Human and soil bacteria swap antibiotic-resistance genes


Chemical exposure in the womb from household items may contribute to obesity

Pregnant women who are highly exposed to common environmental chemicals - polyfluoroalkyl compounds (PFCs) - have babies that are smaller at birth and larger at 20 months of age, according to a study from Emory University's Rollins School of Public Health published online in the August 30 edition of Environmental Health Perspectives.


PLoS Pathogens: Phagocyte Responses to Protozoan Infection and How Toxoplasma gondii Meets the Challenge

Toxoplasma and other tissue-invasive microbial pathogens encounter the innate immune system from the earliest stages of infection. Using genetically altered mice and parasites in combination, we are gaining fascinating insight into the molecular biology of the host-parasite interaction that plays out between Toxoplasma and the phagocytes of innate immunity. The overall theme emerging is that faced with a strong and multi-pronged host innate immune response, Toxoplasma does not retreat but actively engages cells of the innate defense system. Balancing stimulation of host defense with avoidance of immune elimination allows this extraordinary parasite to persist in its host and ensures widespread transmission throughout the vertebrate animal kingdom.

NIH scientists map first steps in flu antibody development, August 29, 2012 News Release - National Institutes of Health (NIH)

Endoplasmic reticulum stress pathway-mediated apoptosis in macrophages contributes to the survival of Mycobacterium tuberculosis.

Apoptosis is thought to play a role in host defenses against intracellular pathogens, including Mycobacterium tuberculosis (Mtb), by preventing the release of intracellular components and the spread of mycobacterial infection. This study aims to investigate the role of endoplasmic reticulum (ER) stress mediated apoptosis in mycobacteria infected macrophages.

METHODOLOGY/PRINCIPAL FINDINGS:

Here, we demonstrate that ER stress-induced apoptosis is associated with Mtb H37Rv-induced cell death of Raw264.7 murine macrophages. We have shown that Mtb H37Rv induced apoptosis are involved in activation of caspase-12, which resides on the cytoplasmic district of the ER. Mtb infection increase levels of other ER stress indicators in a time-dependent manner. Phosphorylation of eIF2α was decreased gradually after Mtb H37Rv infection signifying that Mtb H37Rv infection may affect eIF2α phosphorylation in an attempt to survive within macrophages. Interestingly, the survival of mycobacteria in macrophages was enhanced by silencing CHOP expression. In contrast, survival rate of mycobacteria was reduced by phosphorylation of the eIF2α. Futhermore, the levels of ROS, NO or CHOP expression were significantly increased by live Mtb H37Rv compared to heat-killed Mtb H37Rv indicating that live Mtb H37Rv could induce ER stress response.

CONCLUSION/SIGNIFICANCE:

These findings indicate that eIF2α/CHOP pathway may influence intracellular survival of Mtb H37Rv in macrophages and only live Mtb H37Rv can induce ER stress response. The data support the ER stress pathway plays an important role in the pathogenesis and persistence of mycobacteria.

Epigenetic Drug Improves Cholesterol Levels | The Scientist

A drug that targets epigenetic proteins, aimed at boosting so-called “good” cholesterol levels, showed positive signs in Phase II clinical trial, its maker Resverlogix Corporation announced yesterday (August 28).
The therapy is intended to improve upon statins, which reduce the levels of “bad” cholesterol, or low density lipoprotein (LDL), but do not increase the levels of the beneficial high density lipoprotein (HDL). Trial results showed that the drug RVX-208 from Resverlogix was able to increase HDL levels in treated patients.

News: Vitamin B12 deficiency: tracking the genetic causes

Vitamin B12 is essential to human health. However, some people have inherited conditions that leave them unable to process vitamin B12. As a result they are prone to serious health problems, including developmental delay, psychosis, stroke and dementia. An international research team recently discovered a new genetic disease related to vitamin B12 deficiency by identifying a gene that is vital to the transport of vitamin into the cells of the body. This discovery will help doctors better diagnose this rare genetic disorder and open the door to new treatments. The findings are published in the journal Nature Genetics.

Association of Active Human Herpesvirus-6, -7 and Parvovirus B19 Infection with Clinical Outcomes in Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Frequency of active human herpesvirus-6, -7 (HHV-6, HHV-7) and parvovirus B19 (B19) infection/coinfection and its association with clinical course of ME/CFS was evaluated. 108 ME/CFS patients and 90 practically healthy persons were enrolled in the study. Viral genomic sequences were detected by PCR, virus-specific antibodies and cytokine levels-by ELISA, HHV-6 variants-by restriction analysis. Active viral infection including concurrent infection was found in 64.8% (70/108) of patients and in 13.3% (12/90) of practically healthy persons. Increase in peripheral blood leukocyte DNA HHV-6 load as well as in proinflammatory cytokines' levels was detected in patients during active viral infection. Definite relationship was observed between active betaherpesvirus infection and subfebrility, lymphadenopathy and malaise after exertion, and between active B19 infection and multijoint pain. Neuropsychological disturbances were detected in all patients. The manifestation of symptoms was of more frequent occurrence in patients with concurrent infection. The high rate of active HHV-6, HHV-7 and B19 infection/coinfection with the simultaneous increase in plasma proinflammatory cytokines' level as well as the association between active viral infection and distinctive types of clinical symptoms shows necessity of simultaneous study of these viral infections for identification of possible subsets of ME/CFS.

Diagnosis of Parkinson's disease based on disease-specific autoantibody profiles in human sera.

Parkinson's disease (PD), hallmarked by a variety of motor disorders and neurological decline, is the second most common neurodegenerative disease worldwide. Currently, no diagnostic test exists to identify sufferers, and physicians must rely on a combination of subjective physical and neurological assessments to make a diagnosis. The discovery of definitive blood-borne biomarkers would be a major step towards early and reliable diagnosis. Despite attention devoted to this search, such biomarkers have remained elusive. In the present study, we used human protein microarrays to reveal serum autoantibodies that are differentially expressed among PD and control subjects. The diagnostic significance of each of these autoantibodies was evaluated, resulting in the selection of 10 autoantibody biomarkers that can effectively differentiate PD sera from control sera with a sensitivity of 93.1% and specificity of 100%. PD sera were also distinguishable from sera obtained from Alzheimer's disease, breast cancer, and multiple sclerosis patients with accuracies of 86.0%, 96.6%, and 100%, respectively. Results demonstrate that serum autoantibodies can be used as highly specific and accurate biomarkers for PD diagnosis throughout the course of the disease.

Epstein-Barr virus stimulates torque teno virus replication: a possible relationship to multiple sclerosis.

Viral infections have been implicated in the pathogenesis of multiple sclerosis. Epstein-Barr virus (EBV) has frequently been investigated as a possible candidate and torque teno virus (TTV) has also been discussed in this context. Nevertheless, mechanistic aspects remain unresolved. We report viral replication, as measured by genome amplification, as well as quantitative PCR of two TTV-HD14 isolates isolated from multiple sclerosis brain in a series of EBV-positive and -negative lymphoblastoid and Burkitt's lymphoma cell lines. Our results demonstrate the replication of both transfected TTV genomes up to day 21 post transfection in all the evaluated cell lines. Quantitative amplification indicates statistically significant enhanced TTV replication in the EBV-positive cell lines, including the EBV-converted BJAB line, in comparison to the EBV-negative Burkitt's lymphoma cell line BJAB. This suggests a helper effect of EBV infections in the replication of TTV. The present study provides information on a possible interaction of EBV and TTV in the etiology and progression of multiple sclerosis.

Saturated fats encourage bacteria and promote inflammatory defence: Good fats are antimicrobial

Some fats—mostly unsaturated fats have strong antimicrobial properties. They react chemically with bacterial cell membranes, weakening them. "If you expose unsaturated fats on bacteria, the bacteria have a tendency to lyse. The combination of long chain unsaturated fats, especially omega-3 fatty acids, and innate host defenses like gastric acid and antimicrobial peptides, is particularly lethal to pathogenic bacteria," Alcock said. Saturated fats on the other hand generally lack those antimicrobial properties, and in fact can provide a carbon source that bacteria need to grow and flourish.

Read more at: http://medicalxpress.com/news/2012-08-fats-worse.html#jCp

Small Things Considered: The Road to Microbial Endocrinology

Microbes ae affected hy the host's endocrine system.

Compound discovered that boosts effect of vaccines against HIV and flu

Oxford University scientists have discovered an adjuvant polymer (polyethyleneimine) that boosts the effect of vaccines against viruses like flu, HIV and herpes in mice.

Complement C1q formation of immune complexes with milk caseins and wheat glutens in schizophrenia.

Immune system factors including complement pathway activation are increasingly linked to the etiology and pathophysiology of schizophrenia. Complement protein, C1q, binds to and helps to clear immune complexes composed of immunoglobulins coupled to antigens. The antigenic stimuli for C1q activation in schizophrenia are not known. Food sensitivities characterized by elevated IgG antibodies to bovine milk caseins and wheat glutens have been reported in individuals with schizophrenia. Here, we examined the extent to which these food products might comprise the antigen component of complement C1q immune complexes in individuals with recent onset schizophrenia (n=38), non-recent onset schizophrenia (n=61) and non-psychiatric controls (n=63). C1q seropositivity was significantly associated with both schizophrenia groups (recent onset, odds ratio (OR)=8.02, p≤0.008; non-recent onset, OR=3.15, p≤0.03) compared to controls (logistic regression models corrected for age, sex, race and smoking status). Casein- and/or gluten-IgG binding to C1q was significantly elevated in the non-recent onset group compared to controls (OR=4.36, p≤0.01). Significant amounts of C1q-casein/gluten-related immune complexes and C1q correlations with a marker for gastrointestinal inflammation in non-recent onset schizophrenia suggests a heightened rate of food antigens in the systemic circulation, perhaps via a disease-associated altered intestinal permeability. In individuals who are in the early stages of disease onset, C1q activation may reflect the formation of immune complexes with non-casein- or non-gluten-related antigens, the presence of C1q autoantibodies, and/or a dissociated state of immune complex components. In conclusion, complement activation may be a useful biomarker to diagnose schizophrenia early during the course of the disease. Future prospective studies should evaluate the impacts of casein- and gluten-free diets on C1q activation in schizophrenia.

List of Free Statistical Software

A list of links to free statistics programs, including bioinformatics, psychometrics, econometrics, simulations, database, data mining and spreadsheets software; and some mathematical software (if it is useful in statistics).

The list shouldn’t include demo/student versions (unless highly functional) or temporary trial versions. Scripts to be run within a program shouldn’t be included in this list.

Is the origin of type 1 diabetes in the gut?

n type 1 diabetes, insulin-producing beta-cells in the pancreas are destroyed by immune-mediated mechanisms. The manifestation of the disease is preceded by the so-called pre-diabetic period that may last several years and is characterized by the appearance of circulating autoantibodies against beta-cell antigens. The role of the gut as a regulator of type 1 diabetes was suggested in animal studies, in which changes affecting the gut immune system modulated the incidence of diabetes. Dietary interventions, alterations in the intestinal microbiota and exposure to enteric pathogens, regulate the development of autoimmune diabetes in animal models. It has been demonstrated that these modulations affect the gut barrier mechanisms and intestinal immunity. Because the pancreas and the gut belong to the same intestinal immune system, the link between autoimmune diabetes and the gut is not unexpected. The gut hypothesis in the development of type 1 diabetes is also supported by the observations made in human type 1 diabetes. Early diet could modulate the development of beta-cell autoimmunity; weaning to hydrolysed casein formula decreased the risk of beta-cell autoimmunity by age 10 in the infants at genetic risk. Increased gut permeability, intestinal inflammation with impaired regulatory mechanisms and dysregulated oral tolerance have been observed in children with type 1 diabetes. The factors that contribute to these intestinal alterations are not known, but interest is focused on the microbial stimuli and function of innate immunity. It is likely that our microbial environment does not support the healthy maturation of the gut and tolerance in the gut, and this leads to the increasing type 1 diabetes as well as other immune-mediated diseases regulated by intestinal immune system. Thus, the interventions, aiming to prevent or treat type 1 diabetes in humans, should be targeting the gut immune system.

Microbial Carriage State of Peripheral Blood Dendritic Cells (DCs) in Chronic Periodontitis Influences DC Differentiation, Atherogenic Potential.

The low-grade oral infection chronic periodontitis (CP) has been implicated in coronary artery disease risk, but the mechanisms are unclear. In this study, a pathophysiological role for blood dendritic cells (DCs) in systemic dissemination of oral mucosal pathogens to atherosclerotic plaques was investigated in humans. The frequency and microbiome of CD19(-)BDCA-1(+)DC-SIGN(+) blood myeloid DCs (mDCs) were analyzed in CP subjects with or without existing acute coronary syndrome and in healthy controls. FACS analysis revealed a significant increase in blood mDCs in the following order: healthy controls < CP < acute coronary syndrome/CP. Analysis of the blood mDC microbiome by 16S rDNA sequencing showed Porphyromonas gingivalis and other species, including (cultivable) Burkholderia cepacia. The mDC carriage rate with P. gingivalis correlated with oral carriage rate and with serologic exposure to P. gingivalis in CP subjects. Intervention (local debridement) to elicit a bacteremia increased the mDC carriage rate and frequency in vivo. In vitro studies established that P. gingivalis enhanced by 28% the differentiation of monocytes into immature mDCs; moreover, mDCs secreted high levels of matrix metalloproteinase-9 and upregulated C1q, heat shock protein 60, heat shock protein 70, CCR2, and CXCL16 transcripts in response to P. gingivalis in a fimbriae-dependent manner. Moreover, the survival of the anaerobe P. gingivalis under aerobic conditions was enhanced when within mDCs. Immunofluorescence analysis of oral mucosa and atherosclerotic plaques demonstrate infiltration with mDCs, colocalized with P. gingivalis. Our results suggest a role for blood mDCs in harboring and disseminating pathogens from oral mucosa to atherosclerosis plaques, which may provide key signals for mDC differentiation and atherogenic conversion.

Immunology and Cell Biology - Autoimmunity: innovation in pathogenesis and therapy

Hepatitis C Related Nervous System Disorders

Chronic infection with hepatitis C virus (HCV) is associated with a wide spectrum of extrahepatic manifestations, affecting different organ systems. Neurological complications occur in a large number of patients and range from peripheral neuropathy to cognitive impairment. Pathogenetic mechanisms responsible for nervous system dysfunction are mainly related to the upregulation of the host immune response with production of autoantibodies, immune complexes, and cryoglobulins. Alternative mechanisms include possible extrahepatic replication of HCV in neural tissues and the effects of circulating inflammatory cytokines and chemokines.

MicrobeWorld - New Evidence for Polyomavirus BK Role in Prostate Cancer

Prostate cancer is the leading cause of cancer morbidity and the third greatest cause of cancer death among men in developed countries. A major question in cancer research has been whether virus infection plays a role in cancers of the genitourinary tract. Now a team of Swiss investigators has new evidence suggesting human polyomavirus BK is involved in maintaining and enhancing an environment suitable for prostate cancer growth. The research, published in the August Journal of Virology, could lead to preventive and/or therapeutic prostate cancer vaccines (click source to download a .pdf of the journal article).

Activation of cell-mediated immunity in depression: association with inflammation, melancholia, clinical staging and the fatigue and somatic symptom cluster of depression.

Depression is characterized by activation of cell-mediated immunity (CMI), including increased neopterin levels, and increased pro-inflammatory cytokines (PICs), such as interleukin-1 (IL-1) and tumor necrosis factor-α (TNFα). These PICs may induce depressive, melancholic and chronic fatigue (CF) symptoms.

METHODS:

We examined serum neopterin and plasma PIC levels in depressive subgroups in relation to the depressive subtypes and the melancholic and CF symptoms of depression. Participants were 85 patients with depression and in 26 normal controls. Severity of depression was assessed with the Hamilton Depression Rating Scale (HDRS) and severity of CF with the Fibromyalgia and Chronic Fatigue Syndrome (FF) Rating Scale.

RESULTS:

Serum neopterin was significantly higher in depressed patients and in particular in those with melancholia. There were positive correlations between serum neopterin, the plasma PICs and the number of previous depressive episodes. Neopterin and TNFα were associated with melancholia, while both PICs were associated with CF. Melancholia-group membership was predicted by the HDRS and neopterin, and CF group membership by age, the FF score and serum TNFα.

DISCUSSION:

Depression and melancholia are accompanied by CMI activation, suggesting that neopterin plays a role in their pathophysiology, e.g. through activation of oxidative and nitrosative stress and apoptosis pathways. The intertwined CMI and inflammatory responses are potentially associated with the onset of depression and with the melancholic and CF symptoms of depression. Exposure to previous depressive episodes may magnify the size of CMI and PIC responses, possibly increasing the likelihood of new depressive episodes. CMI activation and inflammation may contribute to the staging or recurrence of depression.

Targeting the Vasculature in Alzheimer's Disease and Vascular Cognitive Impairment | The New York Academy of Sciences

Alzheimer's disease (AD) is a devastating neurodegenerative disorder that affects millions of people worldwide. For more than 100 years, the presence of "senile plaques" and "neurofibrillary tangles" were considered the primary pathological markers for AD. In the last half-century, a growing amount of evidence to support the role of the vascular system as a major causative or exacerbating factor has forced an expanded definition of the classification of pathology in the AD brain. Because of increases in life expectancy and because of the aging population, the rates of neurovascular abnormalities that could lead to cognitive impairment and dementia are also likely to rise. Therefore, the need to identify effective therapeutic targets that will address these neurovascular complexities is critical. At the Targeting the Vasculature in Alzheimer's Disease and Vascular Cognitive Impairment symposium, held on May 4, 2012 and presented by the Brain Dysfunction Discussion Group and the Alzheimer's Drug Discovery Foundation, scientists from academia and industry met to share their knowledge on pathogenic mechanisms, vascular outcomes in clinical trials, and drug discovery targets for Alzheimer's disease.

Viral Catalase Protects Herpes Simplex Virus from Inactivation by Hydrogen Peroxide.

Herpes simplex virus (HSV-1) was shown to contain catalase, an enzyme able to detoxify hydrogen peroxide by converting it to water and oxygen. Studies with a catalase inhibitor indicated that virus-associated catalase can have a role in protecting the virus from oxidative inactivation. HSV-1 was found to be more sensitive to killing by hydrogen peroxide in the presence of a catalase inhibitor than in its absence. The results suggest a protective role for catalase during the time HSV-1 spends in the oxidizing environment outside a host cell.

Field guide to the Epstein-Barr virus charts viral paths toward cancer

Researchers from The Wistar Institute and Memorial Sloan-Kettering Cancer Center (MSKCC) have teamed to publish the first annotated atlas of the Epstein-Barr virus genome, creating the most comprehensive study of how the viral genome interacts with its human host during a latent infection. Epstein-Barr virus (EBV), which is thought to be responsible for one percent of all human cancers, establishes a latent infection in nearly 100 percent of infected adult humans.

Read more at: http://medicalxpress.com/news/2012-08-field-epstein-barr-virus-viral-paths.html#jCp

Scientists discover one of the ways the influenza virus disarms host cells

Prenatal lead levels, plasma amyloid β levels, and gene expression in young adulthood.

Animal studies suggest that early-life lead exposure influences gene expression and production of proteins associated with Alzheimer's disease (AD).

OBJECTIVES:

We attempted to assess the relationship between early-life lead exposure and potential biomarkers for AD among young men and women. We also attempted to assess whether early-life lead exposure was associated with changes in expression of AD-related genes.

METHODS:

We used sandwich enzyme-linked immunosorbent assays (ELISA) to measure plasma concentrations of amyloid β proteins Aβ40 and Aβ42 among 55 adults who had participated as newborns and young children in a prospective cohort study of the effects of lead exposure on development. We used RNA microarray techniques to analyze gene expression.

RESULTS:

Mean plasma Aβ42 concentrations were lower among 13 participants with high umbilical cord blood lead concentrations (≥ 10 μg/dL) than in 42 participants with lower cord blood lead concentrations (p = 0.08). Among 10 participants with high prenatal lead exposure, we found evidence of an inverse relationship between umbilical cord lead concentration and expression of ADAM metallopeptidase domain 9 (ADAM9), reticulon 4 (RTN4), and low-density lipoprotein receptor-related protein associated protein 1 (LRPAP1) genes, whose products are believed to affect Aβ production and deposition. Gene network analysis suggested enrichment in gene sets involved in nerve growth and general cell development.

CONCLUSIONS:

Data from our exploratory study suggest that prenatal lead exposure may influence Aβ-related biological pathways that have been implicated in AD onset. Gene network analysis identified further candidates to study the mechanisms of developmental lead neurotoxicity.

Eukaryotic Initiation Factor 2 (eIF2) Signaling Regulates Proinflammatory Cytokine Expression and Bacterial Invasion

In eukaryotic cells, there are two well characterized pathways that regulate translation initiation in response to stress, and each have been shown to be targeted by various viruses. We recently showed in a yeast-based model that the bacterial virulence factor YopJ disrupts one of these pathways, which is centered on the α-subunit of the translation factor eIF2. Here, we show in mammalian cells that induction of the eIF2 signaling pathway occurs following infection with bacterial pathogens and that, consistent with our yeast-based findings, YopJ reduces eIF2 signaling in response to endoplasmic reticulum stress, heavy metal toxicity, dsRNA, and bacterial infection. We demonstrate that the well documented activities of YopJ, inhibition of NF-κB activation and proinflammatory cytokine expression, are both dependent on an intact eIF2 signaling pathway. Unexpectedly, we found that cells with defective eIF2 signaling were more susceptible to bacterial invasion. This was true for pathogenic Yersinia, a facultative intracellular pathogen, as well as for the intracellular pathogens Listeria monocytogenes and Chlamydia trachomatis. Collectively, our data indicate that the highly conserved eIF2 signaling pathway, which is vitally important for antiviral responses, plays a variety of heretofore unrecognized roles in antibacterial responses.

Toxoplasma Co-opts Host Cells It Does Not Invade.

Like many intracellular microbes, the protozoan parasite Toxoplasma gondii injects effector proteins into cells it invades. One group of these effector proteins is injected from specialized organelles called the rhoptries, which have previously been described to discharge their contents only during successful invasion of a host cell. In this report, using several reporter systems, we show that in vitro the parasite injects rhoptry proteins into cells it does not productively invade and that the rhoptry effector proteins can manipulate the uninfected cell in a similar manner to infected cells. In addition, as one of the reporter systems uses a rhoptry:Cre recombinase fusion protein, we show that in Cre-reporter mice infected with an encysting Toxoplasma-Cre strain, uninfected-injected cells, which could be derived from aborted invasion or cell-intrinsic killing after invasion, are actually more common than infected-injected cells, especially in the mouse brain, where Toxoplasma encysts and persists. This phenomenon has important implications for how Toxoplasma globally affects its host and opens a new avenue for how other intracellular microbes may similarly manipulate the host environment at large.

Soluble interleukin-6 receptor induces motor stereotypies and co-localizes with gp130 in regions linked to cortico-striato-thalamo-cortical circuits.

Soluble cytokine receptors are normal constituents of body fluids that regulate peripheral cytokine and lymphoid activity and whose levels are increased in states of immune activation. Soluble interleukin-6 receptor (sIL-6R) levels positively correlate with disease progression in some autoimmune conditions and psychiatric disorders. Particularly strong links between levels of sIL-6R and the severity of psychotic symptoms occur in schizophrenia, raising the possibility that sIL-6R is involved in this disease. However, there is no evidence that peripheral sIL-6R induces relevant behavioral disturbances. We showed that single subcutaneous injections of sIL-6R (0-1 µg), stimulated novelty stress-induced exploratory motor behaviors in male Balb/c mice within 20-40-min of injection. A progressive increase in vertical stereotypies was observed 40-80 min post injection, persisting for the remainder of the test session. Paralleling these stimulant-like effects, sIL-6R pre-treatment significantly enhanced stereotypy scores following challenge with GBR 12909. We found that peripherally administered sIL-6R crossed the blood-brain barrier, localizing in brain regions associated with cortico-striatal-thalamo-cortical (CSTC) circuits, which are putative neuroanatomical substrates of disorders associated with repetitive stereotypies. Peripherally administered sIL-6R co-localized with gp130, a transmembrane protein involved in IL-6 trans-signaling, in the nucleus accumbens, caudate-putamen, motor and infralimbic cortices, and thalamic nuclei, but not with gp130 in the ventral tegmental area, substantia nigra, or sensorimotor cortex,. The results suggest that peripheral sIL-6R can act as a neuroimmune messenger, crossing the blood brain barrier (BBB) to selectively target CSTC circuits rich in IL-6 trans-signaling protein, and inducing repetitive stereotypies. As such sIL-6R may represent a novel therapeutic agent for relevant psychiatric disorders.

Microbiologists find new approach to fighting viral illnesses

By discovering how certain viruses use their host cells to replicate, UC Irvine microbiologists have identified a new approach to the development of universal treatments for viral illnesses such as meningitis, encephalitis, hepatitis and possibly the common cold.

Toward medicines that recruit the body's natural disease-fighting proteins

Like recruiters pitching military service to a throng of people, scientists are developing drugs to recruit disease-fighting proteins present naturally in everyone's blood in medicine's war on infections, cancer and a range of other diseases. They reported on the latest advances in this new approach here today at the 244th National Meeting & Exposition of the American Chemical Society.


T cells become licensed in the lung to enter the central nervous system : Nature : Nature Publishing Group

The bloodbrain barrier (BBB) and the environment of the central nervous system (CNS) guard the nervous tissue from peripheral immune cells. In the autoimmune disease multiple sclerosis, myelin-reactive T-cell blasts are thought to transgress the BBB and create a pro-inflammatory environment in the CNS, thereby making possible a second autoimmune attack that starts from the leptomeningeal vessels and progresses into the parenchyma Using a Lewis rat model of experimental autoimmune encephalomyelitis, we show here that contrary to the expectations of this concept, T-cell blasts do not efficiently enter the CNS and are not required to prepare the BBB for immune-cell recruitment. Instead, intravenously transferred T-cell blasts gain the capacity to enter the CNS after residing transiently within the lung tissues. Inside the lung tissues, they move along and within the airways to bronchus-associated lymphoid tissues and lung-draining mediastinal lymph nodes before they enter the blood circulation from where they reach the CNS. Effector T cells transferred directly into the airways showed a similar migratory pattern and retained their full pathogenicity. On their way the T cells fundamentally reprogrammed their gene-expression profile, characterized by downregulation of their activation program and upregulation of cellular locomotion molecules together with chemokine and adhesion receptors. The adhesion receptors include ninjurin 1, which participates in T-cell intravascular crawling on cerebral blood vessels. We detected that the lung constitutes a niche not only for activated T cells but also for resting myelin-reactive memory T cells. After local stimulation in the lung, these cells strongly proliferate and, after assuming migratory properties, enter the CNS and induce paralytic disease. The lung could therefore contribute to the activation of potentially autoaggressive T cells and their transition to a migratory mode as a prerequisite to entering their target tissues and inducing autoimmune disease.
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Antibiotics in early life alter the murine colonic microbiome and adiposity : Nature : Nature Publishing Group

Antibiotics administered in low doses have been widely used as growth promoters in the agricultural industry since the 1950s, yet the mechanisms for this effect are unclear. Because antimicrobial agents of different classes and varying activity are effective across several vertebrate species, we proposed that such subtherapeutic administration alters the population structure of the gut microbiome as well as its metabolic capabilities. We generated a model of adiposity by giving subtherapeutic antibiotic therapy to young mice and evaluated changes in the composition and capabilities of the gut microbiome. Administration of subtherapeutic antibiotic therapy increased adiposity in young mice and increased hormone levels related to metabolism. We observed substantial taxonomic changes in the microbiome, changes in copies of key genes involved in the metabolism of carbohydrates to short-chain fatty acids, increases in colonic short-chain fatty acid levels, and alterations in the regulation of hepatic metabolism of lipids and cholesterol. In this model, we demonstrate the alteration of early-life murine metabolic homeostasis through antibiotic manipulation.

hot on the heels of this ........................................

MNT: Childhood Obesity Linked With Antibiotic Use In Infants Under 6 Months Old

Decode-led Team Uncovers Elevated De Novo Mutation Rate in Children of Older Fathers | GenomeWeb Daily News | Sequencing | GenomeWeb

Children born to older fathers tend to have more de novo mutations in their genomes than those with younger dads, according to a study by researchers at Decode Genetics, the University of Iceland, and Illumina Cambridge.
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MNT: Childhood Obesity Linked With Antibiotic Use In Infants Under 6 Months Old

New research, by experts at the NYU School of Medicine and the NYU Wagner School of Public Service, suggests that exposing babies to antibiotics may predispose them to being overweight in childhood.The study, which analyzed over 10,000 children and was published in the International Journal of Obesity, found that kids who weighed more for their height were those who were exposed to antibiotics from birth to 5 months of age.

Microbes manipulate your mind | Mo Costandi | Science | guardian.co.uk

Gut bacteria may influence thoughts and behaviour, while T.Gondii has numerous effects of animal and human behaviour. Pathogens have been implicated in many psychiatric disorders and are clearly able to affect the expression of key brain genes and processes..
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Gene--Environment Interaction in Alzheimer's Disease.

The aim was to examine the gene environment (GxE) interaction with
reference to APO E genotypes, serum lipids and organochlorine pesticides (OCPs)
as one of the factors in the etiology of Alzheimer's disease (AD). Methods: A
case control study was used to examine, APOE HhaI polymorphism by polymerase
chain reaction (PCR)/PCR-restriction fragment length polymorphism method, serum
lipids by autoanalyser and OCPs by gas chromatography (GC). Results: APOE ε4
allele frequency was significantly high (p=0.000, OR=5.73, CI=2.68-12.50) in AD
as compared to controls. The serum cholesterol, β- hexachlorocyclohexane and
dieldrin are risk factors for AD independent of the APOE ε4 risk allele,
recording an odds ratio of 1.16, 11.38 and 10.45 respectively. Conclusion: GxE
interactions exist with APOE ε4 allele status that need to be considered for the 
study design and analysis of such data in future studies of AD.

A safer strategy for targeting AIDS

Scientists at The Scripps Research Institute have discovered a surprisingly simple and safe method to disrupt specific genes within cells. The scientists highlighted the medical potential of the new technique by demonstrating its use as a safer alternative to an experimental gene therapy against HIV infection.The new technique, reported last month in the journal Nature Methods, employs zinc finger nuclease (ZFN) proteins, which can bind and cut DNA at precisely defined locations in the genome. ZFNs are coming into widespread use in scientific experiments and potential disease treatments, but typically are delivered into cells using potentially risky gene therapy methods.
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Impaired functioning in euthymic patients with bipolar disorder--HSV-1 as a predictor.

There is a possible association between infectious agents and psychiatric disorders. Previous studies in the US provided evidence for cognitive impairment correlated with Herpes simplex virus type 1 (HSV-1) infection. For a replication study in Europe we chosed individuals diagnosed with bipolar disorder to analyse the correlation with HSV-1 infection. Antibody prevalence was analyzed by using solid phase immunoassay techniques. Cognitive functioning was tested with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Form A, the Trail Making Test A&B, and two subtests from the WAIS III: the Letter Number Sequencing Task and the subtest on information. History and psychopathology was assessed using structured interviews and validated rating scales (SCID, HRSD-21, YMRS, PANSS). Additionally, we investigated social functioning and quality of life using self-assessment-scales (SAS, LQLP). Prevalence rates of antibodies against diverse infectious agents did not differ significantly between patients and controls. We found a significant correlation between cognitive impairment in patients with bipolar disorder and the prevalence of antibodies directed against HSV-1. Cognitive functions were significantly impaired including language, attention, and immediate memory. The results of this study confirm previous findings suggesting that HSV-1 affects cognitive functions in patients with bipolar disorder. This may also result in more impaired functioning, less quality of life and difficulties in social adjustment.

Cancer-Causing Gut Bacteria | E.Coli The Scientist

A usually benign strain of the gut microbe E. coli produces toxins in mice with inflammatory bowel disease, which can lead to DNA-damage and cancer in the host tissue. The results were reported last week in Science  (August 16).

Intestinal Inflammation Targets Cancer-Inducing Activity of the Microbiota

Stress May Cause Illness By Methylating Genes: MNT

The researchers invited 76 participants in their sixties to undergo two types of stressful event: one was to to take part in a mock job interview, and the other was to solve arithmetic problems under observation. Both these tests are commonly used to produce stress under lab conditions.The participants gave blood samples before the tests, and also twice afterwards: one ten minutes after (post-test), and another 1.5 hours after (follow-up). From these the researchers could measure the amount of DNA methylation in the two genes.They found that the BDNF gene remained unaffected by any of the stress tests.But the OXTR gene showed methylation changes. There was an increase in methylation in a section of the OXTR gene in the post-test measure: this suggests the cells formed fewer receptors.

Good mood foods: Some flavors in some foods resemble a prescription mood stabilizer (valproate)

New evidence reveals the possibility of mood-enhancing effects associated with some flavors, stemming at least in part from natural ingredients bearing a striking chemical similarity to valproic acid, a widely used prescription mood-stabilizing drug, scientists reported in Philadelphia. This effect joins those previously reported for chocolate, teas and some other known comfort foods.(chocolate, blueberries, raspberries, strawberries, teas and certain other foods)
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Virus-producing cells determine the host protein profiles of HIV-1 virion cores.

Upon HIV entry into target cells, viral cores are released and rearranged into reverse transcription complexes (RTCs), which support reverse transcription and also protect and transport viral cDNA to the site of integration. RTCs are composed of viral and cellular proteins that originate from both target and producer cells, the latter entering the target cell within the viral core. However, the proteome of HIV-1 viral cores in the context of the type of producer cells has not yet been characterized. RESULTS: We examined the proteomic profiles of the cores purified from HIV-1 NL4-3 virions assembled in Sup-T1 cells (T lymphocytes), PMA and vitamin D3 activated THP1 (model of macrophages, mMPhi), and non-activated THP1 cells (model of monocytes, mMN) and assessed potential involvement of identified proteins in the early stages of infection using gene ontology information and data from genome-wide screens on proteins important for HIV-1 replication. We identified 202 cellular proteins incorporated in the viral cores (T cells: 125, mMPhi: 110, mMN: 90) with the overlap between these sets limited to 42 proteins. The groups of RNA binding (29), DNA binding (17), cytoskeleton (15), cytoskeleton regulation (21), chaperone (18), vesicular trafficking-associated (12) and ubiquitin-proteasome pathway-associated proteins (9) were most numerous. Cores of the virions from SupT1 cells contained twice as many RNA binding proteins as cores of THP1-derived virus, whereas cores of virions from mMPhi and mMN were enriched in components of cytoskeleton and vesicular transport machinery, most probably due to differences in virion assembly pathways between these cells. Spectra of chaperones, cytoskeletal proteins and ubiquitin-proteasome pathway components were similar between viral cores from different cell types, whereas DNA-binding and especially RNA-binding proteins were highly diverse. Western blot analysis showed that within the group of overlapping proteins, the level of incorporation of some RNA binding (RHA and HELIC2) and DNA binding proteins (MCM5 and Ku80) in the viral cores from T cells was higher thanin the cores from both mMPhi and mMN and did not correlate with the abundance of these proteins in virus producing cells. CONCLUSIONS: Profiles of host proteins packaged in the cores of HIV-1 virions depend on the type of virus producing cell. The pool of proteins present in the cores of all virions is likely to contain factors important for viral functions. Incorporation ratio of certain RNA- and DNA-binding proteins suggests their more efficient, non-random packaging into virions in T cells than in mMPhi and mMN.

Airways More Acidic In Cystic Fibrosis Patients, Less Effective At Killing Bacteria

The human airway is a pretty inhospitable place for microbes. There are numerous immune defense mechanisms poised to kill or remove inhaled bacteria before they can cause problems. But cystic fibrosis (CF) disrupts these defenses, leaving patients particularly susceptible to airway infection, which is the major cause of disease and death in CF.

Turmeric blocks Rift Valley fever virus multiplication

Curcumin, found in turmeric, stopped the potentially deadly Rift Valley Fever virus from multiplying in infected cells, says Aarthi Narayanan, lead investigator on the new study and a research assistant professor with Mason's National Center for Biodefense and Infectious Diseases.
Mosquito-borne Rift Valley Fever virus (RVF) is an acute, fever-causing virus that affects domestic animals such as cattle, sheep and goats, as well as humans. The research appears this month in the Journal of Biological Chemistry.
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Cerebrospinal fluid biomarkers of neuropathologically diagnosed Parkinson's disease subjects.

Parkinson's disease (PD) afflicts approximately 1-2% of the population over 50 years of age. No cures or effective modifying treatments exist and clinical diagnosis is currently confounded by a lack of definitive biomarkers. We sought to discover potential biomarkers in the cerebrospinal fluid (CSF) of neuropathologically confirmed PD cases.METHODS:We compared postmortem ventricular CSF (V-CSF) from PD and normal control (NC) subjects using two-dimensional difference gel electrophoresis (2D-DIGE). Spots exhibiting a 1·5-fold or greater difference in volume between PD patients and controls were excised from the two-dimensional gels, subjected to tryptic digestion and identification of peptides assigned using mass spectrometric/data bank correlation methods.RESULTS:Employing this strategy six molecules: fibrinogen, transthyretin, apolipoprotein E, clusterin, apolipoprotein A-1, and glutathione-S-transferase-Pi, were found to be different between PD and NC populations.DISCUSSION:These molecules have been implicated in PD pathogenesis. Combining biomarker data from multiple laboratories may create a consensus panel of proteins that may serve as a diagnostic tool for this neurodegenerative disorder.

Poxviruses Defeat Antiviral Defenses By Duplicating A Gene: MNT

Scientists have discovered that poxviruses, which are responsible for smallpox and other diseases, can adapt to defeat different host antiviral defenses by quickly and temporarily producing multiple copies of a gene that helps the viruses to counter host immunity. This discovery provides new insight into the ability of large double-stranded DNA viruses to undergo rapid evolution despite their low mutation rates, according to a study published by University of Utah researchers in the Aug. 17, 2012, issue of Cell.
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Toxoplasma gondii parasite may trigger suicide attempts

A parasite (T.Gondii) thought to be harmless and found in many people may actually be causing subtle changes in the brain, leading to suicide attempts.


Inflammation , not genetics, drives Crohn's disease, says study

Inflammation -- not genetic susceptibility -- drives the growth of intestinal bacteria and invasive E. coli linked to Crohn's disease (CD), reports a new Cornell study.

Read more at: http://medicalxpress.com/news/2012-08-inflammation-crohn-disease.html#jCp

Genes carried by E. coli bacteria linked to colon cancer

In a series of experiments conducted with mice prone to intestinal inflammation, the researchers found that inflammation itself causes significant simplification in diverse communities of gut microbes and allows new bacterial populations to establish major footholds. Among the bacterial taxa invading the disturbed intestinal ecosystem, the research team found a greatly increased presence of E. coli and related bacteria. By putting E. coli bacteria into mice that were raised under sterile conditions, the team also found that the presence of E. coli promoted tumor formation. When regions of the E. coli genome known to be involved in DNA damage were removed, the ability of the E. coli to cause tumors was substantially decreased.

Read more at: http://medicalxpress.com/news/2012-08-genes-coli-bacteria-linked-colon.html#jCp
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PLoS Pathogens: Immune Senescence: Relative Contributions of Age and Cytomegalovirus Infection

Immune senescence, defined as the age-associated dysregulation and dysfunction of the immune system, is characterised by impaired protective immunity and decreased efficacy of vaccines. Recent clinical, epidemiological and immunological studies suggest that Cytomegalovirus (CMV) infection may be associated with accelerated immune senescence, possibly by restricting the naïve T cell repertoire. However, direct evidence whether and how CMV-infection is implicated in immune senescence is still lacking. In this study, we have investigated whether latent mouse CMV (MCMV) infection with or without thymectomy (Tx) alters antiviral immunity of young and aged mice. After infection with lymphocytic choriomeningitis virus (LCMV) or Vaccinia virus, specific antiviral T cell responses were significantly reduced in old, old MCMV-infected and/or Tx mice compared to young mice. Importantly, control of LCMV replication was more profoundly impaired in aged MCMV-infected mice compared to age-matched MCMV-naïve or young mice. In addition, latent MCMV infection was associated with slightly reduced vaccination efficacy in old Tx mice. In contrast to the prevailing hypothesis of a CMV-mediated restriction of the naïve T cell repertoire, we found similar naïve T cell numbers in MCMV-infected and non-infected mice, whereas ageing and Tx clearly reduced the naïve T cell pool. Instead, MCMV-infection expanded the total CD8+ T cell pool by a massive accumulation of effector memory T cells. Based on these results, we propose a new model of increased competition between CMV-specific memory T cells and any ‘de novo’ immune response in aged individuals. In summary, our results directly demonstrate in a mouse model that latent CMV-infection impairs immunity in old age and propagates immune senescence.
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PLoS Pathogens: Cytomegalovirus Infection Impairs Immune Responses and Accentuates T-cell Pool Changes Observed in Mice with Aging

Prominent immune alterations associated with aging include the loss of naïve T-cell numbers, diversity and function. While genetic contributors and mechanistic details in the aging process have been addressed in multiple studies, the role of environmental agents in immune aging remains incompletely understood. From the standpoint of environmental infectious agents, latent cytomegalovirus (CMV) infection has been associated with an immune risk profile in the elderly humans, yet the cause-effect relationship of this association remains unclear. Here we present direct experimental evidence that mouse CMV (MCMV) infection results in select T-cell subset changes associated with immune aging, namely the increase of relative and absolute counts of CD8 T-cells in the blood, with a decreased representation of the naïve and the increased representation of the effector memory blood CD8 T-cells. Moreover, MCMV infection resulted in significantly weaker CD8 responses to superinfection with Influenza, Human Herpes Virus I or West-Nile-Virus, even 16 months following MCMV infection. These irreversible losses in T-cell function could not be observed in uninfected or in vaccinia virus-infected controls and were not due to the immune-evasive action of MCMV genes. Rather, the CD8 activation in draining lymph nodes upon viral challenge was decreased in MCMV infected mice and the immune response correlated directly to the frequency of the naïve and inversely to that of the effector cells in the blood CD8 pool. Therefore, latent MCMV infection resulted in pronounced changes of the T-cell compartment consistent with impaired naïve T-cell function.
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Activating killer-cell immunoglobulin-like receptors (KIR) and their cognate HLA ligands are significantly increased in autism.

Killer-cell immunoglobulin-like receptor (KIR) proteins are expressed on natural killer (NK) cells and appear important in innate and adaptive immunity. There are about 14 KIR genes on chromosome 19q13.4, composed of those that inhibit and those that activate NK cell killing. Haplotypes have different combinations of these genes meaning that not all genes are present in a subject. There are two main classes of cognate human leukocyte antigen (HLA) ligands (HLA-Bw4 and HLA-C1/C2) that bind to the inhibitory/activating receptors. As a general rule, the inhibitory state is maintained except when virally infected or tumor cells are encountered; however, both increased activation and inhibition states have been associated with susceptibility and protection against numerous disease states including cancer, arthritis, and psoriasis. Utilizing DNA from 158 Caucasian subjects with autism and 176 KIR control subjects we show for the first time a highly significant increase in four activating KIR genes (2DS5, 3DS1, 2DS1 and 2DS4) as measured by chi square values and odds ratios. In addition, our data suggests a highly significant increase in the activating KIR gene 2DS1 and its cognate HLA-C2 ligand (2DS1+C2; p=0.00003 [Odds ratio=2.87]). This information ties together two major immune gene complexes, the human leukocyte complex and the leukocyte receptor complex, and may partially explain immune abnormalities observed in many subjects with autism.
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Futurity.org – ‘Shadow plumbing’ hauls waste from brain

The highly organized system acts like a series of pipes that piggyback on the brain’s blood vessels, sort of a shadow plumbing system that seems to serve much the same function in the brain as the lymph system does in the rest of the body—to drain away waste products.
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Herpes simplex virus encephalitis and Abeta plaques in human patients: Case reports.

Plaques but not tangles in these case reports

Hair-Loss Drug Linked to Depression -

Young men who took finasteride (Propecia) for hair loss and experienced its sexual side effects also had high rates of depressive symptoms, even after stopping the drug, a retrospective study found. .Finasteride inhibits the conversion of  testosterone to dihydrotestosterone.
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Schizophrenia shows a unique metabolomics signature in plasma.

Schizophrenia is a severe complex mental disorder affecting 0.5-1% of the world population. To date, diagnosis of the disease is mainly based on personal and thus subjective interviews. The underlying molecular mechanism of schizophrenia is poorly understood. Using targeted metabolomics we quantified and compared 103 metabolites in plasma samples from 216 healthy controls and 265 schizophrenic patients, including 52 cases that do not take antipsychotic medication. Compared with healthy controls, levels of five metabolites were found significantly altered in schizophrenic patients (P-values ranged from 2.9 × 10(-8) to 2.5 × 10(-4)) and in neuroleptics-free probands (P-values ranging between 0.006 and 0.03), respectively. These metabolites include four amino acids (arginine, glutamine, histidine and ornithine) and one lipid (PC ae C38:6) and are suggested as candidate biomarkers for schizophrenia. To explore the genetic susceptibility on the associated metabolic pathways, we constructed a molecular network connecting these five aberrant metabolites with 13 schizophrenia risk genes. Our result implicated aberrations in biosynthetic pathways linked to glutamine and arginine metabolism and associated signaling pathways as genetic risk factors, which may contribute to patho-mechanisms and memory deficits associated with schizophrenia. This study illustrated that the metabolic deviations detected in plasma may serve as potential biomarkers to aid diagnosis of schizophrenia.

A single enzyme plays a critical role in helping the body effectively fight viral infection

The body’s initial response to invading bacteria or viruses is mediated by the innate immune system, wherein cells secrete signaling factors called cytokines that promote inflammation and stimulate a generalized counterattack against targets perceived as ‘foreign’. The protein Toll-like receptor 3 (TLR3), for instance, helps initiate the innate immune response against viruses. The researchers identified Bruton’s tyrosine kinase (BTK) as a TLR3-activating enzyme

GUT BACTERIA ASSOCIATED WITH OBESITY AND METABOLIC SYNDROME

Researchers at the University of Maryland School of Medicine have identified 26 species of bacteria in the human gut microbiota that appear to be linked to obesity and related metabolic complications. These include insulin resistance, high blood sugar levels, increased blood pressure and high cholesterol, known collectively as "the metabolic syndrome," which significantly increases an individual’s risk of developing diabetes, cardiovascular disease and stroke.

A vaccine for heart disease? New discovery points up this possibility

Researchers at the La Jolla Institute for Allergy & Immunology have identified the specific type of immune cells (CD4 T cells) that orchestrate the inflammatory attack on the artery wall. Further, the researchers discovered that these immune cells behave as if they have previously seen the antigen that causes them to launch the attack. "The thing that excites me most about this finding is that these immune cells appear to have 'memory' of the molecule brought forth by the antigen-presenting cells," said Klaus Ley, M.D., a renowned expert in vascular immunology, who led the study in mouse models. "Immune memory is the underlying basis of successful vaccines. This means that conceptually it becomes possible to consider the development of a vaccine for heart disease."


Futurity.org – Germ killer in hand soap may weaken muscles (Triclosan)

Triclosan, an antibacterial chemical, hinders muscle contractions at a cellular level, slows swimming in fish, and reduces muscular strength in mice, according to researchers at the University of California, Davis, and the University of Colorado. The team reported full findings in the Proceedings of the National Academy of Sciences.
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Do Bugs Control Our Fate? The Influence of the Microbiome on Autoimmunity.

Autoimmune disease has traditionally been thought to be due to the impact of environmental factors on genetically susceptible individuals causing immune dysregulation and loss of tolerance. However, recent literature has highlighted the importance of the microbiome, (a collective genome of microorganisms in a given niche) in immune homeostasis. Increasingly, it has been recognized that disruptions in the commensal microflora may lead to immune dysfunction and autoimmunity. This review summarizes recent studies investigating the interplay between the microbiome and immune-mediated organ-specific diseases. In particular, we review new findings on the role of the microbiome in inflammatory bowel disease, celiac disease, psoriasis, rheumatoid arthritis, type I diabetes, and multiple sclerosis.

Antisense approach promising for treatment of parasitic infections (Toxoplasmosis)

A targeted approach to treating toxoplasmosis, a parasitic disease, shows early promise in test-tube and animal studies, where it prevented the parasites from making selected proteins. When tested in newly infected mice, it reduced the number of viable parasites by more than 90 percent, researchers from the University of Chicago Medicine report in the Proceedings of the National Academy of Sciences.

Consuming flavanol-rich cocoa may enhance brain function

Study: Junk food laws may help curb kids' obesity

Continuous production of prions after infectious particles are eliminated: implications for Alzheimer's disease.

Rat septal cells, induced to enter a terminal differentiation-like state by temperature shift, produce prion protein (PrP) levels 7x higher than their proliferative counterparts. Host PrP accumulates on the plasma membrane, newly elaborated nanotubes, and cell-to-cell junctions, important conduits for viral spread. To find if elevated PrP increased susceptibility to FU-CJD infection, we determined agent titers under both proliferating and arresting conditions. A short 5 day arrest and a prolonged 140 day arrest increased infectivity by 5x and 122x (>2 logs) respectively as compared to proliferating cells. Total PrP rapidly increased 7x and was even more elevated in proliferating cells that escaped chronic arrest conditions. Amyloid generating PrP (PrP-res), the "infectious prion" form, present at ~100,000 copies per infectious particle, also increased proportionately by 140 days. However, when these highly infectious cells were switched back to proliferative conditions for 60 days, abundant PrP-res continued to be generated even though 4 logs of titer was lost. An identical 4 log loss was found with maximal PrP and PrP-res production in parallel cells under arresting conditions. While host PrP is essential for TSE agent spread and replication, excessive production of all forms of PrP can be inappropriately perpetuated by living cells, even after the initiating infectious agent is eliminated. Host PrP changes can start as a protective innate immune response that ultimately escapes control. A subset of other neurodegenerative and amyloid diseases, including non-transmissible AD, may be initiated by environmental infectious agents that are no longer present.
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How Does Multiple Sclerosis Progress? Possible Clues Discovered: MNT

B cells isolated from multiple sclerosis patients secrete a toxic substance that damages oligodendrocytes
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Identification of a dietary pattern prospectively associated with increased adiposity during childhood and adolescence.

Map of Energy consumption (kcal/person/day) pe...
Map of Energy consumption (kcal/person/day) per country in 1961. World average was 2,253.9 kcal/person/day. This is a modified version of File:World map of Energy consumption 1961.svg but coloured per the same scheme as File:World map of Energy consumption 2001-2003.svg. (Photo credit: Wikipedia)
Specific dietary risk factors for excess adiposity in young people are poorly understood. However, studies in adults suggest dietary energy density, fat and fibre are critical dietary factors.Objective:To examine longitudinal relationships between a dietary pattern (DP) characterised by dietary energy density, % total energy from fat and fibre density and fat mass (FM) in children from 7 to 15 years of age.Design:Subjects were 6772 children from the UK Avon Longitudinal Study of Parents and Children. Dietary intake was assessed using a 3-day food diary at 7, 10 and 13 years of age. An energy-dense, high-fat, low-fibre DP was identified using reduced rank regression and subjects scored for the DP at each age. FM was measured at 11, 13 and 15 years and FM index (FMI) calculated as FM/height((x)). Longitudinal models were adjusted for dietary misreporting, physical activity and maternal factors.Results:DP z-scores at all ages were positively associated with later FMI. A 1 s.d. unit increase in DP z-score was longitudinally associated with an average increase in FMI z-score of 0.04 s.d. units (95% confidence interval (CI), 0.01-0.07). For each 1 s.d. unit increase in DP z-score, the odds of being in the highest quintile for FMI (as a marker of excess adiposity) increased by 13% (95% CI, 1-27%).Conclusions:Dietary habits during childhood are associated with increased adiposity in adolescence, with specific implications for dietary energy density, fat and fibre intake. Improving diet quality may reduce the risk of obesity in young people.International Journal of Obesity
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Translational Psychiatry - Effects of maternal immune activation on gene expression patterns in the fetal brain

We are exploring the mechanisms underlying how maternal infection increases the risk for schizophrenia and autism in the offspring. Several mouse models of maternal immune activation (MIA) were used to examine the immediate effects of MIA induced by influenza virus, poly(I:C) and interleukin IL-6 on the fetal brain transcriptome. Our results indicate that all three MIA treatments lead to strong and common gene expression changes in the embryonic brain. Most notably, there is an acute and transient upregulation of the α, β and γ crystallin gene family. Furthermore, levels of crystallin gene expression are correlated with the severity of MIA as assessed by placental weight. The overall gene expression changes suggest that the response to MIA is a neuroprotective attempt by the developing brain to counteract environmental stress, but at a cost of disrupting typical neuronal differentiation and axonal growth. We propose that this cascade of events might parallel the mechanisms by which environmental insults contribute to the risk of neurodevelopmental disorders such as schizophrenia and autism.

MicrobeWorld - BCG Vaccine May Reverse Type 1 Diabetes

One of the world's oldest vaccines now has a new use. Bacillus Calmette-Guerin, or BCG, is an 80-year-old vaccine designed to tread tuberculosis. Bit it has now been found effective in treating long-term type 1 diabetes, which is on the rise worldwide.

The APP family members are key players in S-adenosylmethionine formation by MAT2A and modify BACE1 and PSEN1 gene expression - relevance for Alzheimer`s disease.

A central hallmark of Alzheimers disease (AD) are senile plaques mainly composed of [beta] amyloid, which is a cleavage product of the amyloid precursor protein (APP). The physiological function of APP and its family members APLP1 and APLP2 is poorly understood. In order to fill this gap, we established a cell-culture based model with simultaneous knockdown of all members of the family. A comprehensive proteome study of the APP/APLP1/APLP2 knockdown cell lysates vs. controls revealed significant protein abundance changes of more than 30 proteins. Targeted validation of selected candidates by immunoblotting supported the significant down-regulation of the methionine adenosyltransferase II, alpha (MAT2A) as well as of peroxiredoxin 4 (PRDX4) in the knockdown cells. Moreover, MAT2A was significantly down-regulated at the mRNA level as well. MAT2A catalyzes the production of S-adenosylmethionine (SAM) from methionine and ATP, which plays a pivotal role in the methylation of neurotransmitters, DNA, proteins, and lipids. MAT2A-dependent significant up-regulation of SAM was also detectable in the knockdown cells compared to controls. Our results point to a role of the APP family proteins in cellular methylation mechanisms and fit to findings of disturbed SAM levels in tissue and CSF of Alzheimer disease patients vs. controls. Importantly, methylation plays a central role for neurotransmitter generation like acetylcholine pointing to a crucial relevance of our findings for AD. In addition, we identified differential gene expression of BACE1 and PSEN1 in the knockdown cells, which is possibly a consequence of MAT2A deregulation and may indicate a self regulatory mechanism.

Gemfibrozil, a lipid-lowering drug, increases myelin genes in human oligodendrocytes via peroxisome proliferator-activated receptor beta.

An increase in CNS remyelination and a decrease in CNS inflammation are important steps to halt the progression of multiple sclerosis (MS). Earlier studies have shown that gemfibrozil, a lipid-lowering drug, has anti-inflammatory properties. The current study identifies another novel property of gemfibrozil in stimulating the expression of myelin-specific genes (MBP, MOG, CNPase, and PLP) in primary human oligodendrocytes, mixed glial cells and spinal cord organotypic cultures. Although gemfibrozil is a known activator of peroxisome proliferator-activated receptor-a (PPAR-a), we were unable to detect PPAR-a in either gemfibrozil-treated or untreated human oligodendrocytes and gemfibrozil increased the expression of myelin genes in oligodendrocytes isolated from both wild type and PPAR-a (-/-) mice. On the other hand, gemfibrozil markedly increased the expression of PPAR-b, but not PPAR-g. Consistently, antisense knockdown of PPAR-b, but not PPAR-g, abrogated the stimulatory effect of gemfibrozil on myelin genes in human oligodendrocytes. Gemfibrozil also did not upregulate myelin genes in oligodendroglia isolated from PPAR-b (-/-) mice. Chromatin immunoprecipitation analysis shows that gemfibrozil induces the recruitment of PPAR-b to the promoter of PLP and MOG genes in human oligodendrocytes. Furthermore, gemfibrozil treatment also led to the recruitment of PPAR-b to the PLP promoter in vivo in the spinal cord of EAE mice and suppression of EAE symptoms in PLP-TCR transgenic mice. These results suggest that gemfibrozil stimulates the expression of myelin genes via PPAR-b and that gemfibrozil, a prescribed drug for humans, may further find its therapeutic use in demyelinating diseases.
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Schizophrenia May Be Associated With Immune Function: MNT

A new Australian study published in the journal Molecular Psychiatry provides the, so far, strongest evidence of an association between schizophrenia and immune function, suggesting that schizophrenic patients' brains could be attacked by the immune system. Researchers have found elevated levels of inflammation in the dorsolateral prefrontal cortex, a key region in the brain that is affected by schizophrenia in 40% of schizophrenics.

Drinking Better Bacteria | The Scientist

Researchers analyzing the bacteria in municipal drinking water find simple measures can increase beneficial bacteria while reducing pathogenic strains.
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Cell Host and Microbe - Monitoring the Inflammatory Response to Infection through the Integration of MALDI IMS and MRI

IMS provides a whole-animal view of the inflammatory response to infection ► IMS identifies protein masses that are abundant at sites of inflammation ► Anatomic information at the site of infection can be generated by MRI ► Integrated IMS and MRI enable a 3D view of the host-pathogen interaction.
Systemic bacterial infection is characterized by a robust whole-organism inflammatory response. Analysis of the immune response to infection involves technologies that typically focus on single organ systems and lack spatial information. Additionally, the analysis of individual inflammatory proteins requires antibodies specific to the protein of interest, limiting the panel of proteins that can be analyzed. Herein we describe the application of matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) to mice systemically infected with Staphylococcus aureus to identify inflammatory protein masses that respond to infection throughout an entire infected animal. Integrating the resolution afforded by magnetic resonance imaging (MRI) with the sensitivity of MALDI IMS provides three-dimensional spatially resolved information regarding the distribution of innate immune proteins during systemic infection, allowing comparisons to in vivo structural information and soft-tissue contrast via MRI. Thus, integrating MALDI IMS with MRI provides a systems-biology approach to study inflammation during infection.
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Study adds to evidence daily aspirin linked to lower cancer mortality

A large new observational study finds more evidence of an association between daily aspirin use and modestly lower cancer mortality, but suggests any reduction may be smaller than that observed in a recent analysis. The study, appearing early online in the Journal of the National Cancer Institute (JNCI), provides additional support for a potential benefit of daily aspirin use for cancer mortality, but the authors say important questions remain about the size of the potential benefit.
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Link Discovered Between Depression And Increased Risk Of Peripheral Artery Disease

Pathogen-driven gastrointestinal cancers: Time for a change in treatment paradigm?

The regulation of cancerous tumor development is converged upon by multiple pathways and factors. Besides environmental factors, gastrointestinal (GI) tract cancer can be caused by chronic inflammation, which is generally induced by bacteria, viruses, and parasites. The role of these inducers in cancer development, cell differentiation and transformation, cell cycle deregulation, and in the expression of tumor-associated genes cannot be ignored. Although Helicobacter pylori activates many oncogenic pathways, particularly those in gastric and colorectal cancers, the role of viruses in tumor development is also significant. Viruses possess significant oncogenic potential to interfere with normal cell cycle control and genome stability, stimulating the growth of deregulated cells. An increasing amount of recent data also implies the association of GI cancers with bacterial colonization and viruses. This review focuses on host-cell interactions that facilitate primary mechanisms of tumorigenesis and provides new insights into novel GI cancer treatments.
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Futurity.org – Lots of fructose sets up metabolic trouble

UC DAVIS (US) — A fructose-heavy diet may contribute to the development of metabolic syndrome—which can increase the risk of developing cardiovascular disease and diabetes.

Blood test for Alzheimer's gaining ground

A subset of the 190 protein levels (17) were significantly different in people with MCI or Alzheimer's. When those markers were checked against data from 566 people participating in the multicenter Alzheimer's Disease Neuroimaging Initiative, only four markers remained: apolipoprotein E, B-type natriuretic peptide, C-reactive protein and pancreatic polypeptide.

Altered natural killer cells' response to herpes virus infection in multiple sclerosis involves KIR2DL2 expression.

The role of herpes viruses as potential triggers of multiple sclerosis (MS) is still debated. Peripheral blood mononuclear cells from MS patients and controls were treated with CpG sequences and infected in vitro with HSV-1. Samples were analyzed for viral yield, TLR9 pathways, cytokine secretion, NK cell activation and killer immunoglobulin-like receptor (KIR) expression. CpG treatment promoted an unexpected sensitivity to herpes virus infection in a subset of MS patients: TLR9 pathways did not show defects while NK cells presented decreased degranulation and cytotoxicity and up-regulated the inhibitory KIR2DL2 receptor. CpG treatment of purified NK cells affected directly KIR2DL2 modulation and cell activation. These data suggest potential implications for viral pathogenesis of MS.
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HVEM signalling at mucosal barriers provides host defence against pathogenic bacteria : Nature : Nature Publishing Group

The herpes virus entry mediator (HVEM), a member of the tumour-necrosis factor receptor family, has diverse functions, augmenting or inhibiting the immune response. HVEM was recently reported as a colitis risk locus in patients, and in a mouse model of colitis we demonstrated an anti-inflammatory role for HVEM3, but its mechanism of action in the mucosal immune system was unknown. Here we report an important role for epithelial HVEM in innate mucosal defence against pathogenic bacteria. HVEM enhances immune responses by NF-κB-inducing kinase-dependent Stat3 activation, which promotes the epithelial expression of genes important for immunity. During intestinal Citrobacter rodentium infection, a mouse model for enteropathogenic Escherichia coli infection, Hvem/ mice showed decreased Stat3 activation, impaired responses in the colon, higher bacterial burdens and increased mortality. We identified the immunoglobulin superfamily molecule CD160 , expressed predominantly by innate-like intraepithelial lymphocytes, as the ligand engaging epithelial HVEM for host protection. Likewise, in pulmonary Streptococcus pneumoniae infection, HVEM is also required for host defence. Our results pinpoint HVEM as an important orchestrator of mucosal immunity, integrating signals from innate lymphocytes to induce optimal epithelial Stat3 activation, which indicates that targeting HVEM with agonists could improve host defence.
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Chronic exposure to staph bacteria may be risk factor for lupus, study finds

Chronic exposure to even small amounts of staph bacteria could be a risk factor for the chronic inflammatory disease lupus, Mayo Clinic research shows. Staph, short for Staphylococcus aureus, is a germ commonly found on the skin or in the nose, sometimes causing infections. In the Mayo study, mice were exposed to low doses of a protein found in staph and developed a lupus-like disease, with kidney disease and autoantibodies like those found in the blood of lupus patients.
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Can thinking that you are fat make you fat?

One explanation may be related to psychosocial stress, which can be associated with gaining weight around the waist. Under this scenario, the psychosocial stress related to having (or not having) an ideal body type, along with the perception of oneself as overweight, can result in weight gain. "Another explanation may be that young people who see themselves as fat often change their eating habits by skipping meals, for example. Research has shown that dropping breakfast can lead to obesity," Cuypers says. Additionally, following a diet that you cannot maintain over time will also be counterproductive, since the body strives to maintain the weight you had before you started the diet

The brains of people with schizophrenia may attempt to heal from the disease

Brain tissue from the orbitofrontal cortex from 38 people with schizophrenia and 38 people without the disease were used in this study. The density of interstitial neurons in the white matter, and the density of GABAergic neurons in the grey matter were measured. An increased density of interstitial white matter neurons in the white matter, and decreased density of GABAergic neurons in the grey matter was found. This pattern suggests that the migration of interstitial white matter neurons towards an area where they are lacking, because of schizophrenia, is a response to the disease.

Glutamine acts as a neuroprotectant against DNA damage, beta-amyloid and H2O2-induced stress.

Glutamine is the most abundant free amino acid in the human blood stream and is 'conditionally essential' to cells. Its intracellular levels are regulated both by the uptake of extracellular glutamine via specific transport systems and by its intracellular synthesis by glutamine synthetase (GS). Adding to the regulatory complexity, when extracellular glutamine is reduced GS protein levels rise. Unfortunately, this excess GS can be maladaptive. GS overexpression is neurotoxic especially if the cells are in a low-glutamine medium. Similarly, in low glutamine, the levels of multiple stress response proteins are reduced rendering cells hypersensitive to H(2)O(2), zinc salts and DNA damage. These altered responses may have particular relevance to neurodegenerative diseases of aging. GS activity and glutamine levels are lower in the Alzheimer's disease (AD) brain, and a fraction of AD hippocampal neurons have dramatically increased GS levels compared with control subjects. We validated the importance of these observations by showing that raising glutamine levels in the medium protects cultured neuronal cells against the amyloid peptide, Aβ. Further, a 10-day course of dietary glutamine supplementation reduced inflammation-induced neuronal cell cycle activation, tau phosphorylation and ATM-activation in two different mouse models of familial AD while raising the levels of two synaptic proteins, VAMP2 and synaptophysin. Together, our observations suggest that healthy neuronal cells require both intracellular and extracellular glutamine, and that the neuroprotective effects of glutamine supplementation may prove beneficial in the treatment of AD.
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Deep sequencing for the detection of virus-like sequences in the brains of patients with multiple sclerosis: detection of GBV-C in human brain.

Multiple sclerosis (MS) is a demyelinating disease of unknown origin that affects the central nervous system of an estimated 400,000 Americans. GBV-C or hepatitis G is a flavivirus that is found in the serum of 1-2% of blood donors. It was originally associated with hepatitis, but is now believed to be a relatively non-pathogenic lymphotropic virus. Fifty frozen specimens from the brains of deceased persons affected by MS were obtained along with 15 normal control brain specimens. RNA was extracted and ribosomal RNAs were depleted before sequencing on the Illumina GAII. These 36 bp reads were compared with a non-redundant database derived from the 600,000+ viral sequences in GenBank organized into 4080 taxa. An individual read successfully aligned to the viral database was considered to be a "hit". Normalized MS specimen hit rates for each viral taxon were compared to the distribution of hits in the normal controls. Seventeen MS and 11 control brain extracts were sequenced, yielding 4-10 million sequences ("reads") each. Over-representation of sequence from at least one of 12 viral taxa was observed in 7 of the 17 MS samples. Sequences resembling other viruses previously implicated in the pathogenesis of MS were not significantly enriched in any of the diseased brain specimens. Sequences from GB virus C (GBV-C), a flavivirus not previously isolated from brain, were enriched in one of the MS samples. GBV-C in this brain specimen was confirmed by specific amplification in this single MS brain specimen, but not in the 30 other MS brain samples available. The entire 9.4 kb sequence of this GBV-C isolate is reported here. This study shows the feasibility of deep sequencing for the detection of occult viral infections in the brains of deceased persons with MS. The first isolation of GBV-C from human brain is reported here.

Muscle-Building Dietary Supplement Creatine Can Fight Depression: MNT

According to a new study published in the August 3 edition of the online issue of the American Journal of Psychiatry, women who suffer from major depression may benefit from creatine, a muscle-building dietary supplement to feel better.

Macrophage migration inhibitory factor mediates the antidepressant actions of voluntary exercise

Voluntary exercise is known to have an antidepressant effect. However, the underlying mechanism for this antidepressant action of exercise remains unclear, and little progress has been made in identifying genes that are directly involved. We have identified macrophage migration inhibitory factor (MIF) by analyzing existing mRNA microarray data and confirmed the augmented expression of selected genes under two experimental conditions: voluntary exercise and electroconvulsive seizure. A proinflammatory cytokine, MIF is expressed in the central nervous system and involved in innate and adaptive immune responses. A recent study reported that MIF is involved in antidepressant-induced hippocampal neurogenesis, but the mechanism remains elusive. In our data, tryptophan hydroxylase 2 (Tph2) and brain-derived neurotrophic factor (Bdnf) expression were induced after MIF treatment in vitro, as well as during both exercise and electroconvulsive seizure in vivo. This increment of Tph2 was accompanied by increases in the levels of total serotonin in vitro. Moreover, the MIF receptor CD74 and the ERK1/2 pathway mediate the MIF-induced Tph2 and Bdnf gene expression as well as serotonin content. Experiments in Mif−/− mice revealed depression-like behaviors and a blunted antidepressant effect of exercise, as reflected by changes in Tph2 and Bdnf expression in the forced swim test. In addition, administration of recombinant MIF protein produced antidepressant-like behavior in rats in the forced swim test. Taken together, these results suggest a role of MIF in mediating the antidepressant action of exercise, probably by enhancing serotonin neurotransmission and neurotrophic factor-induced neurogenesis in the brain.
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Toll-like receptor 4 signaling in T cells promotes autoimmune inflammation

Toll-like receptors (TLRs) are critical components of innate immunity and function as rapid pathogen sensors. TLR4 is expressed on CD4+ T cells as well, the functional significance of which is unclear. In this study, we analyzed the function of TLR4 in T cells but did not find a role in promoting T helper (Th) cell polarization. Instead, TLR4 ligation enhanced both CD4+ T-cell proliferation and survival in vitro. Using the experimental autoimmune encephalomyelitis (EAE) model, we found that the loss of TLR4 solely in CD4+ T cells almost completely abrogated disease symptoms, mainly through blunted Th17 and, to a lesser degree, Th1 responses. Moreover, Tlr4−/− γδ T cells were defective in IL-17 and IFN-γ production following EAE induction. This study supports an important role of this innate receptor in the direct regulation of T-cell activation and survival during autoimmune inflammation.

Widespread dynamic DNA methylation in response to biotic stress

Regulation of gene expression by DNA methylation is crucial for defining cellular identities and coordinating organism-wide developmental programs in many organisms. In plants, modulation of DNA methylation in response to environmental conditions represents a potentially robust mechanism to regulate gene expression networks; however, examples of dynamic DNA methylation are largely limited to gene imprinting. Here we report an unexpected role for DNA methylation in regulation of the Arabidopsis thaliana immune system. Profiling the DNA methylomes of plants exposed to bacterial pathogen, avirulent bacteria, or salicylic acid (SA) hormone revealed numerous stress-induced differentially methylated regions, many of which were intimately associated with differentially expressed genes. In response to SA, transposon-associated differentially methylated regions, which were accompanied by up-regulation of 21-nt siRNAs, were often coupled to transcriptional changes of the transposon and/or the proximal gene. Thus, dynamic DNA methylation changes within repetitive sequences or transposons can regulate neighboring genes in response to SA stress.

SORTALLER:Predicting allergens based on Allergen Family

SORTALLER is an online allergen classifier based on allergen family featured peptide (AFFP) dataset and normalized BLAST E-values, which establish the featured vectors for support vector machine (SVM). AFFPs are allergen-specific peptides panned from irredundant allergens and harbor perfect information with noise fragments eliminated because of their similarity to non-allergens. SORTALLER performed significantly better than other existing software and reached a perfect balance with high specificity (98.4%) and sensitivity (98.6%) for discriminating allergenic proteins from several independent datasets of protein sequences of diverse sources, also highlighting with the Matthews correlation coefficient (MCC) as high as 0.970, fast running speed and rapidly predicting a batch of amino acid sequences with a single click.
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Identifying aberrant pathways through integrated analysis of knowledge in pharmacogenomics

Many complex diseases are the result of abnormal pathway functions instead of single abnormalities. Disease diagnosis and intervention strategies must target these pathways while minimizing the interference with normal physiological processes. Large-scale identification of disease pathways and chemicals that may be used to perturb them requires the integration of information about drugs, genes, diseases and pathways. This information is currently distributed over several pharmacogenomics databases. An integrated analysis of the information in these databases can reveal disease pathways and facilitate novel biomedical analyses.
Results: We demonstrate how to integrate pharmacogenomics databases through integration of the biomedical ontologies that are used as meta-data in these databases. The additional background knowledge in these ontologies can then be used to enable novel analyses. We identify disease pathways using a novel multi-ontology enrichment analysis over the Human Disease Ontology, and we identify significant associations between chemicals and pathways using an enrichment analysis over a chemical ontology. The drug–pathway and disease–pathway associations are a valuable resource for research in disease and drug mechanisms and can be used to improve computational drug repurposing.

Attention-deficit hyperactivity disorder in children chronically exposed to high level of vehicular pollution.

The purpose of this study is to explore whether sustained exposure to vehicular air pollution affects the behavior and activities of children. The prevalence of attention-deficit hyperactivity disorder (ADHD) was assessed in two childhood populations. In a cross-sectional study 969 school-going children (9-17 years) and 850 age- and sex-matched children from rural areas were assessed, following the criteria of Diagnostic and Statistical Manual of conduct disorders (DSM-IV) of American Pediatric Association. Data of ambient particulate matter with a diameter of less than 10 μm (PM₁₀) were obtained from Central Pollution Control Board and aerosol monitor. ADHD was found in 11.0% of urban children in contrast to 2.7% of the control group (p < 0.001). Major risk factors were male gender, lower socioeconomic status, 12-14 year age group, and PM₁₀ level in breathing air. ADHD was more prevalent among boys both in urban and rural areas. It was prevalent among 18.0% of the boys enrolled in Delhi against 4.0% of the girls, giving a male/female ratio of 4.5:1. Inattentive type of ADHD was predominant followed by hyperactive-impulsive type and combined type of ADHD. Controlling potential confounder, ambient PM₁₀ level was positively correlated with ADHD (OR = 2.07; 95% CI, 1.08-3.99). CONCLUSION: The results of this study point to a possible association between air pollution and behavioral problems in children. Though gender, socioeconomic status, and age play a very important factor in ADHD prevalence, the association is highest and strongest between particulate pollution and prevalence of ADHD.