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.
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
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.
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)."
"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."
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".
- Pimozide Inhibits the AcrAB-TolC Efflux Pump in Escherichia coli.
- Activity of trifluoperazine against replicating, non-replicating and drug resistant M. tuberculosis.
Evidence of significant synergism between antibiotics and the antipsychoticantimicrobial drug flupenthixol.
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.
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.
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.
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.
This study evaluated the safety profile, pharmacokinetic parameters, and immunogenicity of GNbAC1 in healthy male volunteers.
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.
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.
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.
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
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.
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.
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.
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.
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).
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.
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.
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.
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.