The Request

Manuscript in Jane Austen's handwriting.Song with keyboard accompaniment: First line 'Tell me babbling echo why'.Jenkyns Collection, Chawton House Library

Contraceptive Efficacy of Oral and Transdermal Hormones When Co-Administered With Protease Inhibitors in HIV-1-Infected Women: Pharmacokinetic Results of ACTG Trial A5188

Pharmacokinetic (PK) interactions between lopinavir/ritonavir (LPV/r) and transdermally delivered ethinyl estradiol (EE) and norelgestromin (NGMN) are unknown

A Mighty Small Heart: The Cardiac Proteome of Adult Drosophila melanogaster

Drosophila melanogaster is emerging as a powerful model system for the study of cardiac disease. Establishing peptide and protein maps of the Drosophila heart is central to implementation of protein network studies that will allow us to assess the hallmarks of Drosophila heart pathogenesis and gauge the degree of conservation with human disease mechanisms on a systems level. Using a gel-LC-MS/MS approach, we identified 1228 protein clusters from 145 dissected adult fly hearts. Contractile, cytostructural and mitochondrial proteins were most abundant consistent with electron micrographs of the Drosophila cardiac tube. Functional/Ontological enrichment analysis further showed that proteins involved in glycolysis, Ca2+-binding, redox, and G-protein signaling, among other processes, are also over-represented. Comparison with a mouse heart proteome revealed conservation at the level of molecular function, biological processes and cellular components. The subsisting peptidome encompassed 5169 distinct heart-associated peptides, of which 1293 (25%) had not been identified in a recent Drosophila peptide compendium. PeptideClassifier analysis was further used to map peptides to specific gene-models. 1872 peptides provide valuable information about protein isoform groups whereas a further 3112 uniquely identify specific protein isoforms and may be used as a heart-associated peptide resource for quantitative proteomic approaches based on multiple-reaction monitoring. In summary, identification of excitation-contraction protein landmarks, orthologues of proteins associated with cardiovascular defects, and conservation of protein ontologies, provides testimony to the heart-like character of the Drosophila cardiac tube and to the utility of proteomics as a complement to the power of genetics in this growing model of human heart disease

TNFα Cooperates with IFN-γ to Repress Bcl-xL Expression to Sensitize Metastatic Colon Carcinoma Cells to TRAIL-mediated Apoptosis

BACKGROUND: TNF-related apoptosis-inducing ligand (TRAIL) is an immune effector molecule that functions as a selective anti-tumor agent. However, tumor cells, especially metastatic tumor cells often exhibit a TRAIL-resistant phenotype, which is currently a major impediment in TRAIL therapy. The aim of this study is to investigate the synergistic effect of TNFα and IFN-γ in sensitizing metastatic colon carcinoma cells to TRAIL-mediated apoptosis. METHODOLOGY/PRINCIPAL FINDINGS: The efficacy and underlying molecular mechanism of cooperation between TNFα and IFN-γ in sensitizing metastatic colon carcinoma cells to TRAIL-mediated apoptosis were examined. The functional significance of TNFα- and IFN-γ-producing T lymphocyte immunotherapy in combination with TRAIL therapy in suppression of colon carcinoma metastasis was determined in an experimental metastasis mouse model. We observed that TNFα or IFN-γ alone exhibits minimal sensitization effects, but effectively sensitized metastatic colon carcinoma cells to TRAIL-induced apoptosis when used in combination. TNFα and IFN-γ cooperate to repress Bcl-xL expression, whereas TNFα represses Survivin expression in the metastatic colon carcinoma cells. Silencing Bcl-xL expression significantly increased the metastatic colon carcinoma cell sensitivity to TRAIL-induced apoptosis. Conversely, overexpression of Bcl-xL significantly decreased the tumor cell sensitivity to TRAIL-induced apoptosis. Furthermore, TNFα and IFN-γ also synergistically enhanced TRAIL-induced caspase-8 activation. TNFα and IFN-γ was up-regulated in activated primary and tumor-specific T cells. TRAIL was expressed in tumor-infiltrating immune cells in vivo, and in tumor-specific cytotoxic T lymphocytes (CTL) ex vivo. Consequently, TRAIL therapy in combination with TNFα/IFN-γ-producing CTL adoptive transfer immunotherapy effectively suppressed colon carcinoma metastasis in vivo. CONCLUSIONS/SIGNIFICANCE: TNFα and IFN-γ cooperate to overcome TRAIL resistance at least partially through enhancing caspase 8 activation and repressing Bcl-xL expression. Combined CTL immunotherapy and TRAIL therapy hold great promise for further development for the treatment of metastatic colorectal cancer

A fidelity study of the Indiana Supported Employment Model for individuals with severe mental illness

A 40-item fidelity scale, the Scale for the Indiana Supported Employment Model (SISTEM), was developed to measure implementation of the Indiana model for Supported Employment. This scale was based in part on a shorter 15-item fidelity scale (IPS Fidelity scale). Staff from 24 Supported Employment (SE) programs for individuals with severe mental illness participated in telephone or on-site interviews. The SISTEM and IPS scales were both administered in a one-hour interview. Data regarding program characteristics, and program outcome were obtained for each site. Outcome data included measures of placement rates, weeks of job retention, wages, and job satisfaction. The results indicated that the SISTEM fidelity scale had good interrater reliability (Total Scale Score intraclass correlation = .97). Agreement between Supervisors and Employment Specialists was generally adequate. However, Follow-along Specialists presented a quite divergent view, suggesting that interview data source is important. Internal consistency of the scale was lower than anticipated but was approaching acceptable levels (Cronbach\u27s alpha = .59). The SISTEM scale was correlated with the IPS subscales, suggesting that there is construct validity for SISTEM. However, there were few correlations found between program fidelity and outcome. In summary, the scale is an improvement over an existing fidelity scale. It was easier to administer and score and provided greater coverage of issues related to interagency and intraagency coordination. However, the scales low internal consistency indicates that the scale needs further development. Implications and suggestions for future use of SE fidelity scales are discussed

A Stroke Transition Of Care Intervention With Stroke Nurse Navigator And Early Stroke Clinic Follow-up Reduces Readmissions For Stroke At 12 Months

Introduction: Stroke is a leading cause of disability in the United States, and one in four occur in people who have already had a stroke. Preventable hospital readmissions contribute to the high medical costs of stroke. Transition of care programs have been successful in reducing hospital readmissions in other diseases, but the data on such programs for stroke is mixed. A transition of care program was implemented at a large urban stroke center, utilizing interventions shown to be effective in the literature, with the goal of reducing recurrent strokes and hospital readmissions

Combination antiretroviral treatment for women previously treated only in pregnancy: week 24 results of AIDS clinical trials group protocol A5227

Submitted by Rodrigo Senorans ([email protected]) on 2015-06-17T18:27:52Z No. of bitstreams: 1 Combination_Antiretroviral_Treatment_for_Women.6.pdf: 419495 bytes, checksum: 6d7dd215a54dec2466c97e5bffda80e2 (MD5)Approved for entry into archive by Anderson Silva ([email protected]) on 2015-06-18T14:16:09Z (GMT) No. of bitstreams: 1 Combination_Antiretroviral_Treatment_for_Women.6.pdf: 419495 bytes, checksum: 6d7dd215a54dec2466c97e5bffda80e2 (MD5)Approved for entry into archive by Anderson Silva ([email protected]) on 2015-06-18T14:16:57Z (GMT) No. of bitstreams: 1 Combination_Antiretroviral_Treatment_for_Women.6.pdf: 419495 bytes, checksum: 6d7dd215a54dec2466c97e5bffda80e2 (MD5)Made available in DSpace on 2015-06-22T15:46:02Z (GMT). No. of bitstreams: 1 Combination_Antiretroviral_Treatment_for_Women.6.pdf: 419495 bytes, checksum: 6d7dd215a54dec2466c97e5bffda80e2 (MD5) Previous issue date: 2014New York Presbyterian Hospital. Cornell University. Weill Cornell Medical College. New York, NY, USA.Harvard School of Public Health. Center for Biostatistics and AIDS Research. Boston, MA, USA.Albert Einstein College of Medicine. Department of Obstetrics and Gynecology. Bronx, NY, USA.Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Laboratório de Pesquisa Clínica em DST e AIDS. Rio de Janeiro, RJ, Brasil.kAsociación Civil Impacta Salud y Educación. Lima, Perú.kAsociación Civil Impacta Salud y Educación. Lima, Perú.Social and Scientific Systems. Inc. Silver Spring, MD, USA.National Institute of Allergy and Infectious Disease. HIV Research Branch. Division of AIDS. Bethesda, MD, USA.University of Rochester. School of Medicine and Dentistry. Rochester, NY, USA.Birmingham Veterans Affairs Medical Center. Birmingham, AL, USA / University of Alabama at Birmingham. School of Medicine, Birmingham, AL, USA.Background: Women with HIV and prior exposure to combination antiretroviral therapy (cART) solely for prevention of Mother to Child Transmission (pMTCT) need to know whether they can later be treated successfully with a commonly used regimen of efavirenz (EFV) and co-formulated emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) Methods: Non-pregnant women with plasma HIV-1 RNA of ≥ 500 copies/mL, previously cART- exposed for pMTCT only, were eligible if they were off ART for ≥ 24 weeks prior to entry, were without evidence of drug resistance on standard genotyping, and were ready to start EFV plus FTC/TDF. The primary endpoint was virologic response (defined as plasma HIV RNA <400 copies/mL) at 24 weeks. Results: 54 women were enrolled between 10/07 and 12/09; 52/54 completed 24 weeks of follow- up. Median baseline CD4+ T-cell count was 265/mm3 and baseline plasma HIV-1 RNA was 4.6 log10 copies/mL. Median prior cART duration was 14 weeks, and median time elapsed from the last pMTCT dose to entry was 22 months. Virologic response at 24 weeks was observed in 42/52 women or 81% (exact 95% CI: 68%–90%). There were no differences in response by country, by number or class of prior pMTCT exposures. While confirmed virologic failure occurred in 8 women, no virologic failures were observed in women reporting perfect early adherence. Conclusions: In this first prospective clinical trial studying combination antiretroviral re- treatment in women with a history of pregnancy-limited cART, the observed virologic response to TDF/FTC and EFV at 24 weeks was 81%. Virologic failures occurred and correlated with self-reported non-adherence