Evaluation of the activity of CYP2C19 in Gujrati and Marwadi subjects living in Mumbai (Bombay)

BACKGROUND: Inherited differences in the metabolism and disposition of drugs, and genetic polymorphisms in the targets of drug therapy (e.g., receptors), can greatly influence efficacy and toxicity of medications. Marked interethnic differences in CYP2C19 (a member of the cytochrome P-450 enzyme superfamily catalyzing phase I drug metabolism) which affects the metabolism of a number of clinically important drugs have been documented. The present study evaluated the activity of CYP2C19 in normal, healthy Gujrati and Marwadi subjects by phenotyping (a western Indian population). METHODS: All subjects received 20 mg of omeprazole, which was followed by blood collection at 3 hrs to estimate the metabolic ratio of omeprazole to 5-hydroxyomeprazole. The analysis was done by HPLC. RESULTS: It was seen that 10.36% of this population were poor metabolizers(PM) whereas 89.63% were extensive metabolizers(EM). CONCLUSION: A genotyping evaluation would better help in identifying population specific genotypes and thus help individualize drug therapy

Exoplanet phase curves: observations and theory

Phase curves are the best technique to probe the three dimensional structure of exoplanets' atmospheres. In this chapter we first review current exoplanets phase curve observations and the particular challenges they face. We then describe the different physical mechanisms shaping the atmospheric phase curves of highly irradiated tidally locked exoplanets. Finally, we discuss the potential for future missions to further advance our understanding of these new worlds.Comment: Fig.5 has been updated. Table 1 and corresponding figures have been updated with new values for WASP-103b and WASP-18b. Contains a table sumarizing phase curve observation

A protein kinase Cβ inhibitor attenuates multidrug resistance of neuroblastoma cells

BACKGROUND: The acquisition of drug resistance is a major reason for poor outcome of neuroblastoma. Protein kinase C (PKC) has been suggested to influence drug resistance in cancer cells. The aim of this study was to elucidate whether inhibition of PKCβ isoforms influences drug-resistance of neuroblastoma cells. METHODS: The effect of the PKCβ inhibitor LY379196 on the growth-suppressing effects of different chemotherapeutics on neuroblastoma cells was analyzed with MTT assays. The effect of LY379196 on the accumulation of [(3)H]vincristine was also investigated RESULTS: The PKCβ inhibitor LY379196 suppressed the growth of three neuroblastoma cell lines. LY379196 also augmented the growth-suppressive effect of doxorubicin, etoposide, paclitaxel, and vincristine, but not of carboplatin. The effect was most marked for vincristine and for the cell-line (SK-N-BE(2)) that was least sensitive to vincristine. No effect was observed on the non-resistant IMR-32 cells. Two other PKC inhibitors, Gö6976 and GF109203X, also enhanced the vincristine effect. The PKC inhibitors caused an increased accumulation of [(3)H]vincristine in SK-N-BE(2) cells. CONCLUSIONS: This indicates that inhibition of PKCβ could attenuate multidrug resistance in neuroblastoma cells by augmenting the levels of natural product anticancer drugs in resistant cells

Get Phases from Arsenic Anomalous Scattering: de novo SAD Phasing of Two Protein Structures Crystallized in Cacodylate Buffer

The crystal structures of two proteins, a putative pyrazinamidase/nicotinamidase from the dental pathogen Streptococcus mutans (SmPncA) and the human caspase-6 (Casp6), were solved by de novo arsenic single-wavelength anomalous diffraction (As-SAD) phasing method. Arsenic (As), an uncommonly used element in SAD phasing, was covalently introduced into proteins by cacodylic acid, the buffering agent in the crystallization reservoirs. In SmPncA, the only cysteine was bound to dimethylarsinoyl, which is a pentavalent arsenic group (As (V)). This arsenic atom and a protein-bound zinc atom both generated anomalous signals. The predominant contribution, however, was from the As anomalous signals, which were sufficient to phase the SmPncA structure alone. In Casp6, four cysteines were found to bind cacodyl, a trivalent arsenic group (As (III)), in the presence of the reducing agent, dithiothreitol (DTT), and arsenic atoms were the only anomalous scatterers for SAD phasing. Analyses and discussion of these two As-SAD phasing examples and comparison of As with other traditional heavy atoms that generate anomalous signals, together with a few arsenic-based de novo phasing cases reported previously strongly suggest that As is an ideal anomalous scatterer for SAD phasing in protein crystallography

Effect of vitamin D on bone mineral density of elderly patients with osteoporosis responding poorly to bisphosphonates

BACKGROUND: Bisphosphonates are indicated in the prevention and treatment of osteoporosis. However, bone mineral density (BMD) continues to decline in up to 15% of bisphosphonate users. While randomized trials have evaluated the efficacy of concurrent bisphosphonates and vitamin D, the incremental benefit of vitamin D remains uncertain. METHODS: Using data from the Canadian Database of Osteoporosis and Osteopenia (CANDOO), we performed a 2-year observational cohort study. At baseline, all patients were prescribed a bisphosphonate and counseled on vitamin D supplementation. After one year, patients were divided into two groups based on their response to bisphosphonate treatment. Non-responders were prescribed vitamin D 1000 IU daily. Responders continued to receive counseling on vitamin D. RESULTS: Of 449 patients identified, 159 were non-responders to bisphosphonates. 94% of patients were women. The mean age of the entire cohort was 74.6 years (standard deviation = 5.6 years). In the cohort of non-responders, BMD at the lumbar spine increased 2.19% (p < 0.001) the year after vitamin D was prescribed compared to a decrease of 0.55% (p = 0.36) the year before. In the cohort of responders, lumbar spine BMD improved 1.45% (p = 0.014) the first year and 1.11% (p = 0.60) the second year. The difference between the two groups was statistically significant the first year (p < 0.001) but not the second (p = 0.60). Similar results were observed at the femoral neck but were not statistically significant. CONCLUSION: In elderly patients with osteoporosis not responding to bisphosphonates, vitamin D 1000 IU daily may improve BMD at the lumbar spine

Ethnic variations in duration of untreated psychosis: report from the CRIS-FEP study

Objectives:  There is inconsistent evidence on the influence of ethnicity on duration of untreated psychosis (DUP). We investigated ethnic differences in DUP in a large epidemiological dataset of first episode psychosis patients in an inner city area of south London, UK. Methods:  We analysed data on 558 first episode psychosis patients at the South London and Maudsley NHS Trust, between 2010 and 2012. We performed multivariable logistic regression to estimate the odds of a short DUP (≤ 6 months) by ethnic group, controlling for confounders. Results:  There was no evidence that ethnicity is associated with duration of untreated psychosis. However, we found evidence that a short DUP was strongly associated with age, living circumstances, and pathways to care variables (involuntary admission, out of office hour contact, accident and emergency referral, criminal justice agency referral and family involvement in help-seeking). Conversely, a long DUP was associated with report of social isolation, living alone, being single and General Practitioner referral. Conclusion:  Our findings suggest that indicators of social isolation were associated with long DUP. Our data also show that pathways into care characteristics play significant role in DUP. Thus, the challenge of tackling the issue of timely access to EI under the new Access and Waiting Time standard for psychosis requires a multilevel approach, including joint working with communities, public awareness of psychosis, less restrictive referral pathways and adequate resourcing of early intervention for psychosis services. These will go a long way in addressing patients’ needs rather than be determined by service structures

The relative efficacy of nine osteoporosis medications for reducing the rate of fractures in post-menopausal women

<p>Abstract</p> <p>Background</p> <p>In the absence of head-to-head trials, indirect comparisons of randomized placebo-controlled trials may provide a viable option to assess relative efficacy. The purpose was to estimate the relative efficacy of reduction of fractures in post-menopausal women, and to assess robustness of the results.</p> <p>Methods</p> <p>A systematic literature review of multiple databases identified randomized placebo-controlled trials with nine drugs for post-menopausal women. Odds ratio and 95% credibility intervals for the rates of hip, non-vertebral, vertebral, and wrist fractures for each drug and between drugs were derived using a Bayesian approach. A drug was ranked as the most efficacious if it had the highest posterior odds ratio, or had the highest effect size.</p> <p>Results</p> <p>30 studies including 59,209 patients reported fracture rates for nine drugs: alendronate (6 studies), denosumab (1 study), etidronate (8 studies), ibandronate (4 studies), raloxifene (1 study), risedronate (7 studies), strontium (2 study), teriparatide (1 study), and zoledronic acid (1 study). The drugs with the highest probability of reducing non-vertebral fractures was etidronate and teriparatide while the drugs with the highest probability of reducing vertebral, hip or wrist fractures were teriparatide, zoledronic acid and denosumab. The drugs with the largest effect size for vertebral fractures were zoledronic acid, teriparatide and denosumab, while the drugs with the highest effect size for non-vertebral, hip or wrist fractures were alendronate or risedronate. Estimates were consistent between Bayesian and classical approaches.</p> <p>Conclusion</p> <p>Teriparatide, zoledronic acid and denosumab have the highest probabilities of being most efficacious for non-vertebral and vertebral fractures, and having the greatest effect sizes. The estimates from indirect comparisons were robust to differences in methodology.</p

Demographic History of Indigenous Populations in Mesoamerica Based on mtDNA Sequence Data

The genetic characterization of Native American groups provides insights into their history and demographic events. We sequenced the mitochondrial D-loop region (control region) of 520 samples from eight Mexican indigenous groups. In addition to an analysis of the genetic diversity, structure and genetic relationship between 28 Native American populations, we applied Bayesian skyline methodology for a deeper insight into the history of Mesoamerica. AMOVA tests applying cultural, linguistic and geographic criteria were performed. MDS plots showed a central cluster of Oaxaca and Maya populations, whereas those from the North and West were located on the periphery. Demographic reconstruction indicates higher values of the effective number of breeding females (Nef) in Central Mesoamerica during the Preclassic period, whereas this pattern moves toward the Classic period for groups in the North and West. Conversely, Nef minimum values are distributed either in the Lithic period (i.e. founder effects) or in recent periods (i.e. population declines). The Mesomerican regions showed differences in population fluctuation as indicated by the maximum Inter-Generational Rate (IGRmax): i) Center-South from the lithic period until the Preclassic; ii) West from the beginning of the Preclassic period until early Classic; iii) North characterized by a wide range of temporal variation from the Lithic to the Preclassic. Our findings are consistent with the genetic variations observed between central, South and Southeast Mesoamerica and the North-West region that are related to differences in genetic drift, structure, and temporal survival strategies (agriculture versus hunter-gathering, respectively). Interestingly, although the European contact had a major negative demographic impact, we detect a previous decline in Mesoamerica that had begun a few hundred years before

Transport of Anthocyanins and other Flavonoids by the Arabidopsis ATP-Binding Cassette Transporter AtABCC2

Flavonoids have important developmental, physiological, and ecological roles in plants and are primarily stored in the large central vacuole. Here we show that both an ATP-binding cassette (ABC) transporter(s) and an H+-antiporter(s) are involved in the uptake of cyanidin 3-O-glucoside (C3G) by Arabidopsis vacuolar membrane-enriched vesicles. We also demonstrate that vesicles isolated from yeast expressing the ABC protein AtABCC2 are capable of MgATP-dependent uptake of C3G and other anthocyanins. The uptake of C3G by AtABCC2 depended on the co-transport of glutathione (GSH). C3G was not altered during transport and a GSH conjugate was not formed. Vesicles from yeast expressing AtABCC2 also transported flavone and flavonol glucosides. We performed ligand docking studies to a homology model of AtABCC2 and probed the putative binding sites of C3G and GSH through site-directed mutagenesis and functional studies. These studies identified residues important for substrate recognition and transport activity in AtABCC2, and suggest that C3G and GSH bind closely, mutually enhancing each other’s binding. In conclusion, we suggest that AtABCC2 along with possibly other ABCC proteins are involved in the vacuolar transport of anthocyanins and other flavonoids in the vegetative tissue of Arabidopsis