All viruses need to bind to specific receptor molecules on the surface of target cells to initiate infection. Virus–receptor binding is highly specific, and this specificity determines both the species and the cell type that can be infected by a given virus. In some well-studied cases, the virus-binding region on the receptor has been found to be unrelated to the receptor's normal cellular function. Resistance to virus infection can thus evolve by selection of mutations that alter amino acids in the binding region with minimal effect on normal function. This sort of positive selection can be used to infer the history of the host–virus “arms race” during their coevolution. In a new study, Demogines et al. use a combination of phylogenetic, structural, and virological analysis to infer the history and significance of positive selection on the transferrin receptor TfR1, a housekeeping protein required for iron uptake and the cell surface receptor for at least three different types of virus. The authors show that only two parts of the rodent TfR1 molecule have been subject to positive selection and that these correspond to the binding sites for two of these viruses—the mouse mammary tumor virus (a retrovirus) and Machupo virus (an arenavirus). They confirmed this result by introducing the inferred binding site mutations into the wild-type protein and testing for receptor function. Related arenaviruses are beginning to spread in human populations in South America as the cause of often fatal hemorrhagic fevers, and, although Demogines et al. could find no evidence of TfR1 mutations in this region that might have been selected as a consequence of human infection, the authors identified one such mutation in Asian populations that affects infection with these viruses.
Translational Psychiatry - Multiple variants aggregate in the neuregulin signaling pathway in a subset of schizophrenia patients
Despite the strongly held view that schizophrenia (SZ) shows substantial genetic heterogeneity, pathway heterogeneity, as seen in cancer where different pathways are affected in similar tumors, has not been explored. We explore this possibility in a case-only study of the neuregulin signaling pathway (NSP), which has been prominently implicated in SZ and for which there is detailed knowledge on the ligand- and receptor-processing steps through β- and γ-secretase cleavage. We hypothesize that more than one damaging variants in the NSP genes might be necessary to cause disease, leading to an apparent clustering of such variants in only the few patients with affected NSP. We analyze linkage and next-generation sequencing results for the genes encoding components of the pathway, including NRG1, NRG3, ERBB4, β-secretase and the γ-secretase complex. We find multiple independent examples of supporting evidence for this hypothesis: (i) increased linkage scores over NSP genes, (ii) multiple positive interlocus correlations of linkage scores across families suggesting each family is linked to either many or none of the genes, (iii) aggregation of predicted damaging variants in a subset of individuals and (iv) significant phenotypic differences of the subset of patients carrying such variants. Collectively, our data strongly support the hypothesis that the NSP is affected by multiple damaging variants in a subset of phenotypically distinct patients. On the basis of this, we propose a general model of pathway heterogeneity in SZ, which, in part, may explain its phenotypic variability and genetic complexity.
ScienceDirect.com - Virology - What is needed for phage therapy to become a reality in Western medicine?
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| B0007272 Bacteriophage (Photo credit: wellcome images) |
Cornell: Researchers Find Common Childhood Asthma Unconnected to Allergens or Inflammation
Little is known about why asthma develops, how it constricts the airway or why response to treatments varies between patients. Now, a team of researchers at Weill Cornell Medical College, Columbia University Medical Center and SUNY Downstate Medical Center has revealed the roots of a common type of childhood asthma, showing that it is very different from other asthma cases.Their report, in Science Translational Medicine, reveals that an over-active gene (ORMDL3) linked in 20 to 30 percent of patients with childhood asthma interrupts the synthesis of lipid molecules (known as sphingolipids) that are part of cell membranes found all over the body.
Changing gut bacteria through diet affects human brain function, UCLA study shows / UCLA Newsroom
UCLA researchers now have the first evidence that bacteria ingested in food can affect brain function in humans. In an early proof-of-concept study of healthy women, they found that women who regularly consumed beneficial bacteria known as probiotics through yogurt showed altered brain function, both while in a resting state and in response to an emotion-recognition task.
Sex-specific epigenetic disruption and behavioral changes following low-dose in utero bisphenol A exposure
Bisphenol A (BPA) is an estrogenic endocrine disruptor widely used in the production of plastics. Increasing evidence indicates that in utero BPA exposure affects sexual differentiation and behavior; however, the mechanisms underlying these effects are unknown. We hypothesized that BPA may disrupt epigenetic programming of gene expression in the brain. Here, we provide evidence that maternal exposure during pregnancy to environmentally relevant doses of BPA (2, 20, and 200 µg/kg/d) in mice induces sex-specific, dose-dependent (linear and curvilinear), and brain region-specific changes in expression of genes encoding estrogen receptors (ERs; ERα and ERβ) and estrogen-related receptor-γ in juvenile offspring. Concomitantly, BPA altered mRNA levels of epigenetic regulators DNA methyltransferase (DNMT) 1 and DNMT3A in the juvenile cortex and hypothalamus, paralleling changes in estrogen-related receptors. Importantly, changes in ERα and DNMT expression in the cortex (males) and hypothalamus (females) were associated with DNA methylation changes in the ERα gene. BPA exposure induced persistent, largely sex-specific effects on social and anxiety-like behavior, leading to disruption of sexually dimorphic behaviors. Although postnatal maternal care was altered in mothers treated with BPA during pregnancy, the effects of in utero BPA were not found to be mediated by maternal care. However, our data suggest that increased maternal care may partially attenuate the effects of in utero BPA on DNA methylation. Overall, we demonstrate that low-dose prenatal BPA exposure induces lasting epigenetic disruption in the brain that possibly underlie enduring effects of BPA on brain function and behavior, especially regarding sexually dimorphic phenotypes.
NIMH · Ketamine Cousin GLYX-13 Rapidly Lifts Depression Without Side Effects
Electrophysiology studies in this brain region showed that GLYX-13 and ketamine promoted long-lasting signal transmission in neurons, known as long-term potentiation/synaptic plasticity. This phenomenon is essential in learning and memory. The researchers propose how GLYX-13 works: GLYX-13 triggers NR2B receptor activation that leads to intracellular calcium influx and the expression of AMPA, which then is responsible for increased communication between neurons.
These results are consistent with data from a recent Phase 2 clinical trial, in which a single administration of GLYX-13 produced statistically significant reductions in depression scores in patients who had failed treatment with current antidepressants. The reductions were evident within 24 hours and persisted for an average of 7 days. After a single dose of GLYX-13, the drug’s antidepressant efficacy nearly doubled that seen with most conventional antidepressants after 4–6 weeks of dosing. GLYX-13 was well tolerated and it did not produce any of the schizophrenia-like effects associated with other NMDA receptor modulating agents.
Pathology supported genetic testing and treatment of cardiovascular disease in middle age for prevention of Alzheimer's disease.
Chronic, multi-factorial conditions caused by a complex interaction between genetic and environmental risk factors frequently share common disease mechanisms, as evidenced by an overlap between genetic risk factors for cardiovascular disease (CVD) and Alzheimer's disease (AD). Single nucleotide polymorphisms (SNPs) in several genes including ApoE, MTHFR, HFE and FTO are known to increase the risk of both conditions. The E4 allele of the ApoE polymorphism is the most extensively studied risk factor for AD and increases the risk of coronary heart disease by approximately 40%. It furthermore displays differential therapeutic responses with use of cholesterol-lowering statins and acetylcholinesterase inhibitors, which may also be due to variation in the CYP2D6 gene in some patients. Disease expression may be triggered by gene-environment interaction causing conversion of minor metabolic abnormalities into major brain disease due to cumulative risk. A growing body of evidence supports the assessment and treatment of CVD risk factors in midlife as a preventable cause of cognitive decline, morbidity and mortality in old age. In this review, the concept of pathology supported genetic testing (PSGT) for CVD is described in this context. PSGT combines DNA testing with biochemical measurements to determine gene expression and to monitor response to treatment. The aim is to diagnose treatable disease subtypes of complex disorders, facilitate prevention of cumulative risk and formulate intervention strategies guided from the genetic background. CVD provides a model to address the lifestyle link in most chronic diseases with a genetic component. Similar preventative measures would apply for optimisation of heart and brain health.
Meta-analysis: Bug and weed killers, solvents may increase risk of Parkinson's disease
"A large analysis of more than 100 studies from around the world shows that exposure to pesticides, or bug and weed killers, and solvents is likely associated with a higher risk of developing Parkinson's disease. The research appears in the May 28, 2013, print issue of Neurology, the medical journal of the American Academy of Neurology."
BBC News - Stroke patients see signs of recovery in stem-cell trial
Five seriously disabled stroke patients have shown small signs of recovery following the injection of stem cells into their brain.
A "candidate-interactome" aggregate analysis of genome-wide association data in multiple sclerosis.
Though difficult, the study of gene-environment interactions in multifactorial diseases is crucial for interpreting the relevance of non-heritable factors and prevents from overlooking genetic associations with small but measurable effects. We propose a "candidate interactome" (i.e. a group of genes whose products are known to physically interact with environmental factors that may be relevant for disease pathogenesis) analysis of genome-wide association data in multiple sclerosis. We looked for statistical enrichment of associations among interactomes that, at the current state of knowledge, may be representative of gene-environment interactions of potential, uncertain or unlikely relevance for multiple sclerosis pathogenesis: Epstein-Barr virus, human immunodeficiency virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, HHV8-Kaposi sarcoma, H1N1-influenza, JC virus, human innate immunity interactome for type I interferon, autoimmune regulator, vitamin D receptor, aryl hydrocarbon receptor and a panel of proteins targeted by 70 innate immune-modulating viral open reading frames from 30 viral species. Interactomes were either obtained from the literature or were manually curated. The P values of all single nucleotide polymorphism mapping to a given interactome were obtained from the last genome-wide association study of the International Multiple Sclerosis Genetics Consortium & the Wellcome Trust Case Control Consortium, 2. The interaction between genotype and Epstein Barr virus emerges as relevant for multiple sclerosis etiology. However, in line with recent data on the coexistence of common and unique strategies used by viruses to perturb the human molecular system, also other viruses have a similar potential, though probably less relevant in epidemiological terms.
Glutathione Deficiency in Gclm Null Mice Results in Complex I Inhibition and Dopamine Depletion following Paraquat Administration.
Depletion of glutathione has been shown to occur in autopsied brains of patients with Parkinson's disease (PD) as well as in animal models of PD. The goal of this study was to determine if chronic GSH deficiency per se resulted in complex I inhibition and/or dopamine depletion and whether these indices were further potentiated by aging or administration of paraquat, a redox-cycling herbicide that produces a PD-like neurodegeneration model in rodents (Brooks et al. 1999; McCormack et al. 2002). Deletion of the rate-limiting GSH synthesis gene, glutamate-cysteine ligase modifier subunit (Gclm) leads to significantly lower GSH concentrations in all tissues including brain. Gclm null (Gclm-/-) mice provide a model of prolonged GSH depletion to explore the relationship between GSH, complex I inhibition and dopamine loss in vivo. Despite ~60% depletion of brain GSH in Gclm-/- mice of ages 3-5 or 14-16 months, striatal complex I activity, dopamine levels, 3-nitrotyroine/tyrosine ratios, aconitase activity and CoASH remained unchanged. Administration of paraquat (10 mg/kg, twice/week, 3 weeks) to 3-5 month old Gclm-/- mice resulted in significantly decreased aconitase activity, complex I activity and dopamine levels but not in 3-5 month old Gclm+/+ mice. Furthermore, paraquat-induced inhibition of complex I and aconitase activities in Gclm-/- mice was observed in the striatum but not cortex. The results suggest that chronic deficiency of GSH in Gclm-/- mice was not sufficient to result in complex I inhibition or dopamine depletion perhaps due to homeostatic mechanisms but required an additional oxidative stress insult as shown with paraquat exposure.
Specific dietary preferences are linked to differing gut microbial metabolic activity in response to dark chocolate intake.
Systems biology approaches are providing novel insights into the role of nutrition for the management of health and disease. In the present study, we investigated if dietary preference for dark chocolate in healthy subjects may lead to different metabolic response to daily chocolate consumption. Using NMR- and MS-based metabolic profiling of blood plasma and urine, we monitored the metabolic response of 10 participants stratified as chocolate desiring and eating regularly dark chocolate (CD) and 10 participants stratified as chocolate indifferent and eating rarely dark chocolate (CI) to a daily consumption of 50 g of dark chocolate as part of a standardized diet over a one week period. We demonstrated that preference for chocolate leads to different metabolic response to chocolate consumption. Daily intake of dark chocolate significantly increased HDL cholesterol by 6% and decreased polyunsaturated acyl ether phospholipids. Dark chocolate intake could also induce an improvement in the metabolism of long chain fatty acid, as noted by a compositional change in plasma fatty acyl carnitines. Moreover, a relationship between regular long-term dietary exposure to a small amount of dark chocolate, gut microbiota, and phenolics was highlighted, providing novel insights into biological processes associated with cocoa bioactives.
The TLR4 antagonist Eritoran protects mice from lethal influenza infection : Nature : Nature Publishing Group
There is a pressing need to develop alternatives to annual influenza vaccines and antiviral agents licensed for mitigating influenza infection. Previous studies reported that acute lung injury caused by chemical or microbial insults is secondary to the generation of host-derived, oxidized phospholipid that potently stimulates Toll-like receptor 4 (TLR4)-dependent inflammation1. Subsequently, we reported that Tlr4−/− mice are highly refractory to influenza-induced lethality2, and proposed that therapeutic antagonism of TLR4 signalling would protect against influenza-induced acute lung injury. Here we report that therapeutic administration of Eritoran (also known as E5564)—a potent, well-tolerated, synthetic TLR4 antagonist3, 4—blocks influenza-induced lethality in mice, as well as lung pathology, clinical symptoms, cytokine and oxidized phospholipid expression, and decreases viral titres. CD14 and TLR2 are also required for Eritoran-mediated protection, and CD14 directly binds Eritoran and inhibits ligand binding to MD2. Thus, Eritoran blockade of TLR signalling represents a novel therapeutic approach for inflammation associated with influenza, and possibly other infections.
Identification of Altered Metabolic Pathways in Plasma and CSF in Mild Cognitive Impairment and Alzheimer's Disease Using Metabolomics.
Alzheimer's Disease (AD) currently affects more than 5 million Americans, with numbers expected to grow dramatically as the population ages. The pathophysiological changes in AD patients begin decades before the onset of dementia, highlighting the urgent need for the development of early diagnostic methods. Compelling data demonstrate that increased levels of amyloid-beta compromise multiple cellular pathways; thus, the investigation of changes in various cellular networks is essential to advance our understanding of early disease mechanisms and to identify novel therapeutic targets. We applied a liquid chromatography/mass spectrometry-based non-targeted metabolomics approach to determine global metabolic changes in plasma and cerebrospinal fluid (CSF) from the same individuals with different AD severity. Metabolic profiling detected a total of significantly altered 342 plasma and 351 CSF metabolites, of which 22% were identified. Based on the changes of >150 metabolites, we found 23 altered canonical pathways in plasma and 20 in CSF in mild cognitive impairment (MCI) vs. cognitively normal (CN) individuals with a false discovery rate <0.05. The number of affected pathways increased with disease severity in both fluids. Lysine metabolism in plasma and the Krebs cycle in CSF were significantly affected in MCI vs. CN. Cholesterol and sphingolipids transport was altered in both CSF and plasma of AD vs. CN. Other 30 canonical pathways significantly disturbed in MCI and AD patients included energy metabolism, Krebs cycle, mitochondrial function, neurotransmitter and amino acid metabolism, and lipid biosynthesis. Pathways in plasma that discriminated between all groups included polyamine, lysine, tryptophan metabolism, and aminoacyl-tRNA biosynthesis; and in CSF involved cortisone and prostaglandin 2 biosynthesis and metabolism. Our data suggest metabolomics could advance our understanding of the early disease mechanisms shared in progression from CN to MCI and to AD.
Molecular Psychiatry - : The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner
Bacterial colonisation of the intestine has a major role in the post-natal development and maturation of the immune and endocrine systems. These processes are key factors underpinning central nervous system (CNS) signalling. Regulation of the microbiome–gut–brain axis is essential for maintaining homeostasis, including that of the CNS. However, there is a paucity of data pertaining to the influence of microbiome on the serotonergic system. Germ-free (GF) animals represent an effective preclinical tool to investigate such phenomena. Here we show that male GF animals have a significant elevation in the hippocampal concentration of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid, its main metabolite, compared with conventionally colonised control animals. Moreover, this alteration is sex specific in contrast with the immunological and neuroendocrine effects which are evident in both sexes. Concentrations of tryptophan, the precursor of serotonin, are increased in the plasma of male GF animals, suggesting a humoral route through which the microbiota can influence CNS serotonergic neurotransmission. Interestingly, colonisation of the GF animals post weaning is insufficient to reverse the CNS neurochemical consequences in adulthood of an absent microbiota in early life despite the peripheral availability of tryptophan being restored to baseline values. In addition, reduced anxiety in GF animals is also normalised following restoration of the intestinal microbiota. These results demonstrate that CNS neurotransmission can be profoundly disturbed by the absence of a normal gut microbiota and that this aberrant neurochemical, but not behavioural, profile is resistant to restoration of a normal gut flora in later life.
BBC News - Feet home to more than 100 fungi
We all have nearly 200 different types of fungi colonising our feet, scientists have discovered.
Fungi live all over the human body, but their favourite spots are the heel, under toenails and between the toes, according to a US study.
A new map of the body's fungal diversity could help combat skin conditions such as athlete's foot, researchers report in Nature journal.
Fungi live all over the human body, but their favourite spots are the heel, under toenails and between the toes, according to a US study.
A new map of the body's fungal diversity could help combat skin conditions such as athlete's foot, researchers report in Nature journal.
Negligible impact of rare autoimmune-locus coding-region variants on missing heritability : Nature : Nature Publishing Group
Genome-wide association studies (GWAS) have identified common variants of modest-effect size at hundreds of loci for common autoimmune diseases; however, a substantial fraction of heritability remains unexplained, to which rare variants may contribute To discover rare variants and test them for association with a phenotype, most studies re-sequence a small initial sample size and then genotype the discovered variants in a larger sample set. This approach fails to analyse a large fraction of the rare variants present in the entire sample set. Here we perform simultaneous amplicon-sequencing-based variant discovery and genotyping for coding exons of 25 GWAS risk genes in 41,911 UK residents of white European origin, comprising 24,892 subjects with six autoimmune disease phenotypes and 17,019 controls, and show that rare coding-region variants at known loci have a negligible role in common autoimmune disease susceptibility. These results do not support the rare-variant synthetic genome-wide-association hypothesis (in which unobserved rare causal variants lead to association detected at common tag variants). Many known autoimmune disease risk loci contain multiple, independently associated, common and low-frequency variants, and so genes at these loci are a priori stronger candidates for harbouring rare coding-region variants than other genes. Our data indicate that the missing heritability for common autoimmune diseases may not be attributable to the rare coding-region variant portion of the allelic spectrum, but perhaps, as others have proposed, may be a result of many common-variant loci of weak effect
Phthalates: Study links chemicals widely found in plastics, processed food to elevated blood pressure in children, teens
"Plastic additives known as phthalates are odorless, colorless and just about everywhere: They turn up in flooring, plastic cups, beach balls, plastic wrap, intravenous tubing and—according to the Centers for Disease Control and Prevention—the bodies of most Americans. Once perceived as harmless, phthalates have come under increasing scrutiny. A growing collection of evidence suggests dietary exposure to phthalates (which can leech from packaging and mix with food) may cause significant metabolic and hormonal abnormalities, especially during early development."
Addiction to unhealthy foods could help explain the global obesity epidemic
"Research presented today shows that high-fructose corn syrup can cause behavioural reactions in rats similar to those produced by drugs of abuse such as cocaine. These results, presented by addiction expert Francesco Leri, Associate Professor of Neuroscience and Applied Cognitive Science at the University of Guelph, suggest food addiction could explain, at least partly, the current global obesity epidemic. These results were presented at the 2013 Canadian Neuroscience Meeting, the annual meeting of the Canadian Association for Neuroscience - Association Canadienne des Neurosciences (CAN-ACN)."
Vitamin C Slays TB Bacteria | The Scientist Magazine®
"High doses of vitamin C can rapidly wipe out entire populations of drug-resistant strains of the bacteria that cause tuberculosis (TB) by inducing a chemical reaction that produces high levels of DNA-damaging oxidative radicals, according to a study published today (May 21) in Nature Communications."
B vitamins could delay dementia
"Despite spending billions of dollars on research and development, drug companies have been unable to come up with effective treatments for dementia and Alzheimer's Disease (AD). Now, A. David Smith at the University of Oxford and his colleagues have discovered that, in some patients experiencing mild cognitive impairment (MCI), a cocktail of high-dose B vitamins could prevent gray matter loss associated with progression to AD. The study appears in the Proceedings of the National Academy of Sciences."
Common food supplement fights degenerative brain disorders
: "Widely available in pharmacies and health stores, phosphatidylserine is a natural food supplement produced from beef, oysters, and soy. Proven to improve cognition and slow memory loss, it's a popular treatment for older people experiencing memory impairment. Now a team headed by Prof. Gil Ast and Dr. Ron Bochner of Tel Aviv University's Department of Human Molecular Genetics have discovered that the same supplement improves the functioning of genes involved in degenerative brain disorders, including Parkinson's disease and Familial Dysautonomia (FD)."
Early-life traffic-related air pollution exposure linked to hyperactivity
"Early-life exposure to traffic-related air pollution was significantly associated with higher hyperactivity scores at age 7, according to new research from the University of Cincinnati (UC) and Cincinnati Children's Hospital Medical Center."
New immune system discovered
"Taking previous research into consideration, we are able to propose the Bacteriophage Adherence to Mucus—or BAM—is a new model of immunity, which emphasizes the important role bacteriophage play in protecting the body from invading pathogens"
Type 1 Diabetes May Be Reversible With Immune Suppressor Protein
"A professor in Melbourne, Australia, who is on a mission to find a cure for type 1 diabetes, believes that the answer, or part of it, lies with an immune suppressor protein called CD52. And if it works for type 1 diabetes, then it may well work for other immune disorders, such as multiple sclerosis and rheumatoid arthritis, where disruption in the balance different kinds of T cell in the immune system causes it to attack the body's own healthy tissue."
Scientists Develop Drug That Improves Memory and Prevents Brain Damage in Mice
A drug developed by scientists at the Salk Institute for Biological Studies, known as J147, improves memory and prevents brain damage in aged mice following short-term treatment. The findings, published May 14 in the journal Alzheimer's Research and Therapy, may pave the way to a new treatment for Alzheimer's disease in humans.J147 was developed at Salk in the laboratory of David Schubert, a professor in the Cellular Neurobiology Laboratory. He and his colleagues bucked the trend within the pharmaceutical industry, which has focused on the biological pathways involved in the formation of amyloid plaques, the dense deposits of protein that characterize the disease. Instead, the Salk team used living neurons grown in laboratory dishes to test whether their new synthetic compounds, which are based upon natural products derived from plants, were effective at protecting brain cells against several pathologies associated with brain aging. From the test results of each chemical iteration of the lead compound, they were able to alter their chemical structures to make them much more potent. Although J147 appears to be safe in mice, the next step will require clinical trials to determine whether the compound will prove safe and effective in humans.
Good cholesterol linked to innate immunity: ASM
Trypanosome Lytic Factor (TLF) has emerged as an arm of innate immunity, present only in humans and select non-human primates. TLF was originally discovered in human blood as a minor form of High-density lipoprotein (HDL), (good cholesterol), that kills the African trypanosome, Trypanosoma brucei, making humans resistant to infection. Participants will discuss this finding as well as how understanding these mechanism will provide insights as to other pathogens that TLF should kill, as well as offer potential avenues to therapeutically augment or mimic TLF action. TLF is a mixture of apolipoproteins APOL1 /igm APOA1 and haptoglobin-related protein
BBC News - Sunshine vitamin D 'may treat asthma'
The amount of time asthma patients spend soaking up the sun may have an impact on the illness, researchers have suggested.
A team at King's College London said low levels of vitamin D, which is made by the body in sunlight, was linked to a worsening of symptoms.
Its latest research shows the vitamin calms an over-active part of the immune system in asthma.
In US, 20% Of Children Have A Mental Disorder
MNT "Nearly 20% of children in the United States suffer from a mental disorder, and the number has been increasing for over a decade, according to a new report released by the Centers for Disease Control and Prevention (CDC)."
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Ketamine shows significant therapeutic benefit in people with treatment-resistant depression
"Patients with treatment-resistant major depression saw dramatic improvement in their illness after treatment with ketamine, an anesthetic, according to the largest ketamine clinical trial to-date led by researchers from the Icahn School of Medicine at Mount Sinai. The antidepressant benefits of ketamine were seen within 24 hours, whereas traditional antidepressants can take days or weeks to demonstrate a reduction in depression."
Now we know why old schizophrenia medicine works on antibiotics-resistant bacteria
Thioridazine is known to possess antibacterial effects, although it was not clear how this worked............ "When we treat the bacteria with antibiotics alone, nothing happens -- the bacteria are not even affected. But when we add both thioridazine and antibiotics, something happens: thioridazine weakens the bacterial cell wall by removing glycine (an amino acid) from the cell wall. In the absence of glycine, the antibiotics can attack the weakened cell wall and kill staphylococcus bacteria," explains Janne Kudsk Klitgaard, visiting scholar at the Department of Biochemistry and Molecular Biology, University of Southern Denmark".
Breathing Emission Particles Turns HDL Cholesterol From 'Good' To 'Bad'
MNT: Academic researchers have found that breathing motor vehicle emissions triggers a change in high-density lipoprotein (HDL) cholesterol, altering its cardiovascular protective qualities so that it actually contributes to clogged arteries.In addition to changing HDL from "good" to "bad," the inhalation of emissions activates other components of oxidation, the early cell and tissue damage that causes inflammation, leading to hardening of the arteries, according to the research team, which included scientists from UCLA and other institutions.
Geographic Variation in the Prevalence of Attention-Deficit/Hyperactivity Disorder: The Sunny Perspective.
Attention-deficit/hyperactivity disorder (ADHD) is the most common psychiatric disorder of childhood, with average worldwide prevalence of 5.3%, varying by region.
METHODS:
We assessed the relationship between the prevalence of ADHD and solar intensity (SI) (kilowatt hours/square meters/day) on the basis of multinational and cross-state studies. Prevalence data for the U.S. were based on self-report of professional diagnoses; prevalence data for the other countries were based on diagnostic assessment. The SI data were obtained from national institutes.
RESULTS:
In three datasets (across 49 U.S. states for 2003 and 2007, and across 9 non-U.S. countries) a relationship between SI and the prevalence of ADHD was found, explaining 34%-57% of the variance in ADHD prevalence, with high SI having an apparent preventative effect. Controlling for low birth weight, infant mortality, average income (socioeconomic status), latitude, and other relevant factors did not change these findings. Furthermore, these findings were specific to ADHD, not found for the prevalence of autism spectrum disorders or major depressive disorder.
CONCLUSIONS:
In this study we found a lower prevalence of ADHD in areas with high SI for both U.S. and non-U.S. data. This association has not been reported before in the literature. The preventative effect of high SI might be related to an improvement of circadian clock disturbances, which have recently been associated with ADHD. These findings likely apply to a substantial subgroup of ADHD patients and have major implications in our understanding of the etiology and possibly prevention of ADHD by medical professionals, schools, parents, and manufacturers of mobile device
GNbAC1, a humanized monoclonal antibody against the envelope protein of multiple sclerosis-associated endogenous retrovirus: a first-in-humans randomized clinical study.
Human endogenous retrovirus (HERV) genes represent about 8% of the human genome. A member of the HERV family W, the Multiple Sclerosis-Associated Retrovirus (MSRV) gene, encodes an envelope protein (Env), which can activate a proinflammatory and autoimmune cascade through its interaction with Toll-like receptor 4. Due to its proinflammatory property and an inhibitory effect on oligodendrocyte precursor cell differentiation, the MSRV-Env protein could play a crucial role in the pathogeny of multiple sclerosis. GNbAC1 is a humanized monoclonal antibody of the immunoglobulin G4 type, which is directed against MSRV-Env. After validation of the MSRV-Env as a therapeutic target in preclinical experimental models, a clinical development program was initiated.
OBJECTIVE:
This study evaluated the safety profile, pharmacokinetic parameters, and immunogenicity of GNbAC1 in healthy male volunteers.
METHODS:
In this first-in-humans, Phase I, randomized, double-blind, placebo-controlled, dose-escalation study, each subject received a single dose of IV GNbAC1 0.0025, 0.025, 0.15, 0.6, 2, or 6 mg/kg or inactive vehicle (placebo), infused over 1 hour. Tolerability and other laboratory parameters were observed, and regular blood sampling was performed, to study the pharmacokinetic properties and immunogenicity of this monoclonal antibody.
RESULTS:
A total of 33 male subjects (mean age, 44 years) completed the study. GNbAC1 was well tolerated after dosing in all subjects and in each dose cohort. Only minor and nonspecific adverse events (AEs) were recorded; no serious AEs were reported. Pharmacokinetic data show a dose-linear pharmacokinetic profile. The mean elimination half-life ranged between 19 and 26 days, with therapeutically efficient concentrations maintained over a 4-week periods at doses of 2 and 6 mg/kg. No emergence of anti-GNbAC1 antibodies were detected after dosing in any subject over the entire observation period of 64 days.
CONCLUSIONS:
In these healthy male subjects, the safety and pharmacokinetic profiles of GNbAC1 appeared favorable. These findings are expected to allow for the launch of a Phase II development program for this innovative therapeutic approach in patients with multiple sclerosis. ClinicalTrials.gov identifier: NCT01699555.
Body mass index of low income African-Americans linked to proximity of fast food restaurants
A new study published online in theAmerican Journal of Public Healthindicates higher BMI associates with residential proximity to a fast food restaurant, and among lower-income African-Americans, the density, or number, of fast food restaurants within two miles of the home
Nonmelanoma skin cancer is associated with reduced Alzheimer disease risk
To explore the association of nonmelanoma skin cancer (NMSC) and Alzheimer disease (AD) in the Einstein Aging Study, an epidemiologic study of aging in New York City.
Methods: Community-residing volunteers aged 70 years or older were assessed annually, followed by multidisciplinary diagnostic consensus. Cancer status and type was obtained by self-report. Cox proportional hazards models were used to test associations between NMSC and subsequent risk of developing a neurocognitive disorder. To deduce a biologically specific association between AD and NMSC, we considered 3 nested outcomes groups: only AD (probable or possible AD as the sole diagnosis), any AD (probable AD or possible AD, as well as mixed AD/vascular dementia), and all-cause dementia.
Results: We followed 1,102 adults with a mean age of 79 years at enrollment. Prevalent NMSC was associated with reduced risk of only AD (hazard ratio = 0.21; 95% confidence interval = 0.051–0.87; p = 0.031) among subjects after adjustment for demographics, hypertension, diabetes, and coronary heart disease. APOE ε4 genotypes were available in 769 individuals. The association was similar in magnitude, but nonsignificant, when the number of APOEε4 alleles was included in the model. No significant association was found between NMSC and subsequent development of any AD or all-cause dementia.
Conclusions: This population-based longitudinal study shows that individuals older than 70 years with NMSC have a significantly reduced risk of developing AD compared with individuals without NMSC. We deduce Alzheimer-specific neuroprotection, because the effect is attenuated or eliminated when considering less-specific diagnoses such as AD with another diagnosis (any AD) or all-cause dementia.
EnrichNet: network-based gene set enrichment analysis.
Assessing functional associations between an experimentally derived gene or protein set of interest and a database of known gene/protein sets is a common task in the analysis of large-scale functional genomics data. For this purpose, a frequently used approach is to apply an over-representation-based enrichment analysis. However, this approach has four drawbacks: (i) it can only score functional associations of overlapping gene/proteins sets; (ii) it disregards genes with missing annotations; (iii) it does not take into account the network structure of physical interactions between the gene/protein sets of interest and (iv) tissue-specific gene/protein set associations cannot be recognized.
RESULTS:
To address these limitations, we introduce an integrative analysis approach and web-application called EnrichNet. It combines a novel graph-based statistic with an interactive sub-network visualization to accomplish two complementary goals: improving the prioritization of putative functional gene/protein set associations by exploiting information from molecular interaction networks and tissue-specific gene expression data and enabling a direct biological interpretation of the results. By using the approach to analyse sets of genes with known involvement in human diseases, new pathway associations are identified, reflecting a dense sub-network of interactions between their corresponding proteins.
AVAILABILITY:
EnrichNet is freely available at http://www.enrichnet.org
In myalgic encephalomyelitis/chronic fatigue syndrome, increased autoimmune activity against 5-HT is associated with immuno-inflammatory pathways and bacterial translocation.
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is accompanied by activation of immuno-inflammatory pathways, increased bacterial translocation and autoimmune responses to serotonin (5-HT). Inflammation is known to damage 5-HT neurons while bacterial translocation may drive autoimmune responses. This study has been carried out to examine the autoimmune responses to 5-HT in ME/CFS in relation to inflammation and bacterial translocation.
METHODS:
We examined 5-HT antibodies in 117 patients with ME/CFS (diagnosed according to the centers for disease control and prevention criteria, CDC) as compared with 43 patients suffering from chronic fatigue (CF) but not fulfilling the CDC criteria and 35 normal controls. Plasma interleukin-1 (IL-1), tumor necrosis factor (TNF)α, neopterin and the IgA responses to Gram-negative bacteria were measured. Severity of physio-somatic symptoms was measured using the fibromyalgia and chronic fatigue syndrome rating scale (FF scale).
RESULTS:
The incidence of positive autoimmune activity against 5-HT was significantly higher (p<0.001) in ME/CFS (61.5%) than in patients with CF (13.9%) and controls (5.7%). ME/CFS patients with 5-HT autoimmune activity displayed higher TNFα, IL-1 and neopterin and increased IgA responses against LPS of commensal bacteria than those without 5-HT autoimmune activity. Anti-5-HT antibody positivity was significantly associated with increased scores on hyperalgesia, fatigue, neurocognitive and autonomic symptoms, sadness and a flu-like malaise.
DISCUSSION:
The results show that, in ME/CFS, increased 5-HT autoimmune activity is associated with activation of immuno-inflammatory pathways and increased bacterial translocation, factors which are known to play a role in the onset of autoimmune reactions. 5-HT autoimmune activity could play a role in the pathophysiology of ME/CFS and the onset of physio-somatic symptoms. These results provide mechanistic support for the notion that ME/CFS is a neuro-immune disorder.
Molecular characteristics of Human Endogenous Retrovirus type-W in schizophrenia and bipolar disorder.
Epidemiological and genome-wide association studies of severe psychiatric disorders such as schizophrenia (SZ) and bipolar disorder (BD), suggest complex interactions between multiple genetic elements and environmental factors. The involvement of genetic elements such as Human Endogenous Retroviruses type 'W' family (HERV-W) has consistently been associated with SZ. HERV-W envelope gene (env) is activated by environmental factors and encodes a protein displaying inflammation and neurotoxicity. The present study addressed the molecular characteristics of HERV-W env in SZ and BD. Hundred and thirty-six patients, 91 with BD, 45 with SZ and 73 healthy controls (HC) were included. HERV-W env transcription was found to be elevated in BD (P<10-4) and in SZ (P=0.012) as compared with HC, but with higher values in BD than in SZ group (P<0.01). The corresponding DNA copy number was paradoxically lower in the genome of patients with BD (P=0.0016) or SZ (P<0.0003) than in HC. Differences in nucleotide sequence of HERV-W env were found between patients with SZ and BD as compared with HC, as well as between SZ and BD. The molecular characteristics of HERV-W env also differ from what was observed in Multiple Sclerosis (MS) and may represent distinct features of the genome of patients with BD and SZ. The seroprevalence for Toxoplasma gondii yielded low but significant association with HERV-W transcriptional level in a subgroup of BD and SZ, suggesting a potential role in particular patients. A global hypothesis of mechanisms inducing such major psychoses is discussed, placing HERV-W at the crossroads between environmental, genetic and immunological factors. Thus, particular infections would act as activators of HERV-W elements in earliest life, resulting in the production of an HERV-W envelope protein, which then stimulates pro-inflammatory and neurotoxic cascades. This hypothesis needs to be further explored as it may yield major changes in our understanding and treatment of severe psychotic disorders.
dsRNA Sensing During Viral Infection: Lessons from Plants, Worms, Insects, and Mammals
Host defense systems often rely on direct and indirect pattern recognition to sense the presence of invading pathogens. Patterns can be molecules directly produced by the pathogen or indirectly generated by changes in host parameters as a consequence of infection. Viruses are intracellular pathogens that hijack the cellular machinery to synthesize their own molecules making direct recognition of viral molecules a great challenge. Antiviral systems in prokaryotes and eukaryotes commonly exploit aberrant nucleic acid sensing to recognize virus infection as host and viral nucleic acid metabolism can greatly differ. Indeed, the generation of dsRNA is often associated with viral infection. In this review, we discuss current knowledge on the mechanisms of viral dsRNA sensing utilized by 2 important antiviral defense systems, RNA interference (RNAi) and the vertebrate immune system. The major viral sensors of the vertebrate immune systems are RIG-like receptors, while RNAi pathways depend on Dicer proteins. These 2 families of sensors share a similar helicase domain with high specificity for dsRNA, which is necessary, but not sufficient for efficient recognition by these receptors. Additional intrinsic features to the dsRNA molecule are also necessary for activation of antiviral systems. Studies utilizing synthetic ligands, in vitro biochemistry and reporter systems have greatly helped increase our knowledge on intrinsic features of dsRNA recognition. However, characteristics such as subcellular localization are extrinsic to the dsRNA itself, but certainly influence the recognition in vivo. Thus, mechanisms of viral dsRNA recognition must address how cellular sensors are recruited to nucleic acids or vice versa. Accessory proteins are likely important for in vivorecognition of extrinsic features of viral RNA, but have mostly remained undiscovered due to the limitations of previous strategies. Hence, the identification of novel components of antiviral systems must take into account the complexities involved in viral recognition in vivo.
Upregulation of ciliary neurotrophic factor in astrocytes by aspirin: Implications for remyelination in multiple sclerosis
Ciliary neurotrophic factor (CNTF) is a promyelinating trophic factor and mechanisms by which CNTF expression could be increased in the brain are poorly understood. Aspirin, acetylsalicylic acid, is one of the most widely-used analgesics. Interestingly, aspirin increased mRNA and protein expression of CNTF in primary mouse and human astrocytes in a dose- and time-dependent manner. Aspirin induced the activation of protein kinase A (PKA), but not protein kinase C (PKC). H-89, an inhibitor of PKA, abrogated aspirin-induced expression of CNTF. The activation of cAMP response element binding (CREB) protein, but not NF-kB, by aspirin, the abrogation of aspirin-induced expression of CNTF by siRNA knockdown of CREB, the presence of a consensus CRE in the promoter of CNTF, and the recruitment of CREB and CREB-binding protein to the CNTF promoter by aspirin suggest that aspirin increases the expression of CNTF gene via the activation of CREB. Furthermore, we demonstrate that aspirin-induced astroglial CNTF was also functionally active and that supernatants of aspirin-treated astrocytes of wild type, but not CNTF null, mice increased myelin-associated proteins in oligodendrocytes and protected oligodendrocytes from TNF-a insult. These results highlight a new and novel myelinogenic property of aspirin, which may be of benefit for multiple sclerosis and other demyelinating disorders.
Virological and Immunological Characteristics of Human Cytomegalovirus Infection Associated with Alzheimer's Disease.
Serum, CSF and cryopreserved lymphocytes from subjects in the Rush Alzheimer's Disease Center Religious Orders Study were analyzed for associations between CMV infection and clinical and pathological markers of Alzheimer's Disease (AD). CMV antibody levels were associated with neurofibrillary tangles (NFT). CSF interferon-γ was only detected in seropositive subjects and was significantly associated with NFT. The percentage of senescent T cells (CD4+ or CD8+/CD28-/CD57+) was significantly higher for CMV-seropositive compared to CMV-seronegative subjects, and marginally associated with the pathologic diagnosis of AD (CD4+) or amyloid-β (CD8+). Immunocytochemical analysis showed induction of amyloid-β in human foreskin fibroblasts (HFF) infected with each of 3 clinical CMV strains. In the same subjects there was no association of HSV-1 antibody levels with CMV antibody levels or clinical or pathological markers of AD. HSV-1 infection of HFF did not induce amyloid-β. These data support an association of CMV with the development of AD.
Animation: Immunology in the Gut Mucosa : Nature Immunology
The gut mucosa is the largest and most dynamic immunological environment of the body. It's often the first point of pathogen exposure and many microbes use it as a beachhead into the rest of the body. The gut immune system therefore needs to be ready to respond to pathogens but at the same time it is constantly exposed to innocuous environmental antigens, food particles and commensal microflora which need to be tolerated. Misdirected immune responses to harmless antigens are the underlying cause of food allergies and debilitating conditions such as inflammatory bowel disease. This animation introduces the key cells and molecular players involved in gut immunohomeostasis and disease. From Nature Immunology
Association of suicide rates and coal-fired electricity plants by county in North Carolina - Journal of Mood Disorders -
Suicide, strongly associated with psychiatric conditions, also correlates with environmental pollution, likely due to quality of life factors which impact mood disorders. This ecological study evaluated the effect of the presence of a coal-fired electricity plant in a county on county suicide rates in North Carolina. Data from the 2000 US Census, 2001-2005 mortality rates from the North Carolina State Center for Health Statistics and the US Environmental Protection Agency were used in multivariable linear regression. Twenty coal plants existed in North Carolina during this study’s period. Only about one third of the population of North Carolina lived in urban areas. Seventy four percent of the population was white, and the mean population per county was nearly 48,000. About 13% of the population lived at or below the poverty level. The median household income of counties was approximately $34,000. County-level suicide rates were higher in North Carolina (12.4/100,000 population) compared to the US population (10.8/100,000). The linear regression model indicated that percent white race, median age of county population and number of coal plants per county explained 25.8% of the variance of county suicide rates. For coal plants, the linear regression model suggests that for each additional coal plant in a given county, there would be an additional 1.96 suicide per 100,000 population. The presence of a coal plant correlated with airborne levels of nickel, mercury, lead, chromium, cadmium, beryllium and arsenic. This is the first study to show that the existence of coal electricity plants is related to population-level suicide rates. Because suicide might be associated with environmental pollution, this study may help inform regulations not only of air pollutants, but also of coal electrical power plant emissions.
Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity
Obesity and type 2 diabetes are characterized by altered gut microbiota, inflammation, and gut barrier disruption. Microbial composition and the mechanisms of interaction with the host that affect gut barrier function during obesity and type 2 diabetes have not been elucidated. We recently isolated Akkermansia muciniphila, which is a mucin-degrading bacterium that resides in the mucus layer. The presence of this bacterium inversely correlates with body weight in rodents and humans. However, the precise physiological roles played by this bacterium during obesity and metabolic disorders are unknown. This study demonstrated that the abundance of A. muciniphila decreased in obese and type 2 diabetic mice. We also observed that prebiotic feeding normalized A. muciniphila abundance, which correlated with an improved metabolic profile. In addition, we demonstrated that A. muciniphila treatment reversed high-fat diet-induced metabolic disorders, including fat-mass gain, metabolic endotoxemia, adipose tissue inflammation, and insulin resistance. A. muciniphila administration increased the intestinal levels of endocannabinoids that control inflammation, the gut barrier, and gut peptide secretion. Finally, we demonstrated that all these effects required viable A. muciniphila because treatment with heat-killed cells did not improve the metabolic profile or the mucus layer thickness. In summary, this study provides substantial insight into the intricate mechanisms of bacterial (i.e., A. muciniphila) regulation of the cross-talk between the host and gut microbiota. These results also provide a rationale for the development of a treatment that uses
The Interaction Of Social Amoeba And Bacteria Defined By Genes
Amoeba eat bacteria and other human pathogens, engulfing and destroying them - or being destroyed by them, but how these single-cell organisms distinguish and respond successfully to different bacterial classes has been largely unexplained.
In a report in the journal Current Biology, researchers from Baylor College of Medicine use the model of the social amoeba -Dictyostelium discoideum - to identify the genetic controls on how the amoeba differentiate the different bacteria and respond to achieve their goal of destruction.
In a report in the journal Current Biology, researchers from Baylor College of Medicine use the model of the social amoeba -Dictyostelium discoideum - to identify the genetic controls on how the amoeba differentiate the different bacteria and respond to achieve their goal of destruction.
Circadian patterns of gene expression in the human brain and disruption in major depressive disorder
A cardinal symptom of major depressive disorder (MDD) is the disruption of circadian patterns. However, to date, there is no direct evidence of circadian clock dysregulation in the brains of patients who have MDD. Circadian rhythmicity of gene expression has been observed in animals and peripheral human tissues, but its presence and variability in the human brain were difficult to characterize. Here, we applied time-of-death analysis to gene expression data from high-quality postmortem brains, examining 24-h cyclic patterns in six cortical and limbic regions of 55 subjects with no history of psychiatric or neurological illnesses (“controls”) and 34 patients with MDD. Our dataset covered ∼12,000 transcripts in the dorsolateral prefrontal cortex, anterior cingulate cortex, hippocampus, amygdala, nucleus accumbens, and cerebellum. Several hundred transcripts in each region showed 24-h cyclic patterns in controls, and >100 transcripts exhibited consistent rhythmicity and phase synchrony across regions. Among the top-ranked rhythmic genes were the canonical clock genes BMAL1(ARNTL), PER1-2-3, NR1D1(REV-ERBa), DBP, BHLHE40 (DEC1), andBHLHE41(DEC2). The phasing of known circadian genes was consistent with data derived from other diurnal mammals. Cyclic patterns were much weaker in the brains of patients with MDD due to shifted peak timing and potentially disrupted phase relationships between individual circadian genes. This transcriptome-wide analysis of the human brain demonstrates a rhythmic rise and fall of gene expression in regions outside of the suprachiasmatic nucleus in control subjects. The description of its breakdown in MDD suggests potentially important molecular targets for treatment of mood disorders.
Agent Orange Linked To Fatal Prostate Cancer
"A new study of US Veterans has found that exposure to Agent Orange is linked to a two-fold higher risk of developing the most lethal forms of prostate cancer. The researchers suggest a history of exposure to the agent, which contains the dioxin 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a dangerous toxin and carcinogen, should be one of the first things to look for when screening Veterans as it could lead to earlier diagnosis and treatment and prolong survival."
( Agent orange was liberally sprayed onto Vietnam, eastern Laos and parts of Cambodia during the Vietnam War) Wikipedia Agent Orange
( Agent orange was liberally sprayed onto Vietnam, eastern Laos and parts of Cambodia during the Vietnam War) Wikipedia Agent Orange
BBC News - Rise in obesity poses 'dementia time bomb'
One study of 8,500 Swedish twins showed that those with a body mass index (BMI) greater than 30, who are classified as obese, were almost four times as likely to develop dementia as those with a normal BMI.
Obesity is a major concern that's going to have a major economic impact on the country”
Even those who were clinically overweight, a BMI between 25 and 30, were 71% more likely to develop dementia.
In England 24% of men and 26% of women are obese.
Researchers from the UK Health Forum used computer models to compare what would happen if obesity rates stayed the same or increased to 46% of men and 31% of women by 2050, which has been predicted by some groups.
They said rates of dementia would go from 4,894 cases in every 100,000 people over 65 to 6,662 cases in every 100,000 people over 65
Antifungal Therapy Could Benefit Nearly 5 Million Asthmatics Worldwide
MNT "An estimated 4,837,000 asthmatics with allergic bronchopulmonary aspergillosis (ABPA) could benefit substantially from antifungal treatment, say researchers from the University of Toronto and Manchester University. "
Lyme disease vaccine shows promise in clinical trial
"The results of a phase 1/2 clinical trial in Europe of an investigational Lyme disease vaccine co-developed by researchers at Stony Brook University, Brookhaven National Laboratory, and at Baxter International Inc., a U.S. based healthcare company, revealed it to be promising and well tolerated, according to a research paper published online in The Lancet Infectious Diseases. The vaccine was shown to produce substantial antibodies against all targeted species of Borrelia, the causative agent of Lyme disease in Europe and the United States. Baxter International conducted the clinical trial of the vaccine."
Super-sized citizens: The relationship between a country's fast-food outlets and its obesity rates
"The conclusions, published in the journal Critical Public Health (De Vogli, Kouvonen & Gimeno, 2011), are clear: the density of Subway's outlets is positively associated with the prevalence of obesity across 26 advanced economies in both men and women. Even after adjusting for the other factors, countries with the highest density of Subway restaurants (such as the United States and Canada) have a higher prevalence of obesity than countries with a low density (like Norway and Japan)."
Brain diseases affecting more people and starting earlier than ever before
"Professor Colin Pritchard's latest research published in journal Public Health has found that the sharp rise of dementia and other neurological deaths in people under 74 cannot be put down to the fact that we are living longer. The rise is because a higher proportion of old people are being affected by such conditions -- and what is really alarming, it is starting earlier and affecting people under 55 years."When asked what he thought caused the increases he replied, "This has to be speculative but it cannot be genetic because the period is too short. Whilst there will be some influence of more elderly people, it does not account for the earlier onset; the differences between countries nor the fact that more women have been affected, as their lives have changed more than men's over the period, all indicates multiple environmental factors. Considering the changes over the last 30 years -- the explosion in electronic devices, rises in background non-ionising radiation- PC's, micro waves, TV's, mobile phones; road and air transport up four-fold increasing background petro-chemical pollution; chemical additives to food etc. There is no one factor rather the likely interaction between all these environmental triggers, reflecting changes in other conditions.
Possible reason for cholesterol-drug side effects such as memory loss
"The U.S. Food and Drug Administration and physicians continue to document that some patients experience fuzzy thinking and memory loss while taking statins, a class of global top-selling cholesterol-lowering drugs."
Comparison of peripheral and central schizophrenia biomarker profiles.
We have recently shown that a molecular biomarker signature comprised of inflammatory, hormonal and growth factors occurs in the blood serum from first onset schizophrenia patients. Here, we use the same platform to investigate post mortem brain tissue (Brodmann area 10) from schizophrenia patients who were mainly chronically ill and drug treated. Twenty-one analytes are differentially expressed in post-mortem brain tissue. Comparison with our previous mRNA profiling studies of the same patient samples in another frontal cortical area showed that 9 of these molecules were also altered at the transcriptional level. Furthermore, 9 of the molecules were also altered in serum from living first onset schizophrenia patients compared to controls. We propose a model in which the brain and periphery are coordinated through hormones and other regulatory molecules released into the blood via the diffuse neuroendocrine system. These findings provide further evidence for the systemic nature of schizophrenia and give added validity to the concept that schizophrenia can be investigated through studies of blood-based biomarkers.
Cancer drug prevents build-up of toxic brain protein
"This drug, ( nilotinib) in very low doses, turns on the garbage disposal machinery inside neurons to clear toxic proteins from the cell. By clearing intracellular proteins, the drug prevents their accumulation in pathological inclusions called Lewy bodies and/or tangles, and also prevents amyloid secretion into the extracellular space between neurons, so proteins do not form toxic clumps or plaques in the brain," says the study's senior investigator, neuroscientist Charbel E-H Moussa, MB, PhD. Moussa heads the laboratory of dementia and Parkinsonism at Georgetown.
When the drug, nilotinib, is used to treat chronic myelogenous leukemia (CML), it forces cancer cells into autophagy—a biological process that leads to death of tumor cells in cancer."
When the drug, nilotinib, is used to treat chronic myelogenous leukemia (CML), it forces cancer cells into autophagy—a biological process that leads to death of tumor cells in cancer."
Multiple sclerosis: autoimmunity and viruses.
This review will explore two new aspects of the involvement of viruses in multiple sclerosis pathogenesis. The first aspect is the complex interactions between viruses. The second aspect is the proposal of a mechanism by which autoreactive T cells are able to escape thymic selection and potentially recognize self and a pathogen.
RECENT FINDINGS:
With regard to viruses, recent work has demonstrated that one virus may enhance the replication of another virus, potentially leading to an increase in inflammation and disease progression. Also, interactions between human endogenous retroviruses, which likely do not replicate, and certain herpes viruses, may also play a role in disease pathogenesis. Mechanistically, T cells expressing dual T-cell receptors would be able to recognize self and a foreign antigen specifically. Therefore, human endogenous retroviruses potentially play a role in multiple sclerosis pathogenesis, and both interactions between multiple viruses and autoreactive CD8 T cells with dual T-cell receptors may play a role in the pathogenesis of the disease.
SUMMARY:
The complex interactions between multiple viral infections, either within the central nervous system or in the periphery, and the host immune response to viral infection may be such that a variety of viral specificities result in the activation of T cells that recognize self and induce multiple sclerosis. Therefore, it is unlikely that any one microbe will be determined to be the causative agent of multiple sclerosis as reflected by the number of potential triggering mechanisms of the disease.
Bacterial infection in mosquitoes renders them immune to malaria parasites
"Scientists funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, have established an inheritable bacterial infection in malaria-transmitting Anopheles mosquitoes that renders them immune to malaria parasites. Specifically, the scientists infected the mosquitoes with Wolbachia, a bacterium common among insects that previously has been shown to prevent malaria-inducing Plasmodium parasites from developing in Anopheles mosquitoes. Before now, researchers had been unable to create mosquitoes with a stable Wolbachia infection that passed consistently from mother to offspring."
The role of microbes and autoimmunity in the pathogenesis of neuropsychiatric illness.
To illustrate how microbes might participate in the pathogenesis of neuropsychiatric illness by triggering the production of autoantibodies that bind to brain targets.
RECENT FINDINGS:
Some studies link exposure to infectious agents to development of brain disorders; others have identified autoantibodies in individuals with these conditions without finding evidence of pathogens. Neither line of work demonstrates consistent associations between a specific neuropsychiatric disease and a particular environmental trigger or immune marker. Growing evidence suggests that the microbiome conditions host immunity to microbes and xenobiotics, and regulates autoimmune responses that can affect the central nervous system (CNS). The presence of CNS receptors for cytokines and other immune molecules underscores the importance of brain-immune crosstalk in maintaining normal function. An increased prevalence of familial autoimmunity, exposure to pathogens prenatally and postnatally, and findings of antibrain antibodies is common in disorders as diverse as schizophrenia, obsessive-compulsive disorder and autism, and suggests that differences in exposure timing and genetic vulnerability toward autoimmunity are important determinants of neuropsychiatric outcomes.
SUMMARY:
Microbes, both pathogenic and commensal, can induce autoantibodies that bind to brain and affect behavior in susceptible hosts. Interventions that correct the microbial balance or diminish autoantibody binding may be effective in diverse neuropsychiatric conditions mediated by autoimmunity.
JAMA Psychiatry | Gestational Influenza and Bipolar Disorder in Adult OffspringGestational Influenza and Bipolar Disorder
Gestational influenza has been associated previously with schizophrenia in offspring, but the relationship between this exposure and bipolar disorder (BD) is unclear. The identification of gestational influenza as a risk factor for BD may have potential for preventive approaches.
Objective To test the hypothesis that maternal influenza during pregnancy is related to BD among offspring.
Design Nested case-control study of a population-based birth cohort from the Child Health and Development Study (CHDS). From January 1, 1959, through December 31, 1966, the CHDS recruited nearly all pregnant women receiving obstetric care from the Kaiser Permanente Medical Care Plan, Northern California Region (KPNC). Data on treated maternal influenza from the CHDS were used. Potential cases with BD from the cohort were identified by database linkages of identifiers among the CHDS, Kaiser Permanente database, and a large county health care database; by a mailed questionnaire to the CHDS cohort with subsequent interviews; and from an earlier psychiatric follow-up study on this birth cohort.
Setting The CHDS, Kaiser Permanente, and county health care databases.
Participants Cases of BD (n = 92) confirmed by structured research interviews and consensus diagnosis among the 214 subjects (48% of those ascertained) who participated and control subjects (n = 722) matched on date of birth, sex, and membership in KPNC or residence in Alameda County.
Exposures Influenza.
Main Outcome and Measures Bipolar I or II disorder, BD not otherwise specified, or BD with psychotic features.
Results We found a significant, nearly 4-fold increase in the risk of BD (odds ratio, 3.82 [95% CI, 1.58-9.24; P = .003]) after exposure to maternal influenza at any time during pregnancy. The findings were not confounded by maternal age, race, educational level, gestational age at birth, and maternal psychiatric disorders.
Conclusions and Relevance Maternal influenza may be a risk factor for BD. Although replication is required, the findings suggest that prevention of maternal influenza during pregnancy may reduce the risk of BD.
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