Neuropsychological Outcome following Perinatal HIE: Utility of MR Spectroscopy

Outcome following hypoxic-ischemic encephalopathy (HIE), a neurodegenerative process caused by prolonged asphyxiation during birth, can vary between minimal impairment and cerebral palsy, mental retardation, or death (30%) (McCulloch, Taylor, & Whyte, 1991). Prognosis after HIE is often difficult to establish because traditional predictors, such as Sarnat scores, Apgar scores, and pH, do not always account for adequate variance in outcome. The prognostic utility of MR Spectroscopy in the pathogenesis of asphyxia is promising (Wyatt, 1994). Innovative research indicates that MR Spectroscopy can accurately predict outcome at one year in 91% of neonates with central nervous system injuries (Holshouser et al., 1997). The current study examined neuropsychological functioning following birth asphyxia-related HIE in nine children 3 years 4 months old to 7 years 8 months old (M = 5 years old, SD = 20 months) using ^HMRS as a predictor of outcome in the following areas: (1) memory and learning; (2) language; (3) visuospatial; (4) attention and executive functioning; and (5) sensorimotor abilities. Results found that both NAA/Cre and NAA/Cho were not correlated with outcome. Elevated Cho/Cre and lactate, however, were the most common finding among more severe HIE, with both metabolites correlated with all outcome areas

Src Family Kinases and p38 Mitogen-Activated Protein Kinases Regulate Pluripotent Cell Differentiation in Culture

Multiple pluripotent cell populations, which together comprise the pluripotent cell lineage, have been identified. The mechanisms that control the progression between these populations are still poorly understood. The formation of early primitive ectoderm-like (EPL) cells from mouse embryonic stem (mES) cells provides a model to understand how one such transition is regulated. EPL cells form from mES cells in response to l-proline uptake through the transporter Slc38a2. Using inhibitors of cell signaling we have shown that Src family kinases, p38 MAPK, ERK1/2 and GSK3β are required for the transition between mES and EPL cells. ERK1/2, c-Src and GSK3β are likely to be enforcing a receptive, primed state in mES cells, while Src family kinases and p38 MAPK are involved in the establishment of EPL cells. Inhibition of these pathways prevented the acquisition of most, but not all, features of EPL cells, suggesting that other pathways are required. L-proline activation of differentiation is mediated through metabolism and changes to intracellular metabolite levels, specifically reactive oxygen species. The implication of multiple signaling pathways in the process suggests a model in which the context of Src family kinase activation determines the outcomes of pluripotent cell differentiation

SerpinB2 deficiency in mice reduces bleeding times via dysregulated platelet activation

SerpinB2, also known as plasminogen activation inhibitor type 2 (PAI-2), is classically viewed as an inhibitor of fibrinolysis. However, we show herein a distinct, hitherto unrecognized role for SerpinB2 in hemostasis. Mice deficient in SerpinB2 expression and mice with an active site mutation in SerpinB2, both showed significant reductions in tail bleeding times. This hemostatic phenotype was associated with platelets, with SerpinB2 and SerpinB2-urokinase complexes clearly present in platelet fractions, and immunohistochemistry of blood clots suggesting SerpinB2 is associated with platelet aggregates. Thromboelastography illustrated faster onset of clot formation in blood from SerpinB2 deficient mice, whereas clotting of platelet-free plasma was unaffected. The results appear consistent with the low circulating SerpinB2 levels and hypercoagulation seen during pre-eclampsia; however, SerpinB2 was not detected in human platelets.This work was supported by the National Health and Medical Research Council of Australi

Uranium(III) coordination chemistry and oxidation in a flexible small-cavity macrocycle

U(III) complexes of the conformationally flexible, small-cavity macrocycle trans-calix[2]benzene[2]pyrrolide (L)2–, [U(L)X] (X = O-2,6-tBu2C6H3, N(SiMe3)2), have been synthesized from [U(L)BH4] and structurally characterized. These complexes show binding of the U(III) center in the bis(arene) pocket of the macrocycle, which flexes to accommodate the increase in the steric bulk of X, resulting in long U–X bonds to the ancillary ligands. Oxidation to the cationic U(IV) complex [U(L)X][B(C6F5)4] (X = BH4) results in ligand rearrangement to bind the smaller, harder cation in the bis(pyrrolide) pocket, in a conformation that has not been previously observed for (L)2–, with X located between the two ligand arene rings

Effectiveness of an Inpatient Movement Disorders Program for Patients with Atypical Parkinsonism

This paper investigated the effectiveness of an inpatient movement disorders program for patients with atypical parkinsonism, who typically respond poorly to pharmacologic intervention and are challenging to rehabilitate as outpatients. Ninety-one patients with atypical parkinsonism participated in an inpatient movement disorders program. Patients received physical, occupational, and speech therapy for 3 hours/day, 5 to 7 days/week, and pharmacologic adjustments based on daily observation and data. Differences between admission and discharge scores were analyzed for the functional independence measure (FIM), timed up and go test (TUG), two-minute walk test (TMW), Berg balance scale (BBS) and finger tapping test (FT), and all showed significant improvement on discharge (P > .001). Clinically significant improvements in total FIM score were evident in 74% of the patients. Results were similar for ten patients whose medications were not adjusted. Patients with atypical parkinsonism benefit from an inpatient interdisciplinary movement disorders program to improve functional status

A Neutralizing Monoclonal Antibody Targeting the Acid-Sensitive Region in Chikungunya Virus E2 Protects from Disease.

The mosquito-borne alphavirus, chikungunya virus (CHIKV), has recently reemerged, producing the largest epidemic ever recorded for this virus, with up to 6.5 million cases of acute and chronic rheumatic disease. There are currently no licensed vaccines for CHIKV and current anti-inflammatory drug treatment is often inadequate. Here we describe the isolation and characterization of two human monoclonal antibodies, C9 and E8, from CHIKV infected and recovered individuals. C9 was determined to be a potent virus neutralizing antibody and a biosensor antibody binding study demonstrated it recognized residues on intact CHIKV VLPs. Shotgun mutagenesis alanine scanning of 98 percent of the residues in the E1 and E2 glycoproteins of CHIKV envelope showed that the epitope bound by C9 included amino-acid 162 in the acid-sensitive region (ASR) of the CHIKV E2 glycoprotein. The ASR is critical for the rearrangement of CHIKV E2 during fusion and viral entry into host cells, and we predict that C9 prevents these events from occurring. When used prophylactically in a CHIKV mouse model, C9 completely protected against CHIKV viremia and arthritis. We also observed that when administered therapeutically at 8 or 18 hours post-CHIKV challenge, C9 gave 100% protection in a pathogenic mouse model. Given that targeting this novel neutralizing epitope in E2 can potently protect both in vitro and in vivo, it is likely to be an important region both for future antibody and vaccine-based interventions against CHIKV

Protein expression of the gp78 E3 ligase predicts poor breast cancer outcome based on race

Women of African ancestry suffer higher rates of breast cancer mortality compared with all other groups in the United States. Though the precise reasons for these disparities remain unclear, many recent studies have implicated a role for differences in tumor biology. Using an epitope-validated antibody against the endoplasmic reticulum-associated E3 ligase, gp78, we show that elevated levels of gp78 in patient breast cancer cells predict poor survival. Moreover, high levels of gp78 are associated with poor outcomes in both ER+ and ER- tumors, and breast cancers expressing elevated amounts of gp78 protein are enriched in gene expression pathways that influence cell cycle, metabolism, receptor-mediated signaling, and cell stress response pathways. In multivariate analysis adjusted for subtype and grade, gp78 protein is an independent predictor of poor outcomes in women of African ancestry. Furthermore, gene expression signatures, derived from patients stratified by gp78 protein expression, are strong predictors of recurrence and pathological complete response in retrospective clinical trial data and share many common features with gene sets previously identified to be overrepresented in breast cancers based on race. These findings implicate a prominent role for gp78 in tumor progression and offer insights into our understanding of racial differences in breast cancer outcomes.Fil: Singhal, Sandeep K.. No especifíca;Fil: Byun, Jung S.. National Institutes of Health; Estados UnidosFil: Yan, Tingfen. National Institutes of Health; Estados UnidosFil: Yancey, Ryan. Columbia University; Estados UnidosFil: Caban, Ambar. Columbia University; Estados UnidosFil: Hernandez, Sara Gil. National Institutes of Health; Estados UnidosFil: Bufford, Sediqua. No especifíca;Fil: Hewitt, Stephen M.. No especifíca;Fil: Winfield, Joy. Columbia University; Estados UnidosFil: Pradhan, Jaya. Columbia University; Estados UnidosFil: Mustkov, Vesco. Columbia University; Estados UnidosFil: McDonald, Jasmine A.. No especifíca;Fil: Pérez Stable, Eliseo J.. National Institutes of Health; Estados UnidosFil: Nápoles, Anna María. National Institutes of Health; Estados UnidosFil: Vohra, Nasreen. No especifíca;Fil: de Siervi, Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Yates, Clayton. No especifíca;Fil: Davis, Melissa B.. No especifíca;Fil: Yang, Mei. No especifíca;Fil: Tsai, Yien Che. No especifíca;Fil: Weissman, Allan M.. No especifíca;Fil: Gardner, Kevin. Columbia University; Estados Unido

Application and Validation of Case-Finding Algorithms for Identifying Individuals with Human Immunodeficiency Virus from Administrative Data in British Columbia, Canada

Objective To define a population-level cohort of individuals infected with the human immunodeficiency virus (HIV) in the province of British Columbia from available registries and administrative datasets using a validated case-finding algorithm. Methods Individuals were identified for possible cohort inclusion from the BC Centre for Excellence in HIV/AIDS (CfE) drug treatment program (antiretroviral therapy) and laboratory testing datasets (plasma viral load (pVL) and CD4 diagnostic test results), the BC Centre for Disease Control (CDC) provincial HIV surveillance database (positive HIV tests), as well as databases held by the BC Ministry of Health (MoH); the Discharge Abstract Database (hospitalizations), the Medical Services Plan (physician billing) and PharmaNet databases (additional HIV-related medications). A validated case-finding algorithm was applied to distinguish true HIV cases from those likely to have been misclassified. The sensitivity of the algorithms was assessed as the proportion of confirmed cases (those with records in the CfE, CDC and MoH databases) positively identified by each algorithm. A priori hypotheses were generated and tested to verify excluded cases. Results A total of 25,673 individuals were identified as having at least one HIV-related health record. Among 9,454 unconfirmed cases, the selected case-finding algorithm identified 849 individuals believed to be HIV-positive. The sensitivity of this algorithm among confirmed cases was 88%. Those excluded from the cohort were more likely to be female (44.4% vs. 22.5%; p<0.01), had a lower mortality rate (2.18 per 100 person years (100PY) vs. 3.14/100PY; p<0.01), and had lower median rates of health service utilization (days of medications dispensed: 9745/100PY vs. 10266/100PY; p<0.01; days of inpatient care: 29/100PY vs. 98/100PY; p<0.01; physician billings: 602/100PY vs. 2,056/100PY; p<0.01). Conclusions The application of validated case-finding algorithms and subsequent hypothesis testing provided a strong framework for defining a population-level cohort of HIV infected people in BC using administrative databases