Is Amitriptyline Effective in Reducing Headache Days in Pediatric Patients with Migraines and Chronic Headaches Compared to Topiramate, Propranolol, or No Treatment?

Objective: The objective of this selective EBM review is to determine whether or not “Is amitriptyline effective in reducing headache days in pediatric patients with migraines and chronic headaches compared to topiramate, propranolol, or no treatment?” Study design: Systematic review of two randomized control trials (RCTs) and one case series published in peer-reviewed journals in English after 2007. Data Sources: Two RCTs and one case series were found using PubMed. Outcome(s) Measured: Headache frequency was measured using a headache diary or calendar. A secondary objective included headache severity that was measured using a ten-point scale or the Pediatric Migraine Disability Assessment (PedMIDAS). Results: Powers et al. found that headache frequency did not vary significantly between amitriptyline, topiramate, or placebo.2 It was also recorded that there was no significant variation among reduction in scores on the PedMIDAS.2 Eidlitz-Markus et al. stated that this trial showed no significant difference between amitriptyline and propranolol(p-value=0.8).4 Sezer et al. found that 31% of patients in the topiramate group and 28% of patients in the amitriptyline group “reported freedom from headache.”5 It was also recorded that the severity of headaches also decreased 4.5 points on a visual analog scale in both treatment groups. Conclusions: Amitriptyline in these three trials is less effective in reducing the frequency of chronic headaches and migraines when compared to topiramate, propranolol, or a placebo.2,4,5 These results could be affected by subjectivity, drug adherence, or misunderstanding between younger subjects and their parents. The safety of amitriptyline should always be in question because the FDA warns that antidepressants can cause suicidal thoughts or actions in children under eighteen years old

Nutritional Manipulation of One-Carbon Metabolism: Effects on Arsenic Methylation and Toxicity

Exposure to arsenic (As) through drinking water is a substantial problem worldwide. The methylation of As, a reactive metalloid, generates monomethyl- (MMA) and dimethyl-arsenical (DMA) species. The biochemical pathway that catalyzes these reactions, one-carbon metabolism, is regulated by folate and other micronutrients. Arsenic methylation exerts a critical influence on both its urinary elimination and chemical reactivity. Mice having the As methyltransferase null genotype show reduced urinary As excretion, increased As retention, and severe systemic toxicity. The most toxic As metabolite in vitro is MMAIII, an intermediate in the generation of DMAV, a much less toxic metabolite. These findings have raised the question of whether As methylation is a detoxification or bioactivation pathway. Results of population-based studies suggest that complete methylation of inorganic As to DMA is associated with reduced risk for As-induced health outcomes, and that nutrients involved in one-carbon metabolism, such as folate, can facilitate As methylation and elimination

Chronic Arsenic Exposure and Blood Glutathione and Glutathione Disulfide Concentrations in Bangladeshi Adults

Background: In vitro and rodent studies have shown that arsenic (As) exposure can deplete glutathione (GSH) and induce oxidative stress. GSH is the primary intracellular antioxidant; it donates an electron to reactive oxygen species, thus producing glutathione disulfide (GSSG). Cysteine (Cys) and cystine (CySS) are the predominant thiol/disulfide redox couple found in human plasma. Arsenic, GSH, and Cys are linked in several ways: a) GSH is synthesized via the transsulfuration pathway, and Cys is the rate-limiting substrate; b) intermediates of the methionine cycle regulate both the transsulfuration pathway and As methylation; c) GSH serves as the electron donor for reduction of arsenate to arsenite; and d) As has a high affinity for sulfhydryl groups and therefore binds to GSH and Cys. Objectives: We tested the hypothesis that As exposure is associated with decreases in GSH and Cys and increases in GSSG and CySS (i.e., a more oxidized environment). Methods: For this cross-sectional study, the Folate and Oxidative Stress Study, we recruited a total of 378 participants from each of five water As concentration categories: & 10 (n = 76), 10–100 (n = 104), 101–200 (n = 86), 201–300 (n = 67), and < 300 µg/L (n = 45). Concentrations of GSH, GSSG, Cys, and CySS were measured using HPLC. Results: An interquartile range (IQR) increase in water As was negatively associated with blood GSH (mean change, –25.4 µmol/L; 95% CI: –45.3, –5.31) and plasma CySS (mean change, –3.00 µmol/L; 95% CI: –4.61, –1.40). We observed similar associations with urine and blood As. There were no significant associations between As exposure and blood GSSG or plasma Cys. Conclusions: The observed associations are consistent with the hypothesis that As may influence concentrations of GSH and other nonprotein sulfhydryls through binding and irreversible loss in bile and/or possibly in urine

Mathematical modeling of the effects of glutathione on arsenic methylation

Background: Arsenic is a major environmental toxin that is detoxified in the liver by biochemical mechanisms that are still under study. In the traditional metabolic pathway, arsenic undergoes two methylation reactions, each followed by a reduction, after which it is exported and released in the urine. Recent experiments show that glutathione plays an important role in arsenic detoxification and an alternative biochemical pathway has been proposed in which arsenic is first conjugated by glutathione after which the conjugates are methylated. In addition, in rats arsenic-glutathione conjugates can be exported into the plasma and removed by the liver in the bile. Methods: We have developed a mathematical model for arsenic biochemistry that includes three mechanisms by which glutathione affects arsenic methylation: glutathione increases the speed of the reduction steps; glutathione affects the activity of arsenic methyltranferase; glutathione sequesters inorganic arsenic and its methylated downstream products. The model is based as much as possible on the known biochemistry of arsenic methylation derived from cellular and experimental studies. Results: We show that the model predicts and helps explain recent experimental data on the effects of glutathione on arsenic methylation. We explain why the experimental data imply that monomethyl arsonic acid inhibits the second methylation step. The model predicts time course data from recent experimental studies. We explain why increasing glutathione when it is low increases arsenic methylation and that at very high concentrations increasing glutathione decreases methylation. We explain why the possible temporal variation of the glutathione concentration affects the interpretation of experimental studies that last hours. Conclusions: The mathematical model aids in the interpretation of data from recent experimental studies and shows that the Challenger pathway of arsenic methylation, supplemented by the glutathione effects described above, is sufficient to understand and predict recent experimental data. More experimental studies are needed to explicate the detailed mechanisms of action of glutathione on arsenic methylation. Recent experimental work on the effects of glutathione on arsenic methylation and our modeling study suggest that supplements that increase hepatic glutathione production should be considered as strategies to reduce adverse health effects in affected populations

Major and Minor Group Rhinoviruses Elicit Differential Signaling and Cytokine Responses as a Function of Receptor-Mediated Signal Transduction

Major- and minor-group human rhinoviruses (HRV) enter their host by binding to the cell surface molecules ICAM-1 and LDL-R, respectively, which are present on both macrophages and epithelial cells. Although epithelial cells are the primary site of productive HRV infection, previous studies have implicated macrophages in establishing the cytokine dysregulation that occurs during rhinovirus-induced asthma exacerbations. Analysis of the transcriptome of primary human macrophages exposed to major- and minor-group HRV demonstrated differential gene expression. Alterations in gene expression were traced to differential mitochondrial activity and signaling pathway activation between two rhinovirus serotypes, HRV16 (major-group) and HRV1A (minor-group), upon initial HRV binding. Variances in phosphorylation of kinases (p38, JNK, ERK5) and transcription factors (ATF-2, CREB, CEBP-alpha) were observed between the major- and minor-group HRV treatments. Differential activation of signaling pathways led to changes in the production of the asthma-relevant cytokines CCL20, CCL2, and IL-10. This is the first report of genetically similar viruses eliciting dissimilar cytokine release, transcription factor phosphorylation, and MAPK activation from macrophages, suggesting that receptor use is a mechanism for establishing the inflammatory microenvironment in the human airway upon exposure to rhinovirus

The Multiwavelength Survey by Yale-Chile (MUSYC): Deep Near-Infrared Imaging and the Selection of Distant Galaxies

We present deep near-infrared JHK imaging of four 10'x10' fields. The observations were carried out as part of the Multiwavelength Survey by Yale-Chile (MUSYC) with ISPI on the CTIO 4m telescope. The typical point source limiting depths are J~22.5, H~21.5, and K~21 (5sigma; Vega). The effective seeing in the final images is ~1.0". We combine these data with MUSYC UBVRIz imaging to create K-selected catalogs that are unique for their uniform size, depth, filter coverage, and image quality. We investigate the rest-frame optical colors and photometric redshifts of galaxies that are selected using common color selection techniques, including distant red galaxies (DRGs), star-forming and passive BzKs, and the rest-frame UV-selected BM, BX, and Lyman break galaxies (LBGs). These techniques are effective at isolating large samples of high redshift galaxies, but none provide complete or uniform samples across the targeted redshift ranges. The DRG and BM/BX/LBG criteria identify populations of red and blue galaxies, respectively, as they were designed to do. The star-forming BzKs have a very wide redshift distribution, a wide range of colors, and may include galaxies with very low specific star formation rates. In comparison, the passive BzKs are fewer in number, have a different distribution of K magnitudes, and have a somewhat different redshift distribution. By combining these color selection criteria, it appears possible to define a reasonably complete sample of galaxies to our flux limit over specific redshift ranges. However, the redshift dependence of both the completeness and sampled range of rest-frame colors poses an ultimate limit to the usefulness of these techniques.Comment: 17 pages in emulateapj style, 13 figures. Submitted to the Astronomical Journal. Data will be made available upon publicatio

Urinary and Dietary Analysis of 18,470 Bangladeshis Reveal a Correlation of Rice Consumption with Arsenic Exposure and Toxicity

Background: We utilized data from the Health Effects of Arsenic Longitudinal Study (HEALS) in Araihazar, Bangladesh, to evaluate the association of steamed rice consumption with urinary total arsenic concentration and arsenical skin lesions in the overall study cohort (N=18,470) and in a subset with available urinary arsenic metabolite data (N=4,517). Methods: General linear models with standardized beta coefficients were used to estimate associations between steamed rice consumption and urinary total arsenic concentration and urinary arsenic metabolites. Logistic regression models were used to estimate prevalence odds ratios (ORs) and their 95% confidence intervals (CIs) for the associations between rice intake and prevalent skin lesions at baseline. Discrete time hazard models were used to estimate discrete time (HRs) ratios and their 95% CIs for the associations between rice intake and incident skin lesions. Results: Steamed rice consumption was positively associated with creatinine-adjusted urinary total arsenic (β=0.041, 95% CI: 0.032-0.051) and urinary total arsenic with statistical adjustment for creatinine in the model (β=0.043, 95% CI: 0.032-0.053). Additionally, we observed a significant trend in skin lesion prevalence (P-trend=0.007) and a moderate trend in skin lesion incidence (P-trend=0.07) associated with increased intake of steamed rice. Conclusions: This study suggests that rice intake may be a source of arsenic exposure beyond drinking water

The Sloan Digital Sky Survey Reverberation Mapping Project : UV–optical accretion disk measurements with the Hubble Space Telescope

Funding: Y.H., J.R.T., and G.F.A. acknowledge support from NASA grants HST-GO-15650 and 18-2ADAP18-0177 and NSF grant CAREER-1945546. K.H. acknowledges support from STFC grant ST/R000824/1. C.J.G. acknowledges support from NSF grant AST-2009949. Y.S. acknowledges support from NSF grants AST-1715579 and AST-2009947. P.H. acknowledges support from the Natural Sciences and Engineering Research Council of Canada (NSERC), funding reference number 2017-05983. L.C.H. was supported by the National Science Foundation of China (11721303, 11991052) and the National Key R&D Program of China (2016YFA0400702).We present accretion-disk structure measurements from UV–optical reverberation mapping (RM) observations of a sample of eight quasars at 0.24 < z < 0.85. Ultraviolet photometry comes from two cycles of Hubble Space Telescope monitoring, accompanied by multiband optical monitoring by the Las Cumbres Observatory network and Liverpool Telescopes. The targets were selected from the Sloan Digital Sky Survey Reverberation Mapping project sample with reliable black hole mass measurements from Hβ RM results. We measure significant lags between the UV and various optical griz bands using JAVELIN and CREAM methods. We use the significant lag results from both methods to fit the accretion-disk structure using a Markov Chain Monte Carlo approach. We study the accretion disk as a function of disk normalization, temperature scaling, and efficiency. We find direct evidence for diffuse nebular emission from Balmer and Fe ii lines over discrete wavelength ranges. We also find that our best-fit disk color profile is broadly consistent with the Shakura & Sunyaev disk model. We compare our UV–optical lags to the disk sizes inferred from optical–optical lags of the same quasars and find that our results are consistent with these quasars being drawn from a limited high-lag subset of the broader population. Our results are therefore broadly consistent with models that suggest longer disk lags in a subset of quasars, for example, due to a nonzero size of the ionizing corona and/or magnetic heating contributing to the disk response.Publisher PDFPeer reviewe

Similarities and differences in surface receptor expression by THP-1 monocytes and differentiated macrophages polarized using seven different conditioning regimens

We would like to acknowledge the assistance of the Iain Fraser Cytometry Centre at the University of Aberdeen. Funding for this project was provided by the Wellcome Trust (094847).Peer reviewedPostprin