to be larger, and were more likely to appear to be poised to destroy a synapse. When the lights came back on, most of those activities reversed.

“The fact that microglia change their behavior based on visual input is a remarkable feat for a cell whose role supposedly is all about brain injury and disease. Just the fact that microglia can sense that something has changed in the environment is a novel idea,” said Majewska, who is assistant professor in the Department of Neurobiology and Anatomy.

The team showed how microglia send out their extensions, which are like tentacles, constantly, oftentimes targeting synapses. In time-lapse video of their experiments, microglia literally dance across the screen, sending their extensions this way and that throughout the brain constantly. The cells also are known to travel remarkably quickly through the very dense and convoluted environment of the brain, traveling perhaps two millionths of a meter in a minute – remarkably fast on a molecular scale.

Tremblay and Majewska showed that microglia touch and wrap around synapses constantly and may have some say in deciding which synapses will survive and which will disappear. Microglia also appear key to creating or changing the extracellular space around synapses, a factor that would profoundly affect synapse function.

Electron micrograph of a microglia cell (shown in black) touching surrounding cells in the synapse, including dendritic spines (pink) and axon terminals (blue).

The scientists found that dendritic spines that were touched by microglial processes during Tremblay’s first imaging session were more than three times as likely to be eliminated within the next two days compared to spines that were not. And microglia interacted more often with smaller dendritic spines, which generally indicate synapses that are either in the early stage of formation or that can easily be broken.

The research helps move microglia up into the pantheon of brain cells known to affect brain signaling. Years ago, brain signaling was thought to be the exclusive domain of neurons. During the last two decades, scientists have found that astrocytes also have vast signaling networks. Now, microglia also seem to be an important player in the brain’s ability to adapt immediately and constantly to the environment and to shift its resources accordingly.

The findings are timely for scientists who are increasingly studying links between the nervous and immune systems, Tremblay said. The role of microglial cells themselves is being looked at in an array of conditions, including Parkinson’s and Alzheimer’s diseases, schizophrenia, obsessive-compulsive disorder and even autism.

Former technician Rebecca Lowery is also an author of the paper. Also contributing were Gayle Schneider and Karen Bentley of the Electron Microscope Research Core Facility. The work was funded by the National Eye Institute, the Whitehall Foundation, the Alfred P. Sloan Foundation, and a Career Award from the Burroughs Wellcome Fund. Tremblay has also been supported by a Fonds de la recherche en santé du Québec postdoctoral training award.

Material adapted from University of Rochester Medical Center.

Download / Reference
Tremblay M-È, Lowery RL, Majewska AK. (2010). Microglial Interactions with Synapses Are Modulated by Visual Experience. PLoS Biol 8(11): e1000527. doi:10.1371/journal.pbio.1000527

“The study shows for the first time that the concentration of PGEs, propylene glycol and glycol ethers, in bedroom air was linked to an increased risk of developing asthma, hay fever, and eczema in children,” says Carl-Gustaf Bornehag, professor of public health science at Karlstad University and associated with the SP Technical Research Institute of Sweden. “The increase in risk varied between 50 and 180 percent. It was also found that a higher concentration of PGEs in indoor air was associated with children evincing antibodies (IgE) against allergens such as cats, dogs, pollen. Our analyses also revealed that the use of water-based paint in the dwelling, as well as water-based cleansers, was linked to a higher concentration of PGEs in bedroom air.”

What does this mean?
In recent decades a huge number of chemicals have been introduced into our everyday environments. Such chemicals are primarily related to construction materials, paints, etc. and a great number of common consumer products, such as cleansers, plastics, toys, cosmetics, and packaging.

“We have previously shown that phthalates from soft PVD could be tied to allergic conditions in children,” says Carl-Gustaf Bornehag. “Now we have focused on PGEs, which are a group of volatile organic compounds found in water-based indoor paints and cleansers, for example. Among the PGE substances identified are compounds suspected of disturbing hormones, which was also the case regarding the phthalates we studied earlier.”

“Our findings once again raise the question of the health-related aspects of the use of chemicals in our everyday lives,” says Carl-Gustaf Bornehag. “Particularly when it comes to exposure in our home environments, since small children and pregnant women spend a great deal of their time there and there are many indications that exposing fetuses and infants is probably more risky. Our current research is addressing this, that is, what does it entail in terms of chronic conditions later in life that we expose fetuses and infants to a great number of chemicals that are suspected of being toxic.”

The study comprised 198 preschool children with asthma and allergy and 202 healthy controls included in the Housing-Children-Health Study in the county of Värmland. Dwellings were examined by professional inspectors, and air samples were taken in the children’s bedrooms, where eight groups of volatile compounds were analyzed. The children were examined by physicians. Moreover, parents responded to a questionnaire about the family’s health, lifestyle, etc.

The article is a result of a collaboration between Karlstad University and the Harvard School of Public Health in the U.S.

Material adapted from Expertanswer (Expertsvar in Swedish).

Download / Reference
Choi H, Schmidbauer N, Sundell J, Hasselgren M, Spengler J, et al. (2010). Common Household Chemicals and the Allergy Risks in Pre-School Age Children. PLoS ONE 5(10): e13423. doi:10.1371/journal.pone.0013423

“There is a strong correlation between flu vaccination and Medicaid reimbursement rates,” said Byung-Kwang Yoo, M.D., Ph.D., an assistant professor in the Department of Community and Preventive Medicine at URMC and the lead author of the study. “Improving reimbursement rates could improve vaccine coverage among poor children.”

The study looked at data from the National Immunization Survey (NIS) for the 2005-2006, 2006-2007, and 2007-2008 flu seasons. The survey, which is sponsored by the Centers for Disease Control and Prevention (CDC), compiles detailed information – including socio-economic data such as the family’s income level, number of children, ethnicity, and mother’s education level and marital status – on childhood immunization rates.

The authors looked at immunization rates for children between the ages of 6 and 23 months. The CDC first recommended that children in this age group receive the annual flu vaccine in 2004. Using the NIS data they were able to determine the vaccination rates in each state by family income level.

The income threshold for Medicaid eligibility varies by state, so the study compared rates for children at or below the federal poverty – $22,000 or less for a family of four – a population that is universally covered by state Medicaid programs. Children in families below the federal poverty level have the lowest vaccination rates.

The authors then compared the vaccination rates in each state with the amount of money physicians are reimbursed by Medicaid for administering the vaccine. In 1993, the U.S. Congress created the Vaccines for Children program which covers the actual cost of flu vaccine for Medicaid-eligible children. However, doctor’s offices still incur costs for administering the vaccine (e.g. overhead, nurses and staff time, etc.)

Medicaid reimbursement rates for services are determined on a state-by-state basis and, in the case of vaccine administration, are widely divergent. Reimbursement rates during the period studied ranged from $2 in Colorado, Connecticut, and Hawaii to almost $18 in New York. The average reimbursement was $9. In a previous study, Yoo and his colleagues calculated that the actual cost to doctor’s offices for administering vaccines was $20.

“In most states the reimbursement from Medicaid is far below the actual cost,” said Yoo. “The may create an obvious disincentive when physician’s offices lose money every time they give a flu shot, even though vaccines are provided for free.”

Their analysis showed that states with lower Medicaid reimbursement rates had lower vaccination rates. Using mathematic models, the authors were then able to calculate the impact on vaccination rates if Medicaid reimbursement rates were increased. They found that for every extra dollar in reimbursement, vaccination rates could increase by between 0.6 and 0.9 percentage points. Meaning a $10 increase in reimbursement could raise vaccination rates by up to 10 percentage points among low income children.

While it is clear that raising reimbursement rates come at a cost, the authors point out that there is a significant financial burden associated with the treatment of flu. Among U.S. children under the age of 5 years it is estimated that the annual cost associated with hospitalization as a result of influenza is upwards of $163 million. The annual cost burden of emergency room visits is estimated to be as high as $279 million.

“The more children with access to seasonal flu vaccinations, the lower the overall burden will be on our health care system from the costs associated with treating influenza,” said URMC pediatrician Peter Szilagyi, M.D, M.P.H., a co-author of the study. “This study demonstrates that we can remove one of the barriers to higher vaccination rates among poor children by more closely aligning reimbursement with cost.”

Additional co-authors of the study include Megumi Kasajima and Andrea Berry, both the URMC Department of Community and Preventive Medicine. The study was funded by the National Institute of Allergy and Infectious Disease.

Material adapted from University of Rochester Medical Center.

Lead author Linda Carpenter, associate professor of psychiatry and human behavior, said that prior research has revealed preliminary associations between inflammatory markers, (such as cytokines or proteins released in the bloodstream such as interleuken-6) and depression and anxiety disorders, so this new finding could ultimately improve doctors’ understanding of how stressors in childhood shape the risk people face for developing those conditions later in life.

“Animal models have given us some signals about how the functioning of an organism’s stress response system can run amok for the rest its life as a result of some of the earliest environment exposures — adverse ones in particular,” said Carpenter, who also treats patients with mood disorders at Butler. “This is one of a number of studies we’ve been doing with generally healthy adults, looking at the effects of adverse early environment and how it might create a biological abnormality that could predispose somebody to future depression or another medical disorders.”

A study in 2006 at Emory University had shown that men who were mistreated as kids and were now struggling with symptoms of depression as adults had an elevated inflammatory response to stress, Carpenter said. The goal of her team in this pilot study was to find out whether the same is true of adults who endured early life adversity, but are not experiencing psychiatric disorders like depression. The results supported the idea that people who struggled with childhood abuse and neglect have exaggerated immune system reactions later in life, Carpenter said, perhaps in dictating a trajectory toward future health challenges.

Stress test
To conduct the research, the team recruited 69 adults, ranging in age from their late teens to early 60s. After administering a battery of tests to ensure that the subjects were psychiatrically healthy and not taking any medicines or drugs that would bias the results, the team surveyed them extensively about their childhood experiences. Of the group, 19 reported moderate to severe neglect or abuse.

To measure each group’s inflammatory response to stress, the researchers then asked them to undergo a laboratory role-play called the Trier Social Stress Test, in which they had to appear before a panel of “judges” and both speak about their qualifications for their job and then count backward from a number by 13s. All the while, the researchers were measuring various vital signs and collecting blood samples.

Among the subjects who reported adverse childhood experiences, the concentrations of interleukin-6 in their blood were always elevated above those of the control group, and the gap widened considerably as the subject recovered from the psychological stress during several hours after the role-play.

Advancing disease understanding
Further research is necessary, – for instance, expanding this small study to incorporate a larger sample size – Carpenter said. That, combined with more work exploring the connection between immune system function and depression, could eventually lead to a blood test that would be used to assess a patient’s risk for developing depression or other medical disorders. It might also guide the choice of treatments or prevention measures.

“We’re not yet at a point,where we can say to healthy people ‘Go get your stress-test cytokine profile done’ as a tool to prevent, diagnose, or treat medical disorders,” she said. “But what’s clear is that a life of excessive stress-induced inflammatory chemicals in your bloodstream is unlikely to be a good thing.”

In the future, the way to help some patients, Carpenter added, might be in finding ways to ratchet down that inflammatory response to stress.

Material adapted from Brown University.

Alex Palacios, a special representative of the GAVI Alliance, a public-private partnership aimed at increasing immunization rates in poor countries, said that despite public health advances in the US and other wealthy countries over the last 60 years, regular diseases that have all but been eradicated can still threaten lives if immunization rates fall.

“Whooping cough, diphtheria and diseases that some of us don’t even recognize anymore are not gone forever. They are widespread in developing countries and do also arise here in the US,” said Palacios. “It is important that vaccine-preventable diseases are kept under control no matter where they crop up, whether it be in Texas or in Kenya. Diseases don’t recognize borders.”

Last year, 3,358 Texans had whooping cough, also known as pertussis, and three of them died. It was the highest number of cases in a half-century. So far this year, Texas has reported 1,783 cases. California has at least 4,017 cases of the highly infectious disease and is on track to break a 55-year-old record. Ohio has reported 1,019 cases. In contrast, in Kenya last year, there were an estimated 1,900 deaths due to pertussis; 7,500 deaths to rotavirus, a diarrheal disease; and 36,000 deaths due to pneumonia and influenza.

Anna Dragsbaek, President and CEO of The Immunization Partnership, said that Texans should be concerned about outbreaks of vaccine-preventable diseases anywhere in the world.

“As long as there is polio and other vaccine-preventable diseases in the world, outbreaks are only a plane flight away,” she said. “It may seem like it’s safe to be complacent. But in actuality, diseases such as whooping cough and measles arise only because we have been complacent. We are still all at risk because not enough people are immunized worldwide. The health of people in developing countries matters to Texas.”

Vaccination of children and adults can prevent pertussis. The pertussis vaccine is given along with diphtheria and tetanus vaccines in the same shot (called DTaP) for children. DTaP cannot be given to babies less than six weeks old or to anyone seven years of age or older. After that, children and adults are given a booster shot.

Experts say that the lack of vaccine coverage among adults in the US is the main reason for the upsurge in the last two years of whooping cough. Infants, who are too young to be fully immunized against the illness, are at particular risk. Health officials recommend that parents and caretakers receive booster shots to extend their immunity to the disease and lower the risk to babies.

Palacios and Dragsbaek will speak on the global state of immunizations at the Texas Immunization Summit 2010 in Fort Worth on September 30th, hosted by The Immunization Partnership and sponsored by St. David’s Foundation. Palacios will give a keynote address over lunch on “The Global Health Equity Challenge: New Vaccines Against Pneumonia and Rotavirus” on October 1st. He will also be speaking at a World Affairs Council of Dallas/Fort Worth event on “Saving the Future: Global Efforts to Reduce Child Mortality” on September 30th.

Last week at the United Nations Summit on the Millennium Development Goals in New York City, global political leaders endorsed immunization of the world’s children as one of the priorities to saving lives and improving health.

Palacios, who attended the UN Summit, said people everywhere, including in the United States, will be affected by the outcome of discussions about stopping vaccine-preventable diseases around the world.

“There is the potential to save four million lives over the next five years if we can immunize a significant number of the world’s poor children against the two biggest childhood killers: pneumonia and diarrhea,” he said.

He noted that the GAVI Alliance requires $4.3 billion in order to introduce the vaccines.

In its first 10 years, with funding from the Bill & Melinda Gates Foundation and the United States and other nations, GAVI has helped to deliver vaccines to more then 250 million children, an investment that is expected to save 5.4 million lives in the poorest nations.

In the last decade, despite the progress of developing countries in using more childhood vaccines, an estimated eight million children died from pneumococcal disease, a leading cause of pneumonia and meningitis, and five million children died from rotavirus, the major cause of severe diarrhoea among young children that is most deadly in poor nations. Experts predict that the introduction of the two vaccines can eventually save the lives of one million children per year.

“Vaccines are great value for money, and their impact is measured in the number of children whose lives we can save,” said Palacios.

Material adapted from GAVI Alliance.

In a paper published last week in the journal Science, Hongrong Liu, a UCLA postdoctoral researcher in microbiology, immunology and molecular genetics, and colleagues reveal an atomically accurate structure of the adenovirus that shows the interactions among its protein networks. The work provides critical structural information for researchers around the world attempting to modify the adenovirus for use in vaccine and gene-therapy treatments for cancer.

To modify a virus for gene therapy, researchers remove its disease-causing DNA, replace it with medications and use the virus shell, which has been optimized by millions of years of evolution, as a delivery vehicle.

Lily Wu, a UCLA professor of molecular and medical pharmacology and co-lead author of the study, and her group have been attempting to manipulate the adenovirus for use in gene therapy, but the lack of information about receptors on the virus’s surface had hampered their quest.

The structure of an adenovirus. By averaging thousands of noisy cryo-electron microscopy images (left bottom), researchers have determined the atomic structure of the human adenovirus (color). This structure reveals complex interactions among protein networks (center). Such interactions can be targeted to optimize an adenovirus for anti-cancer and gene therapy applications.

“We are engineering viruses to deliver gene therapy for prostate and breast cancers, but previous microscopy techniques were unable to visualize the adapted viruses,” Wu said. “This was like trying to a piece together the components of a car in the dark, where the only way to see if you did it correctly was to try and turn the car on.”

To better visualize the virus, Wu sought assistance from Hong Zhou, a UCLA professor of microbiology, immunology and molecular genetics and the study’s other lead author. Zhou uses cryo-electron microscopy (cryoEM) to produce atomically accurate three-dimensional models of biological samples such as viruses.

Wu, who is also a researcher at the California NanoSystems Institute (CNSI) at UCLA, learned of Zhou’s work after he was jointly recruited to UCLA from the University of Texas Medical School at Houston by the UCLA Department of Microbiology, Immunology and Molecular Genetics and UCLA’s CNSI.

About a year ago, once the transfer of Zhou’s lab was complete, Sok Boon Koh, one of Wu’s students, sought out Zhou’s group for their expertise and initiated the collaboration.

“This project exemplifies my excitement about being part of an institute as innovative as CNSI,” Zhou said. “Not only am I able to work with state-of-the-art equipment, but because CNSI is the hub for nanotechnology research and commercialization at UCLA, I have the opportunity to collaborate with colleagues across many disciplines.”

Working in the Electron Imaging Center for Nanomachines at the CNSI, a lab run by Zhou, the researchers used cryoEM to create a 3-D reconstruction of the human adenovirus from 31,815 individual particle images.

“Because the reconstruction reveals details up to a resolution of 3.6 angstroms, we are able to build an atomic model of the entire virus, showing precisely how the viral proteins all fit together and interact,” Zhou said. An angstrom is the distance between the two hydrogen atoms in a water molecule, and the entire adenovirus is about 920 angstroms in diameter.

Armed with this new understanding, Wu and her group are now moving forward with their engineered versions of adenovirus to use for gene therapy treatment of cancer.

“This breakthrough is a great leap forward, but there are still many obstacles to overcome,” Wu said. “If our work is successful, this therapy could be used to treat most forms of cancer, but our initial efforts have focused on prostate and breast cancers because those are the two most common forms of cancer in men and women, respectively.”

The group is working with the adenovirus because previous research has established it as a good candidate for gene therapy due to its efficiency in delivering genetic materials inside the body. The virus shell is also a safe delivery vehicle; tests have shown that the shell does not cause cancer, a problem encountered with some other virus shells. The adenovirus is relatively non-pathogenic naturally, causing only temporary respiratory illness in 5 to 10 percent of people.

CryoEM enables such a high-resolution reconstruction of biological structures because samples, in water, are imaged directly. In contrast, with X-ray crystallography (the conventional technique for atomic resolution models of biological structures), researchers grow crystal structures replicating the sample and then use diffraction to solve the crystal structure. This technique is limited because it is difficult to grow crystals for all proteins, samples for x-ray crystallography need to be very pure and uniform, and crystals of large complexes may not diffract to high resolution. These limitations resulted in critical areas of the adenovirus surface being unresolved using x-ray crystallography.

The study was funded by the National Cancer Institute and the U.S. Department of Defense.

Material adapted from UCLA.

That way, the drugs reach only their intended targets, greatly reducing the risk to the patient. The new approach could dramatically improve the success rate of immune-cell therapies, which hold promise for treating many types of cancer, says Darrell Irvine, senior author of a paper describing the technique in the Aug. 15 issue of Nature Medicine.

“What we’re looking for is the extra nudge that could take immune-cell therapy from working in a subset of people to working in nearly all patients, and to take us closer to cures of disease rather than slowing progression,” says Irvine, associate professor of biological engineering and materials science and engineering and a member of MIT’s David H. Koch Institute for Integrative Cancer Research.

MIT engineers have developed a way to attach drug-carrying pouches (yellow) to the surfaces of cells. (Image-Darrell Irvine and Matthias Stephan)

The new method could also be used to deliver other types of cancer drugs or to promote blood-cell maturation in bone-marrow transplant recipients, according to the researchers.

To perform immune-cell therapy, doctors remove a type of immune cells called T cells from the patient, engineer them to target the tumor, and inject them back into the patient. Those T cells then hunt down and destroy tumor cells. Clinical trials are under way for ovarian and prostate cancers, as well as melanoma.

Although immune-cell therapy is a promising approach to treating cancer, success has been limited by difficulties in generating enough T cells that are specific to the cancer cells and getting those T cells to function properly in the patient.

To overcome those obstacles, researchers have tried injecting patients with adjuvant drugs that stimulate T-cell growth and proliferation. One class of drugs that has been tested in clinical trials is interleukins — naturally occurring chemicals that help promote T-cell growth but have severe side effects, including heart and lung failure, when given in large doses.

Irvine and his colleagues took a new approach: To avoid toxic side effects, they designed drug-carrying pouches made of fatty membranes that can be attached to sulfur-containing molecules normally found on the T-cell surface.

In the Nature Medicine study, the researchers injected T cells, each carrying about 100 pouches loaded with the interleukins IL-15 and IL-21, into mice with lung and bone marrow tumors. Once the cells reached the tumors, the pouches gradually degraded and released the drug over a week long period. The drug molecules attached themselves to receptors on the surface of the same cells that carried them, stimulating them to grow and divide.

Within 16 days, all of the tumors in the mice treated with T cells carrying the drugs disappeared. Those mice survived until the end of the 100-day experiment, while mice that received no treatment died within 25 days, and mice that received either T cells alone or T cells with injections of interleukins died within 75 days.

Irvine’s approach to delivering the adjuvant drugs is both simple and innovative, says Dranoff. “The idea of modifying T cells in the lab to make them work better is something many people are exploring through more complicated approaches such as gene modification,” he says. “But here, the possibility of just attaching a carefully engineered nanoparticle to the surface of cells could be a much simpler procedure.”

While he is now focusing on immune-cell therapy, Irvine believes his cell pouches could be useful for other applications, including targeted delivery of chemotherapy agents. “There are lots of people studying nanoparticles for drug delivery, especially in cancer therapy, but the vast majority of nanoparticles injected intravenously go into the liver or the spleen. Less than 5 percent reach the tumor,” says Irvine, who is also a Howard Hughes Medical Institute Investigator.

With a new way to carry drugs specifically to tumors, scientists may be able to resurrect promising drugs that failed in clinical trials because they were cleared from the bloodstream before they could reach their intended targets, or had to be given in doses so high they had toxic side effects.

Irvine and his colleagues also demonstrated that they could attach their pouches to the surface of immature blood cells found in the bone marrow, which are commonly used to treat leukemia. Patients who receive bone-marrow transplants must have their own bone marrow destroyed with radiation or chemotherapy before the transplant, which leaves them vulnerable to infection for about six months while the new bone marrow produces blood cells.

Delivering drugs that accelerate blood-cell production along with the bone-marrow transplant could shorten the period of immunosuppression, making the process safer for patients, says Irvine. In the Nature Medicine paper, his team reports successfully enhancing blood-cell maturation in mice by delivering one such drug along with the cells.

Irvine is now starting to work on making sure the manufacturing process will yield nanoparticles safe to test in humans. Once that is done, he hopes the particles could be used in clinical trials in cancer patients, possibly within the next two or three years.

Material adapted from Massachusetts Institute of Technology.

Kay believes PIE12-trimer is ideally suited for use as a vaginal microbicide (topically applied drug) to prevent HIV infection. His research group is particularly focused on preventing the spread of HIV in Africa, which has an estimated two-thirds of the world’s 33 million HIV patients according to the World Health Organization.

“We believe that PIE12-trimer could provide a major new weapon in the arsenal against HIV/AIDS. Because of its ability to block the virus from infecting new cells, PIE12-trimer has the potential to work as a microbicide to prevent people from contracting HIV and as a treatment for HIV infected people. HIV can develop resistance rapidly to existing drugs, so there is a constant need to develop new drugs in hopes of staying ahead of the virus.” Kay said.

PIE12-trimer was designed with a unique “resistance capacitor” that provides it with a strong defense against the emergence of drug-resistant viruses.

Peptide drugs have great therapeutic potential, but are often hampered by their rapid degradation in the body. D-peptides are mirror-image versions of natural peptides that cannot be broken down, potentially leading to higher potency and longevity in the body. Despite these potential advantages, no D-peptides have yet been developed.

PIE12-trimer consists of three D-peptides (PIE12) linked together that block a “pocket” on the surface of HIV critical for HIV’s gaining entry into the cell. “Clinical trials will determine if PIE12-trimer is as effective in humans as it is in the lab,” Kay said.

Across the world, HIV occurs in many different strains and has the ability to mutate to resist drugs aimed at stopping it. Due to the high conservation of the pocket region across strains, PIE12-trimer worked against all major HIV strains worldwide, from Southeast Asia and South America to the United States and Africa.

To help advance toward human clinical trials, Kay and co-authors Brett D. Welch, Ph.D., and Debra M. Eckert, Ph.D., research assistant professor of biochemistry, formed a company, Kayak Biosciences, which is owned by the University of Utah Research Foundation. If PIE12-trimer proves to be an effective and safe drug against HIV, the same D-Peptide drug design principles can be applied against other viruses, according to Kay. Approval of the first D-peptide drug would also greatly stimulate development of other D-peptide drugs.

University of Utah Health Sciences

Psychoneuroimmunology Theory
According to psychoneuroimmunology theory, the central nervous system (CNS), peripheral nervous system (PNS), endocrine system, and immune system are part of an intricate communication and feedback system. Any action that causes change or illness in one part of this system, such as the CNS, can potentially cause changes in the other parts of the psychoneuroimmunology system, such as endocrine or immune systems. Evidence suggesting that psychological stressors such as depression can alter immunological functions and possibly increase susceptibility to physical disease has accumulated over the past several decades [2].

Methods
Scores on the Beck Depression Inventory (BDI) were used to divide 40 non-hospitalized Caucasian women between the ages of 18 and 65 years into either the control or depression comparison group using psychoneuroimmunology theory and a descriptive comparison design.

Results
Women with depression reported significantly more incidences of illness over the previous two months, and they had significantly more indicators of illness at the time of the exam as compared to the controls. Thus, this research suggests that depression may play a role in the subsequent development of minor acute infectious and inflammatory conditions as measured by outcomes on a brief physical exam.

However, contrary to what has been documented in some earlier research, women with depression in the current study did not have significantly different immune function measures as compared to the control group. There was also no significant correlation between scores on the BDI and natural killer cell cytotoxicity in this study.

Discussion
While these results support a connection between depression and both increased self-report of illness and increased signs and symptoms of minor illness or inflammation on physical exam, this study did not find that these effects were related to decreased immune function as measured by natural killer cell activity or white blood cell counts.

However, researchers could not rule out the effect of depression on other immune system parameters, or the effect of depression on health outcomes via behavioral choices. Future research should include a wider variety of both behavioral measures and immune function outcomes to further delineate the effects of all of these factors on health outcomes in women with depression.

Material adapted by CFisher from:
Howk, C., & Bennet, M. (2010). Immune function and health outcomes in women with depression. BioPsychoSocial Medicine, 4:3.

References
[1] Kessler RC, Chiu W, Demler O, Walters EE: Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005 , 62(6):617-27.

[2] Glaser R: Stress-associated immune dysregulation and its importance for human health: a personal history of psychoneuroimmunology. Brain Behav Immun 2005 , 19(1):3-11.

Better understanding how the flu virus replicates and evolves to infect new hosts will help scientists find new ways to fight the flu. One option is the development of therapies that take advantage of the new findings by promoting mutagenesis – treatments designed to generate increased mutations that will ultimately kill the virus.

“These new findings give us insights into how we may be able to control viral evolution,” said Baek Kim, Ph.D. professor in the department of Microbiology and Immunology at the University of Rochester Medical Center and lead study author. “This research presents an attractive strategy for tackling the flu – making the influenza virus kill itself by amplifying the number of mutations made beyond the desired level, which is lethal for the virus.”

In the new study, published in the online journal PLoS One, scientists disprove the widely accepted idea that the flu virus evolves so efficiently due to its error-prone replication process. The virus requires a high number of genomic mutations to jump from one species to another, such as from a pig to a human, and up until this point scientists believed the error-prone replication process facilitated the mutations needed for the flu to spread. In reality, its replication process is not prone to errors; rather, the virus goes through multiple rounds of RNA genome replication in each viral infection cycle, allowing it to produce more than enough genomic mutations necessary for viral evolution and host adaptation.

The flu’s accurate replication process also keeps the virus in check. Given the flu’s multiple rounds of RNA replication per infection, too many mutations would result if the process was highly prone to error, leading to catastrophic mutagenesis.

“The perception has always been that the flu virus mutates a lot, and in order to do that it has to have an enzyme that makes a lot of mistakes, but Kim’s work shows that is not the case at all,” said David Topham, Ph.D., associate professor of Microbiology and Immunology at Rochester and an expert on how the body fights the flu. “There is a selection pressure, perhaps related to the flu’s multiple replication strategy, which helps certain mutations develop and avoid immunity so that the virus can spread.”

Topham, Kim and John Treanor, M.D.,chief of the Infectious Diseases Division of the Department of Medicine at Rochester, lead the New York Influenza Center of Excellence (NYICE), which funded the current research. NYICE is one of five centers nationwide designated by the National Institutes of Health to further our understanding of the flu virus through basic research and surveillance studies, and to facilitate the nation’s preparations for a potential pandemic.

To pin down the mechanisms behind flu virus evolution, researchers conducted unique biochemical analyses comparing flu virus replication to HIV replication, which has been well characterized in past research. While both viruses require efficient mutation production to adapt and thrive in their host environments, they replicate their genetic information very differently. HIV has evolved so that the virus only has a few chances to replicate its genome per infection and generate sufficient mutations, while the flu virus has ample chances to make and accumulate genomic mutations in each viral infection cycle.

At the center of the new finding are the polymerases, or enzymes, responsible for viral replication. Because the AIDS virus only has a few opportunities to replicate its genome in each infection cycle, its polymerases are highly error prone in order to generate sufficient mutations within its limited replication window. In contrast, the flu virus polymerases are high-fidelity enzymes – they are accurate and not prone to error. Even without copious changes in genetic material, the flu’s multiple replication strategy allows the virus to produce genomic mutations sufficient for viral evolution and host adaptation.

“Kim’s team has developed some very important new methodology for studying the function of the flu polymerase that could easily result in the development of new antivirals or other methods to control influenza,” said Treanor. “I think this research will stimulate a lot of additional research about the flu polymerase.”

In addition to Kim, Shilpa Aggarwal, Ph.D., Birgit Bradel-Tretheway, Ph.D., Toru Takimoto, D.V.M., Ph.D., and Stephen Dewhurst, Ph.D., from the University of Rochester Medical Center participated in the study.

Material adapted from University of Rochester by CFisher.

“The increase in the proportion of aged individuals in modern society makes finding innovative ways to thwart the deterioration of the immune system a priority,” said lead author Dr. Fandi Ibrahim from the University of Turku in Finland. “The intake of probiotic bacteria has been reported to enhance the immune response through other products and now we have discovered that cheese can be a carrier of the same bacteria.”

Dr. Ibrahim’s team believe that the daily intake of probiotic cheese can tackle the age-related deterioration of the immune system known as immunosenescene. This deterioration means the body is unable to kill tumor cells and reduces the immune response to vaccinations and infections. Infectious diseases, chronic inflammation disorders, and cancer are hallmarks of Immunosenescene.

To tackle immunosenescene the team targeted the gastrointestinal tract, which is the main entry for bacteria cells into the body through food and drink and is also the site where 70% of vital immunoglobulin cells are created.

The team asked volunteers aged between 72 and 103, all of which lived in the same care home, to eat one slice of either placebo or probiotic Gouda cheese with their breakfast for four weeks. Blood tests where then carried out to discover the effect of probiotic bacteria contained within the cheese on the immune system.

The results revealed a clear enhancement of natural and acquired immunity through the activation of NK blood cells and an increase in phagocytic activity.

“The aim of our study was to see if specific probiotic bacteria in cheese would have immune enhancing effects on healthy older individuals in a nursing home setting,” concluded Ibrahim. “We have demonstrated that the regular intake of probiotic cheese can help to boost the immune system and that including it in a regular diet may help to improve an elderly person’s immune response to external challenges.”

Material adapted from Wiley-Blackwell by CFisher.

Previous research has found that, when people see someone who looks sick, they have a psychological response they feel disgusted and want to stay away. Schaller, Gregory E. Miller, Will M. Gervais, Sarah Yager, and Edith Chen, all at the University of British Columbia, wanted to go one step farther, to see if looking at sick people might also affect how the immune system itself works.

For this study, published in Psychological Science, a journal of the Association for Psychological Science, volunteers were shown two 10-minute slide shows on two different days. The first one was a neutral slide show, with pictures of furniture. The second was one of two options: a disease slide show, showing people with pox, blowing their noses, sneezing, and so forth, or a slide show of guns. Before and after the slide shows, a blood sample was taken from each volunteer. A little bacteria was added to the blood sample, then the researchers measured the strength of the immune response (specifically, how much of a substance called interleukin-6 the immune cells produced).

People who had looked at the pictures of people sneezing, coughing, or otherwise showing signs of disease had a stronger immune response than people who had looked at pictures of men aiming guns at them. This kind of response to the sight of diseased people may have been evolutionarily adaptive, according to Schaller and his colleagues. Although an aggressive immune response has infection-fighting benefits, it’s also costly – it consumes energy and can be temporarily debilitating. It may have been adaptive for the immune system to react especially aggressively when additional information indicates that the threat of infection appears high. According to Schaller, “The things we see around us, such as the sight of sick people, can provide that kind of information. And it makes sense for the immune system to respond to it.”

Material adapted from Association for Psychological Science by CFisher.

These and other findings from the Phase II clinical trial of GAMMAGARD LIQUID and GAMMAGARD S/D Immune Globulin Intravenous (Human) (IGIV) for Alzheimer’s disease (AD) were presented today at the American Academy of Neurology (AAN) meeting in Toronto.

In a Late-Breaking News presentation at the AAN on Wednesday, April 14, at 7:30 am, Dr. Norman Relkin, director of the Memory Disorders Program at NewYork-Presbyterian/Weill Cornell, will report that patients receiving IGIV once or twice a month for 18 months had significantly lower rates of ventricular enlargement (6.7% vs 12.7% per year) and less whole-brain atrophy (1.6% vs 2.2% per year) than control subjects who initially received placebo. Dr. Relkin’s findings were based on two independent analyses of brain-imaging data from 20 patients who underwent serial MRI scans during the Phase II study of IGIV for AD.

Ventricular Atrophy Maps: Placebo-treated subject (credit: Weill Cornell Medical Center)

“Past AD studies that used MRI measures found no change or an accelerated rate of brain shrinkage after investigational treatments,” Dr. Relkin notes. “To the best of my knowledge, this is the first trial in which long-term clinical benefits in Alzheimer’s patients were accompanied by objective signs of reduced brain degeneration.” Dr. Relkin is also an associate professor of clinical neurology and neuroscience at Weill Cornell Medical College in New York City. He was the principal investigator in the Phase II study and is currently leading a multicenter Phase III study of IGIV for Alzheimer’s.

Ventricular Atrophy Maps: IVIg treated subject (credit: Weill Cornell Medical Center)

A typical AD patient’s brain shrinks three to four times faster than a healthy older adult’s as a consequence of accelerated brain cell death. This shrinkage of brain tissue causes the fluid-filled ventricles at the center of the brain to enlarge at a faster than normal rate. Changes in the size of the brain and ventricles can be measured accurately by analyzing results from two or more MRI scans obtained at an interval of at least several months apart.

Scale of ventricular atrophy (credit: Weill Cornell Medical Center)

The unprecedented reductions in these measures after IGIV reported by Dr. Relkin and his colleagues could indicate that IGIV exerts a disease-modifying effect that the current generation of approved AD treatments lack.

Dr. Relkin also found that rates of brain shrinkage after IGIV intervention were independent of the subject’s age, gender and brain volume at the start of the study but strongly correlated with dose of IGIV and the clinical outcomes after 18 months of intervention.

The Weill Cornell research team also found that AD patients who responded best to IGIV did not measurably decline over 18 months, and had an average rate of brain shrinkage and average rate of ventricular enlargement comparable to the rate previously reported in normal elderly individuals. “A dose-related effect of an Alzheimer’s intervention on brain ventricular enlargement has never been seen before, and it suggests that IGIV may, indeed, be sparing brain tissue,” says Dr. James Brewer, a neurologist and assistant professor of neurology at the University of California at San Diego.

Dr. Brewer independently analyzed the MRIs from the Phase II IGIV study, and his findings closely matched those obtained by Dr. Dana Moore, a postdoctoral fellow working with Dr. Relkin at Weill Cornell. “I am particularly looking forward to examining the Phase III data when that study is completed,” Dr. Brewer states. “Since it involves a considerably larger group of patients, it will permit us to obtain more detailed measures of atrophy in the brain regions specifically vulnerable to Alzheimer’s disease.”

More details about the study’s cognitive testing results will be reported in a later presentation at the AAN meeting by Dr. Diamanto Tsakanikas, who performed cognitive and other testing of the study’s participants. Dr. Tsakanikas is a clinical assistant attending neuropsychologist at NewYork-Presbyterian Hospital/Weill Cornell Medical Center and an instructor of neuropsychology in the Department of Neurology and Neuroscience at Weill Cornell Medical College. While conducting the testing, Dr. Tsakanikas was blinded to whether patients were receiving IGIV or placebo and to the IGIV dose.

When the unblinded study results were later analyzed, her testing indicated that AD patients who received uninterrupted IGIV for 18 months showed significantly less decline in their overall function and thinking abilities than AD patients initially given an inactive placebo. In some cases, IGIV intervention resulted in improvements in certain areas of cognitive functioning. “Functions mediated by the frontal regions of the brain showed the most consistent benefits in IGIV responders,” says Dr. Tsakanikas.

The Phase II study involved 24 patients with mild to moderate Alzheimer’s disease who were randomly assigned to receive IGIV (16 patients) or saline placebo (eight patients) for six months. Over the following 12 months, the initially placebo-treated group were subsequently received various doses of IGIV while the other 16 patients had uninterrupted IGIV at the initially assigned dose. The study included a comparison of four dosing regimens of IGIV, with doses ranging from 0.2 g/kg every two weeks to 0.8 g/kg every four weeks. “The Phase II study was carried out with the explicit goal of determining whether further testing of IGIV for Alzheimer’s was justified,” Dr. Relkin points out. “It succeeded in achieving that goal with a relatively small number of subjects. However, we now have to await the results of the larger, pivotal Phase III study to establish the magnitude of its effects on rate of brain atrophy and to confirm whether IGIV is safe and effective for treating AD.”

IGIV is being tested as a potential agent for AD immunotherapy because it contains antibodies against beta-amyloid (Aβ), which is the main constituent of amyloid plaques in the brains of AD patients. IGIV is not approved to treat Alzheimer’s disease but it is approved in the United States and other countries for certain immune deficiency and autoimmune disorders. A critical Phase III study of IGIV for AD, supported jointly by the National Institutes of Health (NIH) and Baxter Healthcare, is currently enrolling patients at 35 sites in North America. Visit the link below for more information.

Material adapted from Weill Cornell Medical Center by CFisher.

The study is believed to be the first time researchers evaluated the association between secondhand smoke and chronic rhinosinusitis, one of the most common health conditions in the United States affecting more than 39 million people, or one in seven adults, every year.

Chronic rhinosinusitis, or CRS, is a form of sinusitis in which the moist tissues of the nose and paranasal sinuses are inflamed for at least 12 weeks.

The findings are being published in the April issue of the Archives of Otolaryngology-Head & Neck Surgery.

“Our findings reaffirm the health hazards of secondhand smoke,” says Amanda Holm, MPH, a co-author of the study and project manager in Henry Ford’s Center for Health Promotion and Disease Prevention.

“The poisons found in secondhand smoke are quite an irritant to the sinus and nasal passages and are a major contributor to the development of rhinosinusitis.”

Holm says primary care physicians and otolaryngologists should advise their patients to avoid secondhand smoke whenever possible. On May 1, Michigan becomes the 38th state to limit smoking in public places including government buildings, workplaces, bars and restaurants.

“Even modest levels of secondhand smoke exposure carry some risk” to rhinosinusitis, Holm says.

Secondhand smoke accounts for an estimated 3,000 lung cancer deaths and 30,000 heart disease deaths annually.

For the case control study, researchers conducted telephone interviews with 306 patients diagnosed with rhinosinusitis from 2000-2004 and 306 otherwise healthy patients who had been free of rhinosinusitis for five years prior to the study. Data collected included medical history, age, gender, ethnicity, diet and exposure to other potential irritants like air pollution and chemicals.

Data on secondhand smoke exposure were collected for four primary sources: home, work, public places and private social functions like parties and weddings. Previous studies have not considered secondhand smoke exposure at private social functions, which Henry Ford researchers consider to be under reported.

Cases of rhinosinusitis were confirmed by medical record data on computed tomography and/or endoscopy.

Key points in the study:

• The largest amount of secondhand smoke exposure occurred in public places and private social functions. Public places included bars, restaurants, casinos, bowling alleys and nightclubs.
• Participants were twice as likely to be exposed to secondhand smoke at work and at private social functions.

Material adapted from Henry Ford Health System.