Impact of organic solvents on cytochrome P450 probe reactions: filling the gap with (S)-Warfarin and midazolam hydroxylation.

(S)-Warfarin 7-hydroxylation and midazolam 1'-hydroxylation are among the preferred probe substrate reactions for CYP2C9 and CYP3A4/5, respectively. The impact of solvents on enzyme activity, kinetic parameters, and predicted in vivo hepatic clearance (Cl(H)) associated with each reaction has not been evaluated. The effects of increasing concentrations [0.

A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response.

The jumonji (JMJ) family of histone demethylases are Fe2+- and α-ketoglutarate-dependent oxygenases that are essential components of regulatory transcriptional chromatin complexes. These enzymes demethylate lysine residues in histones in a methylation-state and sequence-specific context. Considerable effort has been devoted to gaining a mechanistic understanding of the roles of histone lysine demethylases in eukaryotic transcription, genome integrity and epigenetic inheritance, as well as in development, physiology and disease.

Mental health needs and service utilization by Hispanic immigrants residing in mid-southern United States.

Purpose: This study assessed mental health needs and service utilization patterns in a convenience sample of Hispanic immigrants.

Design: A total of 84 adult Hispanic participants completed a structured diagnostic interview and a semistructured service utilization interview with trained bilingual research assistants.

Results: In the sample, 36% met diagnostic criteria for at least one mental disorder.

Over expression of wild type or a catalytically dead mutant of Sirtuin 6 does not influence NFκB responses.

SIRT6 is involved in inflammation, aging and metabolism potentially by modulating the functions of both NFκB and HIF1α. Since it is possible to make small molecule activators and inhibitors of Sirtuins we wished to establish biochemical and cellular assays both to assist in drug discovery efforts and to validate whether SIRT6 represents a valid drug target for these indications. We confirmed in cellular assays that SIRT6 can deacetylate acetylated-histone H3 lysine 9 (H3K9Ac), however this deacetylase activity is unusually low in biochemical assays.

Pilot study of rosiglitazone as an in vivo probe of paclitaxel exposure.

What Is Already Known About This Subject: • Paclitaxel and rosiglitazone are primarily metabolized by CYP2C8 and their in vitro metabolism by human liver microsomes is correlated. Probe assays that quantify the in vivo activity of CYP enzymes which are important in drug metabolism have been developed for use in clinical pharmacology research. A probe of CYP2C8 that is easy to administer and interpret may be valuable for individualized dosing of paclitaxel.

Cognitive appraisals of specialty mental health services and their relation to mental health service utilization in the rural population.

Purpose: Rural individuals utilize specialty mental health services (eg, psychiatrists, psychologists, counselors, and social workers) at lower rates than their urban counterparts. This study explores whether cognitive appraisals (ie, individual perceptions of need for services, outcome expectancies, and value of a positive therapeutic outcome) of help-seeking for depression symptoms are related to the utilization of specialty mental health services in a rural sample.

Methods: Demographic and environmental characteristics, cultural barriers, cognitive appraisals, and depression symptoms were assessed in one model predicting specialty mental health service utilization (MHSU) in a rural sample.

Cyclophosphamide and 4-hydroxycyclophosphamide pharmacokinetics in patients with glomerulonephritis secondary to lupus and small vessel vasculitis.

Aims: Cyclophosphamide, the precursor to the active 4-hydroxycyclophosphamide, is used in active glomerulonephritis despite limited pharmacokinetics data. The pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide were evaluated. The influence of laboratory and pharmacogenomic covariates on pharmacokinetics was evaluated as a secondary aim.

5-Aryl-4-carboxamide-1,3-oxazoles: potent and selective GSK-3 inhibitors.

5-Aryl-4-carboxamide-1,3-oxazoles are a novel, potent and selective series of GSK-3 inhibitors. The optimization of the series to yield compounds with cell activity and brain permeability is described.

Configuration of a high-content imaging platform for hit identification and pharmacological assessment of JMJD3 demethylase enzyme inhibitors.

The biological complexity associated with the regulation of histone demethylases makes it desirable to configure a cellular mechanistic assay format that simultaneously encompasses as many of the relevant cellular processes as possible. In this report, the authors describe the configuration of a JMJD3 high-content cellular mechanistic imaging assay that uses single-cell multiparameter measurements to accurately assess cellular viability and the enzyme-dependent demethylation of the H3K27(Me)3 mark by exogenously expressed JMJD3. This approach couples robust statistical analyses with the spatial resolving power of cellular imaging.

Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons.

Angelman syndrome is a severe neurodevelopmental disorder caused by deletion or mutation of the maternal allele of the ubiquitin protein ligase E3A (UBE3A). In neurons, the paternal allele of UBE3A is intact but epigenetically silenced, raising the possibility that Angelman syndrome could be treated by activating this silenced allele to restore functional UBE3A protein. Using an unbiased, high-content screen in primary cortical neurons from mice, we identify twelve topoisomerase I inhibitors and four topoisomerase II inhibitors that unsilence the paternal Ube3a allele.

Depression literacy: rates and relation to perceived need and mental health service utilization in a rural American sample.

Introduction: Mental health literacy assists patients to recognize, manage and prevent emotional disorders such as depression. Depression literacy is a specific type that varies among populations; however, there is a paucity of research on the depression literacy of rural Americans. The purposes of this study were to evaluate the depression literacy of a rural American sample, and to examine the relationship of depression literacy with perceived need for and utilization of different types of services for those with emotional problems.

Development of a liquid chromatography-tandem mass spectrometry assay of six antimicrobials in plasma for pharmacokinetic studies in premature infants.

This method provides a simple extraction procedure, as well as a validated, sensitive, and specific liquid chromatography-tandem mass spectrometry assay for the simultaneous quantification of ampicillin, piperacillin, tazobactam, meropenem, acyclovir, and metronidazole in human plasma. The method was validated over concentration ranges specific for each compound, with a lower limit of quantification of 50-300 ng/mL and a sample volume of 50 μL. The method is accurate and precise, with within- and between-day accuracy ranging from 85 to 110% and 92 to 110%, respectively, and within- and between-day precision of 89-111% and 91-109%, respectively.

Republished original article: Resident-initiated interventions to improve inpatient heart-failure management.

Background: Third-year internal medicine residents participating in a quality improvement rotation identified gaps between the Joint Commission's ORYX quality guidelines and clinical practices for the inpatient management of heart failure (HF) at the William S. Middleton Memorial Veterans Hospital. Residents focused on the performance metrics associated with tobacco-cessation counselling documentation, ejection fraction assessment and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker prescriptions.

A rare case of ovarian carcinoid causing heart failure.

Carcinoid tumours are rare tumours of the neuro-endocrine system. They most commonly present in the gut; however, they can present in other organs. In all, 0.

Enabling lead discovery for histone lysine demethylases by high-throughput RapidFire mass spectrometry.

A high-throughput RapidFire mass spectrometry assay is described for the JMJD2 family of Fe(2+), O(2), and α-ketoglutarate-dependent histone lysine demethylases. The assay employs a short amino acid peptide substrate, corresponding to the first 15 amino acid residues of histone H3, but mutated at two positions to increase assay sensitivity. The assay monitors the direct formation of the dimethylated-Lys9 product from the trimethylated-Lys9 peptide substrate.

Directing the biological activities of heparan sulfate oligosaccharides using a chemoenzymatic approach.

Heparan sulfate (HS) and heparin are highly sulfated polysaccharides exhibiting essential physiological functions. The sulfation patterns determine the functional selectivity for HS and heparin. Chemical synthesis of HS, especially those larger than a hexasaccharide, remains challenging.

Identification of 2-(4-pyridyl)thienopyridinones as GSK-3β inhibitors.

The discovery of a novel series of 2-(4-pyridyl)thienopyridinone GSK-3β inhibitors is reported. X-ray crystallography reveals its binding mode and enables rationalization of the SAR. The initial optimization of the template for improved cellular activity and predicted CNS penetration is also presented.

The anti-estrogenic activity of sediments from agriculturally intense watersheds: assessment using in vivo and in vitro assays.

The goal of the current study was to determine whether sediments from agriculturally intense watersheds can act as a potential source of anti-estrogenic endocrine-disrupting compounds. The specific objectives of the current study were to determine (1) whether female fathead minnows (Pimephales promelas) experience alterations in endocrine function when exposed to sediments collected from agriculturally intense watersheds and (2) if these sediments display anti-estrogenic activity in an in vitro assay. In addition, sediment samples were analyzed for the presence of steroid hormones and pesticides associated with local agricultural practices.

Efficacy study of novel diamidine compounds in a Trypanosoma evansi goat model.

Three diamidines (DB 75, DB 867 and DB 1192) were selected and their ability to cure T. evansi experimentally infected goats was investigated. A toxicity assessment and pharmacokinetic analysis of these compounds were additionally carried out.

Pharmacologic and phenotypic study of docetaxel in patients with ovarian or primary peritoneal cancer.

Purpose: The objectives of this study were to determine whether the midazolam clearance predicted docetaxel pharmacokinetics, CA-125 change, and response and to assess the impact of cytochrome P450 (CYP) 3A5 and ATP-binding cassette, subfamily B, member 1 (ABCB1) genotypes on docetaxel pharmacokinetics and pharmacodynamics in ovarian or primary peritoneal cancer patients.

Methods: Thirty-four patients with advanced ovarian and primary peritoneal cancer were administered docetaxel at 75 mg/m(2) as a 1-h infusion in combination with carboplatin IV over 30 min at a target AUC of 5 mg/ml min. Cycles were repeated every 21 days for 6 cycles.

Resident-initiated interventions to improve inpatient heart-failure management.

Background: Third-year internal medicine residents participating in a quality improvement rotation identified gaps between the Joint Commission's ORYX quality guidelines and clinical practices for the inpatient management of heart failure (HF) at the William S. Middleton Memorial Veterans Hospital. Residents focused on the performance metrics associated with tobacco-cessation counselling documentation, ejection fraction assessment and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker prescriptions.

Disseminated zygomycosis heralded by a subtle cutaneous finding.

Background: Zygomycosis is the preferred name for the angiotropic infection produced by the Zygomycete class of fungi. Although healthy individuals may be affected, the majority of patients diagnosed with zygomycosis have diabetes, malignancy, or have had solid organ or bone marrow transplantation. Unlike other filamentous fungi that tend to disseminate hematogenously to skin, cutaneous zygomycosis most commonly arises via direct inoculation.

Rheumatoid vasculitis: vanishing menace or target for new treatments?

Rheumatoid vasculitis is a rare but serious complication of rheumatoid arthritis. Herein we examine the pathophysiology, epidemiology, clinical diagnosis, and treatment of rheumatoid vasculitis. Seropositivity, specific HLA variations, and tobacco use are among the genetic and environmental predictors of rheumatoid vasculitis.

Contamination aversion and repeated exposure to disgusting stimuli.

Recent research has highlighted the central role of disgust in the etiology and maintenance of contamination aversion (CA). Data would also suggest that, although amendable to the treatment of choice for CA (exposure and response prevention [ERP]), disgust is resistant to habituation. However, with regard to CA, it is not yet known if disgust's resistance to habituation is an artifact of the emotion or the disorder.