Can Valproic Acid be an Inducer of Clozapine Metabolism?

Introduction: Prior clozapine studies indicated no effects, mild inhibition or induction of valproic acid (VPA) on clozapine metabolism. The hypotheses that (i) VPA is a net inducer of clozapine metabolism, and (ii) smoking modifies this inductive effect were tested in a therapeutic drug monitoring study. Methods: After excluding strong inhibitors and inducers, 353 steady-state total clozapine (clozapine plus norclozapine) concentrations provided by 151 patients were analyzed using a random intercept linear model. Results: VPA appeared to be an inducer of clozapine metabolism since total plasma clozapine concentrations in subjects taking VPA were significantly lower (27% lower; 95% confidence interval, 14-39%) after controlling for confounding variables including smoking (35% lower, 28-56%). Discussion: Prospective studies are needed to definitively establish that VPA may (i) be an inducer of clozapine metabolism when induction prevails over competitive inhibition, and (ii) be an inducer even in smokers who are under the influence of smoking inductive effects on clozapine metabolism

Fagerstrom test for nicotine dependence vs heavy smoking index in a general population survey

<p>Abstract</p> <p>Background</p> <p>The Fagerström Test for Nicotine Dependence (FTND) is used for assessing nicotine dependence. A shorter test derived from the FTND used for the general population is the Heavy Smoking Index (HSI) (six questions vs. two). The objective of this study is to compare the validity of the HSI versus the FTND.</p> <p>Methods</p> <p>A survey of tobacco use in the general population was carried out in the northern Spanish region of Galicia using both the FTND and the HSI to study a representative sample of 1655 daily smokers. The HSI was compared with the FTND, considered the gold standard. Measures of sensitivity, specificity and predictive values were calculated. Concordance between the tests was also established (Cohen's kappa).</p> <p>Results</p> <p>Cohen's kappa showed good agreement between measures (Kappa = 0.7); specificity values were also high (Sp = 96.2%). Sensitivity analysis in females (Se = 62.3%) did not show good agreement.</p> <p>Conclusions</p> <p>The HSI can be used as a reasonably good screening test in order to identify daily smokers with high nicotine dependence. Nevertheless, for populations or subpopulations having low nicotine dependence, such as women, the FTND is more reliable.</p

Telomere Lengths, Pulmonary Fibrosis and Telomerase (<i>TERT</i>) Mutations

Background: Telomerase is an enzyme that catalyzes the addition of nucleotides on the ends of chromosomes. Rare loss of function mutations in the gene that encodes the protein component of telomerase (TERT) have been described in patients with idiopathic pulmonary fibrosis (IPF). Here we examine the telomere lengths and pulmonary fibrosis phenotype seen in multiple kindreds with heterozygous TERT mutations.Methods and Findings: We have identified 134 individuals with heterozygous TERT mutations from 21 unrelated families. Available medical records, surgical lung biopsies and radiographs were evaluated retrospectively. Genomic DNA isolated from circulating leukocytes has been used to measure telomere lengths with a quantitative PCR assay. We find that telomere lengths of TERT mutation carriers decrease in an age-dependent manner and show progressive shortening with successive generations of mutation inheritance. Family members without TERT mutations have a shorter mean telomere length than normal, demonstrating epigenetic inheritance of shortened telomere lengths in the absence of an inherited TERT mutation. Pulmonary fibrosis is an age-dependent phenotype not seen in mutation carriers less than 40 years of age but found in 60% of men 60 years or older; its development is associated with environmental exposures including cigarette smoking. A radiographic CT pattern of usual interstitial pneumonia (UIP), which is consistent with a diagnosis of IPF, is seen in 74% of cases and a pathologic pattern of UIP is seen in 86% of surgical lung biopsies. Pulmonary fibrosis associated with TERT mutations is progressive and lethal with a mean survival of 3 years after diagnosis. Overall, TERT mutation carriers demonstrate reduced life expectancy, with a mean age of death of 58 and 67 years for males and females, respectively.Conclusions: A subset of pulmonary fibrosis, like dyskeratosis congenita, bone marrow failure, and liver disease, represents a “telomeropathy” caused by germline mutations in telomerase and characterized by short telomere lengths. Family members within kindreds who do not inherit the TERT mutation have shorter telomere lengths than controls, demonstrating epigenetic inheritance of a shortened parental telomere length set-point.</p

The Impact of Opuntia ficus-indica and Other Vegetables on Serum Cholesterol and Triglycerides: A Cross-Sectional Analysis

Background: Cholesterol is primarily synthesized in the liver. Treatment with statins and diet regulation are commonly prescribed for people with hypercholesterolemia. Previous claims suggest that the consumption of nopal and other vegetables may have a significant effect on diabetes but scarce is known about its relationship with cholesterol and triglycerides. The aim of this study was to evaluate the impact of nopal and other vegetables on serum cholesterol and triglyceride level in population not related with hypercholesterolemia. Methods: We analyzed a dataset comprising of students from UMAN and their relatives totaling 198 participants. Participants completed an informed consent, filled out questionnaires, anthropometric and serum lipid measurements. A semi-quantitative food questionnaire assessed the frequency and amount of consumption for 56-specific foods. We did a factor analysis with varimax rotation using 7 specific foods we were interested. We conducted linear regression analyses with total cholesterol, LDL-c, and triglycerides as dependent variables. Age, sex, BMI, body fat percentage, and consumption factors (fruits, vegetables, and grains) were included as predictors. Collinearity was assessed using VIF calculations. Results: Approximately 48% of participants consumed nopal on a weekly basis, with most considering their intake to be of median to large amounts, while only 11% reported never consuming nopal. Participants with diabetes showed higher nopal consumption [3.1 (s.e.m. 0.24) vs non-diabetic 2.7 (0.22) vs unknown 1.7 (0.28), p\u3c0.04]. A slight correlation was observed between high self-efficacy in diet and nopal ingestion (rho 0.15, p=0.02), but no significant correlations were found for fruits or grains. Regression analysis revealed that LDL-c was associated with obesity (b=-20, p=0.04) and marginally with body fat percentage (adjusted b=0.83, p=0.069), but not with any of the consumption factors. Total cholesterol was explained by age (adjusted b=0.5, p=0.002) and body fat percentage (b=1.05, p=0.024). HDL-c was marginally associated with sex (Male b=-8.3, p=0.08), while triglycerides were associated with age and obesity (overweight and Class-I, b=0.04, p=0.001 and b=0.04, p=0.04, respectively). No collinearity was found in the analyzed regressions (VIF between 0.1 and 3.4). Conclusion: Our findings suggest that cholesterol and other lipid traits are primarily influenced by genetic factors, with diet playing a minor role. Nopal, vegetables, and fruit showed no significant effects on serum lipid levels in our study. A limitation of our study is its cross-sectional design, and future research could benefit from longitudinal studies with controlled amounts of nopal and other foods

The Sensitivity of HAWC to High-Mass Dark Matter Annihilations

The High Altitude Water Cherenkov (HAWC) observatory is a wide field-of-view detector sensitive to gamma rays of 100 GeV to a few hundred TeV. Located in central Mexico at 19 degrees North latitude and 4100 m above sea level, HAWC will observe gamma rays and cosmic rays with an array of water Cherenkov detectors. The full HAWC array is scheduled to be operational in Spring 2015. In this paper, we study the HAWC sensitivity to the gamma-ray signatures of high-mass (multi- TeV) dark matter annihilation. The HAWC observatory will be sensitive to diverse searches for dark matter annihilation, including annihilation from extended dark matter sources, the diffuse gamma-ray emission from dark matter annihilation, and gamma-ray emission from non-luminous dark matter subhalos. Here we consider the HAWC sensitivity to a subset of these sources, including dwarf galaxies, the M31 galaxy, the Virgo cluster, and the Galactic center. We simulate the HAWC response to gamma rays from these sources in several well-motivated dark matter annihilation channels. If no gamma-ray excess is observed, we show the limits HAWC can place on the dark matter cross-section from these sources. In particular, in the case of dark matter annihilation into gauge bosons, HAWC will be able to detect a narrow range of dark matter masses to cross-sections below thermal. HAWC should also be sensitive to non-thermal cross-sections for masses up to nearly 1000 TeV. The constraints placed by HAWC on the dark matter cross-section from known sources should be competitive with current limits in the mass range where HAWC has similar sensitivity. HAWC can additionally explore higher dark matter masses than are currently constrained.Comment: 15 pages, 4 figures, version to be published in PR

The 2HWC HAWC Observatory Gamma Ray Catalog

We present the first catalog of TeV gamma-ray sources realized with the recently completed High Altitude Water Cherenkov Observatory (HAWC). It is the most sensitive wide field-of-view TeV telescope currently in operation, with a 1-year survey sensitivity of ~5-10% of the flux of the Crab Nebula. With an instantaneous field of view >1.5 sr and >90% duty cycle, it continuously surveys and monitors the sky for gamma ray energies between hundreds GeV and tens of TeV. HAWC is located in Mexico at a latitude of 19 degree North and was completed in March 2015. Here, we present the 2HWC catalog, which is the result of the first source search realized with the complete HAWC detector. Realized with 507 days of data and represents the most sensitive TeV survey to date for such a large fraction of the sky. A total of 39 sources were detected, with an expected contamination of 0.5 due to background fluctuation. Out of these sources, 16 are more than one degree away from any previously reported TeV source. The source list, including the position measurement, spectrum measurement, and uncertainties, is reported. Seven of the detected sources may be associated with pulsar wind nebulae, two with supernova remnants, two with blazars, and the remaining 23 have no firm identification yet.Comment: Submitted 2017/02/09 to the Astrophysical Journa

Towards the clinical implementation of pharmacogenetics in bipolar disorder.

BackgroundBipolar disorder (BD) is a psychiatric illness defined by pathological alterations between the mood states of mania and depression, causing disability, imposing healthcare costs and elevating the risk of suicide. Although effective treatments for BD exist, variability in outcomes leads to a large number of treatment failures, typically followed by a trial and error process of medication switches that can take years. Pharmacogenetic testing (PGT), by tailoring drug choice to an individual, may personalize and expedite treatment so as to identify more rapidly medications well suited to individual BD patients.DiscussionA number of associations have been made in BD between medication response phenotypes and specific genetic markers. However, to date clinical adoption of PGT has been limited, often citing questions that must be answered before it can be widely utilized. These include: What are the requirements of supporting evidence? How large is a clinically relevant effect? What degree of specificity and sensitivity are required? Does a given marker influence decision making and have clinical utility? In many cases, the answers to these questions remain unknown, and ultimately, the question of whether PGT is valid and useful must be determined empirically. Towards this aim, we have reviewed the literature and selected drug-genotype associations with the strongest evidence for utility in BD.SummaryBased upon these findings, we propose a preliminary panel for use in PGT, and a method by which the results of a PGT panel can be integrated for clinical interpretation. Finally, we argue that based on the sufficiency of accumulated evidence, PGT implementation studies are now warranted. We propose and discuss the design for a randomized clinical trial to test the use of PGT in the treatment of BD

Impact of Fiber-Rich Foods on Glucose Levels in Relation to Liver Fat Infiltration: Preliminary results.

Introduction: Previous studies have indicated the consumption of fiber-rich food rich can decrease glucose levels. Additionally, fat infiltration is a common finding in people with type 2 diabetes Mellitus (T2D) and may contribute to metabolic imbalances. However, there needs to be more research investigating the combined effects of fiber intake and liver fat infiltration on glucose levels. In this study, we aimed to analyze the impact of fiber-rich foods on glucose levels, considering the scores of liver fat infiltration. Methods: After obtaining written consent was approved by the UAT IRB, the participants (relatives of students) were invited at 7 am for anthropometry, blood was drawn for biochemistry measurements, complete fill questionnaires of food preferences and perform elastography (Fibroscan®, ELF). Factor analysis for five groups of food preferences questionnaire was computed with a Varimax rotation. Two factors were obtained: F1 vegetables, F2 pulsars, integral bread, and F3 fruits. A non-parametric kernel regression was performed to analyze the glucose levels (dependent variable) by food rich in fiber adjusted by stages of liver fat infiltration. The 95%CI of the coefficients was calculated with 100 bootstrap repetitions. Results: We included 234 participants (females 68%) with lipid panel and ELF. The CAP score 0 was 65% (152/234), score 1 was 9% (n=22), score 2 was 12% (n=28), and score 3 was 14% (n=32). The kernel regression supported the presence of score class associated to an increase in levels of glucose: For the levels of fat infiltration, the coefficients were S0= 100.9 (95%CI 94.8, 109.4), S1= 105.2 (96.9, 112.9), S2= 113.4 (101.8, 124.8), and S3= 116.6 (107.6, 128.3) mg/dL. When we added the F2, had observed better glucose control for people with diabetes despite the CAP score. The final model suggested the high ingestion of fiver beneficially affects glucose levels despite the CAP score. The model explained about 15% of the variance of glucose concentration. Conclusions: These preliminary findings provide valuable insights into the effects of fatty liver and metabolic conditions. The amount of fiber in food (factor 2) interacts with the degree of fatty liver infiltration, affecting glucose excursions. As liver fat increases, glucose levels also rise, but there is a significant decrease in glucose levels in the presence of high fiber intake. This study represents a crossover design, and future research incorporating controlled diets and longitudinal follow-ups will further elucidate these relationships

Physicochemical and biological characterization of 1E10 Anti-Idiotype vaccine

<p>Abstract</p> <p>Background</p> <p>1E10 monoclonal antibody is a murine anti-idiotypic antibody that mimics N-glycolyl-GM3 gangliosides. This antibody has been tested as an anti-idiotypic cancer vaccine, adjuvated in Al(OH)₃, in several clinical trials for melanoma, breast, and lung cancer. During early clinical development this mAb was obtained <it>in vivo </it>from mice ascites fluid. Currently, the production process of 1E10 is being transferred from the <it>in vivo </it>to a bioreactor-based method.</p> <p>Results</p> <p>Here, we present a comprehensive molecular and immunological characterization of 1E10 produced by the two different production processes in order to determine the impact of the manufacturing process in vaccine performance. We observed differences in glycosylation pattern, charge heterogeneity and structural stability between <it>in vivo</it>-produced 1E10 and bioreactor-obtained 1E10. Interestingly, these modifications had no significant impact on the immune responses elicited in two different animal models.</p> <p>Conclusions</p> <p>Changes in 1E10 primary structure like glycosylation; asparagine deamidation and oxidation affected 1E10 structural stability but did not affect the immune response elicited in mice and chickens when compared to 1E10 produced in mice.</p