Mechanism of the antioxidant to pro-oxidant switch in the behavior of dehydroascorbate during LDL oxidation by copper(II) ions.

Oxidised low density lipoprotein (LDL) may be involved in the pathogenesis of atherosclerosis. We have therefore investigated the mechanisms underlying the antioxidant/pro-oxidant behavior of dehydroascorbate, the oxidation product of ascorbic acid, toward LDL incubated with Cu(2+) ions. By monitoring lipid peroxidation through the formation of conjugated dienes and lipid hydroperoxides, we show that the pro-oxidant activity of dehydroascorbate is critically dependent on the presence of lipid hydroperoxides, which accumulate during the early stages of oxidation.

IKKbeta inhibition attenuates myocardial injury and dysfunction following acute ischemia-reperfusion injury.

Despite years of experimental and clinical research, myocardial ischemia-reperfusion (IR) remains an important cause of cardiac morbidity and mortality. The transcription factor nuclear factor-kappaB (NF-kappaB) has been implicated as a key mediator of reperfusion injury. Activation of NF-kappaB is dependent upon the phosphorylation of its inhibitor, IkappaBalpha, by the specific inhibitory kappaB kinase (IKK) subunit, IKKbeta.

Human hepatic stem cells from fetal and postnatal donors.

Human hepatic stem cells (hHpSCs), which are pluripotent precursors of hepatoblasts and thence of hepatocytic and biliary epithelia, are located in ductal plates in fetal livers and in Canals of Hering in adult livers. They can be isolated by immunoselection for epithelial cell adhesion molecule-positive (EpCAM+) cells, and they constitute approximately 0.5-2.

Discovery and optimization of p38 inhibitors via computer-assisted drug design.

Integration of computational methods, X-ray crystallography, and structure-activity relationships will be disclosed, which lead to a new class of p38 inhibitors that bind to p38 MAP kinase in a Phe out conformation.

Proteasome inhibition attenuates infarct size and preserves cardiac function in a murine model of myocardial ischemia-reperfusion injury.

Background: Despite improvements in protection, myocardial ischemia-reperfusion remains an important cause of cardiac dysfunction. Multiple strategies exist experimentally; few are clinically accessible. Nuclear factor kappa-B (NF-kappaB) is a transcription factor central to the inflammatory response and is implicated in reperfusion injury.

Diagnostic validity of two instruments for assessing anxiety and depression among pregnant women in Hyderabad, Pakistan.

The objective of this study was to compare the diagnostic validity of two measures, the Aga Khan University Anxiety and Depression Scale (AKUADS) and the How I Feel scale, for assessing anxiety and depression among pregnant women in Pakistan. The sample included 200 pregnant women in Hyderabad, Pakistan. Using psychiatrist-administered Diagnostic and Statistical Manual of Mental Disorders-fourth edition (DSM-IV) criteria, 71 (36%) of the women were diagnosed with depression or anxiety or both.

The discovery of carboline analogs as potent MAPKAP-K2 inhibitors.

The discovery of a series of potent, carboline-based MK2 inhibitors is described. These compounds inhibit MK2 with IC50s as low as 10 nM, as measured in a DELFIA assay. An X-ray crystal structure reveals that they bind in a region near the p-loop and the hinge region of MK2a.

New modifications to the area of pyrazole-naphthyl urea based p38 MAP kinase inhibitors that bind to the adenine/ATP site.

Discovery of the pyrazole-naphthyl urea class of p38 MAP kinase inhibitors typified by the clinical candidate BIRB 796 has encouraged further exploration of this particular scaffold. Modification to the part of the inhibitor that occupies the adenine/ATP binding site has resulted in a new way to obtain potent inhibitors that possess favorable in vitro and in vivo properties.

The use of chlorhexidine to reduce maternal and neonatal mortality and morbidity in low-resource settings.

Of the 4 million neonatal deaths and 500,000 maternal deaths that occur annually worldwide, almost 99% are in developing countries and one-third are associated with infections. Implementation of proven interventions and targeted research on a select number of promising high-impact preventative and curative interventions are essential to achieve Millennium Development Goals for reduction of child and maternal mortality. Feasible, simple, low-cost interventions have the potential to significantly reduce the mortality and severe morbidity associated with infection in these settings.

Measuring antenatal depression and anxiety: findings from a community-based study of women in Hyderabad, Pakistan.

This study evaluated the psychometric properties of two possible measures of depression and anxiety among pregnant women in Pakistan for use in the Global Network for Women's and Children's Health Research project, a collaborative, international multi-site research network investigating methods for improving pregnancy and birth outcomes in developing countries. The first measure, the Aga Khan University Anxiety and Depression Scale (AKUADS), is an Urdu language scale originally developed for the general Pakistani population, whereas the second measure, the How I Feel scale, was designed for pregnant women in the United States. In an earlier pilot study, we found that the two scales demonstrated similar levels of diagnostic validity.

BIRB 796 enhances cytotoxicity triggered by bortezomib, heat shock protein (Hsp) 90 inhibitor, and dexamethasone via inhibition of p38 mitogen-activated protein kinase/Hsp27 pathway in multiple myeloma cell lines and inhibits paracrine tumour growth.

We have previously shown that heat shock protein (Hsp) 27 or its upstream activator p38 mitogen-activated protein kinase (MAPK) confers resistance to bortezomib and dexamethasone (Dex) in multiple myeloma (MM) cells. This study examined anti-MM activity of a novel p38 MAPK inhibitor, BIRB 796, alone and in combination with conventional and novel therapeutic agents. BIRB 796 blocked baseline and bortezomib-triggered upregulation of p38 MAPK and Hsp27 phosphorylation, thereby enhancing cytotoxicity and caspase activation.

A review of quality of life and psychosocial issues in scoliosis.

Study Design: Recent literature regarding the psychological impact of scoliosis was reviewed.

Objective: To determine the impact of scoliosis on health-related quality of life (HRQL), psychosocial functioning, and body image to improve patient outcomes.

Summary Of Background Data: Adolescents and adults with adolescent idiopathic scoliosis have been known to score lower than healthy controls on HRQL measures.

Oral misoprostol in preventing postpartum haemorrhage in resource-poor communities: a randomised controlled trial.

Background: Postpartum haemorrhage is a major cause of maternal mortality in the developing world. Although effective methods for prevention and treatment of such haemorrhage exist--such as the uterotonic drug oxytocin--most are not feasible in resource-poor settings where many births occur at home. We aimed to investigate whether oral misoprostol, a potential alternative to oxytocin, could prevent postpartum haemorrhage in a community home-birth setting.

Discovery and design of benzimidazolone based inhibitors of p38 MAP kinase.

A new class of benzimidazolone p38 MAP kinase inhibitors was discovered through high-throughput screening. X-ray crystallographic data of the lead molecule with p38 were used to design analogues with improved binding affinity and potency in a cell assay of LPS-induced TNFalpha production. Herein, we report the SAR of this new class of p38 inhibitors.

Drape estimation vs. visual assessment for estimating postpartum hemorrhage.

Objective: To compare (1) visual estimation of postpartum blood loss with estimation using a specifically designed blood collection drape and (2) the drape estimate with a measurement of blood loss by photospectrometry.

Methods: A randomized controlled study was performed with 123 women delivered at the District Hospital, Belgaum, India. The women were randomized to visual or drape estimation of blood loss.

Modulation of voltage-dependent Shaker family potassium channels by an aldo-keto reductase.

The beta subunit (Kvbeta) of the Shaker family voltage-dependent potassium channels (Kv1) is a cytosolic protein that forms a permanent complex with the channel. Sequence and structural conservation indicates that Kvbeta resembles an aldo-keto reductase (AKR), an enzyme that catalyzes a redox reaction using an NADPH cofactor. A putative AKR in complex with a Kv channel has led to the hypothesis that intracellular redox potential may dynamically influence the excitability of a cell through Kvbeta.

A cluster randomized controlled trial of a behavioral intervention to facilitate the development and implementation of clinical practice guidelines in Latin American maternity hospitals: the Guidelines Trial: Study protocol [ISRCTN82417627].

BACKGROUND: A significant proportion of the health care administered to women in Latin American maternity hospitals during labor and delivery has been demonstrated to be ineffective or harmful, whereas effective interventions remain underutilized. The routine use of episiotomies and the failure to use active management of the third stage of labor are good examples. METHODS/DESIGN: The aim of this trial is to evaluate the effect of a multifaceted behavioral intervention on the use of two evidence-based birth practices, the selective use of episiotomies and active management of the third stage of labor (injection of 10 International Units of oxytocin).

"Street medicine": Collaborating with a faith-based organization to screen at-risk youths for sexually transmitted diseases.

Chlamydia and gonorrhea rates among African American youths in San Francisco are far higher than those among young people of the city's other racial and ethnic groups. A geographically targeted sexually transmitted disease education and screening intervention performed in collaboration with a local faith-based organization was able to screen hundreds of at-risk youths. The screened individuals included friends and sex partners from an extensive social-sexual network that transcended the boundaries of the target population.

Comparison of effects of GnRH and prostaglandin in combination, and prostaglandin on conception rates and time to conception in dairy cows.

Objective: To assess the effectiveness of a gonadotrophin-releasing hormone (GnRH) / prostaglandin program (GnRH-PG-GnRH, Ovsynch) on conception rates and time to conception of lactating dairy cows compared with a PG program (double prostaglandin injection).

Design: A randomised multi-centre cohort study was conducted with 778 cows from nine dairy herds. Cows at different stages of lactation were randomly assigned, after matching for days open at the time of treatment, to either the PG or Ovsynch program.

Structure-activity relationships of the p38alpha MAP kinase inhibitor 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)naph- thalen-1-yl]urea (BIRB 796).

We report on the structure-activity relationships (SAR) of 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]urea (BIRB 796), an inhibitor of p38alpha MAP kinase which has advanced into human clinical trials for the treatment of autoimmune diseases. Thermal denaturation was used to establish molecular binding affinities for this class of p38alpha inhibitors. The tert-butyl group remains a critical binding element by occupying a lipophilic domain in the kinase which is exposed upon rearrangement of the activation loop.

The kinetics of binding to p38MAP kinase by analogues of BIRB 796.

BIRB 796, a member of the N-pyrazole-N'-naphthly urea class of p38MAPK inhibitors, binds to the kinase with both slow association and dissociation rates. Prior to binding, the kinase undergoes a reorganization of the activation loop exposing a critical binding domain. We demonstrate that, independent of the loop movement, association rates are governed by low energy conformations of the inhibitor and polar functionality on the tolyl ring.

Optimization of 2-phenylaminoimidazo[4,5-h]isoquinolin-9-ones: orally active inhibitors of lck kinase.

The tyrosine kinase p56lck (lck) is essential for T cell activation; thus, inhibitors of lck have potential utility as autoimmune agents. Our initial disclosure of a new class of lck inhibitors based on the phenylaminoimidazoisoquinolin-9-one showed reasonable cellular activity but did not work in vivo upon oral administration. Our current work highlights the further use of rational drug design and molecular modeling to produce a series of lck inhibitors that demonstrate cellular activity below 100 nM and are as efficacious as cyclosporin A in an in vivo mouse model of anti-CD3-induced IL-2 production.

The epidemiology of subfertility in non-seasonal calving dairy herds in the Camden region of New South Wales: preliminary investigation of risk factors.

Objective: To investigate relationships between biographic, reproductive, production and disease traits and subfertility among 965 Holstein cows from 10 non-seasonal calving dairy herds in the Camden region of New South Wales.

Design: A retrospective case-control study

Methods: Biographical, disease and reproductive data were collated from computerised records for cows with lactations that commenced between 1 July 1995 and 30 June 1996 and univariable and bivariable associations with subfertility were determined.

Results: Records from 965 cows that conceived were considered for risk factor analyses.

The epidemiology of subfertility in non-seasonal calving dairy herds in the Camden region of New South Wales: description of population and incidence.

Objective: To describe biographic, reproductive, production and disease characteristics of 965 Holstein cows from 10 non-seasonal calving dairy herds in the Camden region of New South Wales, and to describe the incidence of subfertility, that is, conception requiring > 2 inseminations, in this population.

Design: A retrospective epidemiologic study.

Methods: Computer records were used to determine biographic, reproductive, production and disease characteristics in all lactations that commenced between 1 July 1995 and 30 June 1996 and resulted in conception during that lactation.