The rockefeller university

Nonmedical use of the prescription opioid oxycodone has become a major public health problem in the United States, with special concern for adolescents. Although adults and adolescents have different sensitivities for drugs, little is known about the rewarding effects of oxycodone in adolescents compared to adults, even in rodent models. Here, we investigate sensitivity to oxycodone by the conditioned place preference assay of conditioned reward, and effect on the locomotor activity in adolescent (4 weeks old) and adult (10 weeks old) C57BL/6J mice. Mice of both ages were trained with multiple doses of oxycodone (0, 0.3, 1, and 3 mg/kg) and showed conditioned preference in a dose-dependent manner. The adult mice developed conditioned preference to the lowest dose tested (0.3 mg/kg), but adolescent mice did not. Dose-dependent oxycodone-induced increases in locomotor activity were observed across the conditioning session. Interestingly, adolescent mice developed greater sensitization to the locomotor-activating effects of oxycodone than adult mice. Thus differences in sensitivity to oxycodone, such as the lower initial sensitivity for conditioned preference but greater locomotor sensitization in adolescent mice, may indicate contributing factors in oxycodone abuse and later addiction in human adolescents. (C) 2013 Elsevier Inc. All rights reserved.

Rationale: The antianginal ranolazine blocks the human ether-a-go-go-related gene-based current I-Kr at therapeutic concentrations and causes QT interval prolongation. Thus, ranolazine is contraindicated for patients with preexisting long-QT and those with repolarization abnormalities. However, with its preferential targeting of late I-Na (I-NaL), patients with disease resulting from increased I-NaL from inherited defects (eg, long-QT syndrome type 3 or disease-induced electric remodeling (eg, ischemic heart failure) might be exactly the ones to benefit most from the presumed antiarrhythmic properties of ranolazine. Objective: We developed a computational model to predict if therapeutic effects of pharmacological targeting of I-NaL by ranolazine prevailed over the off-target block of I-Kr in the setting of inherited long-QT syndrome type 3 and heart failure. Methods and Results: We developed computational models describing the kinetics and the interaction of ranolazine with cardiac Na+ channels in the setting of normal physiology, long-QT syndrome type 3-linked KPQ mutation, and heart failure. We then simulated clinically relevant concentrations of ranolazine and predicted the combined effects of Na+ channel and I-Kr blockade by both the parent compound ranolazine and its active metabolites, which have shown potent blocking effects in the therapeutically relevant range. Our simulations suggest that ranolazine is effective at normalizing arrhythmia triggers in bradycardia-dependent arrhythmias in long-QT syndrome type 3 as well tachyarrhythmogenic triggers arising from heart failure-induced remodeling. Conclusions: Our model predictions suggest that acute targeting of I-NaL with ranolazine may be an effective therapeutic strategy in diverse arrhythmia-provoking situations that arise from a common pathway of increased pathological I-NaL.

We summarize and combine direct measurements of the mass of the W boson in root s = 1.96 TeV proton-antiproton collision data collected by CDF and D0 experiments at the Fermilab Tevatron Collider. Earlier measurements from CDF and D0 are combined with the two latest, more precise measurements: a CDF measurement in the electron and muon channels using data corresponding to 2.2 fb(-1) of integrated luminosity, and a D0 measurement in the electron channel using data corresponding to 4.3 fb(-1) of integrated luminosity. The resulting Tevatron average for the mass of the W boson is M-W = 80387 +/- 16 MeV. Including measurements obtained in electron-positron collisions at LEP yields the most precise value of M-W = 80385 +/- 15 MeV.

Please cite this paper as: Liang K, Meyers K, Zeng W, Gui X. Predictors of elective pregnancy termination among women diagnosed with HIV during pregnancy in two regions of China, 2004-2010. BJOG 2013;120:1207-1214. Objective To document the rates of abortion among women diagnosed with HIV during pregnancy in two regions of China, and to investigate the sociodemographic factors associated with women's decisions to terminate their pregnancy. Design Prospective cohort study. Setting Three central Chinese provinces (Hubei, Hebei and Shanxi) and Yining, Xinjiang. Population Women diagnosed with HIV during pregnancy, 2004-2010. Methods Of 798 HIV-infected pregnant women identified through routine screening of pregnant women via antenatal care between 2004 and 2010, 499 women made decisions about the outcome of pregnancy. Chi-squared test was used to describe the characteristics of women who chose to terminate their pregnancies. Logistic regression models were used to identify potential predictors for pregnancy outcome for one cohort of women in central China and a second cohort of women in Yining, Xinjiang. Main outcome measures Pregnancy outcome, trends of elective pregnancy termination. Results In the central China cohort, 76 of 161 pregnancies (47.2%) were terminated. In Yining, the proportion was significantly less, at only 61 of 338 (18.0%). Factors associated with pregnancy termination included unmarried marital status, already having one or more children and earlier trimester of pregnancy at the time of diagnosis. Conclusions The rate of pregnancy termination in these cohorts of HIV-infected women appears to be higher than the rate in the general population of women in China. More work needs to be carried out to decrease the social stigma related to HIV and to convey clear messages about the effectiveness of prevention of mother to child transmission to women and their families. The significantly lower rate of pregnancy termination in Yining relative to central China is probably a result of the cultural and religious reservations towards pregnancy termination. Healthcare workers providing services to HIV-infected pregnant women need to be sensitive to cultural factors influencing women's decisions with regard to pregnancy termination.

Background Chronic mucocutaneous candidiasis disease (CMCD) may result from various inborn errors of interleukin (IL)-17-mediated immunity. Twelve of the 13 causal mutations described to date affect the coiled-coil domain (CCD) of STAT1. Several mutations, including R274W in particular, are recurrent, but the underlying mechanism is unclear. Objective To investigate and describe nine patients with CMCD in Eastern and Central Europe, to assess the biochemical impact of STAT1 mutations, to determine cytokines in supernatants of Candida-exposed blood cells, to determine IL-17-producing T cell subsets and to determine STAT1 haplotypes in a family with the c.820C>T (R274W) mutation. Results The novel c.537C>A (N179K) STAT1 mutation was gain-of-function (GOF) for -activated factor (GAF)-dependent cellular responses. In a Russian patient, the cause of CMCD was the newly identified c.854 A>G (Q285R) STAT1 mutation, which was also GOF for GAF-dependent responses. The c.1154C>T (T385M) mutation affecting the DNA-binding domain (DBD) resulted in a gain of STAT1 phosphorylation in a Ukrainian patient. Impaired Candida-induced IL-17A and IL-22 secretion by leucocytes and lower levels of intracellular IL-17 and IL-22 production by T cells were found in several patients. Haplotype studies indicated that the c.820C>T (R274W) mutation was recurrent due to a hotspot rather than a founder effect. Severe clinical phenotypes, including intracranial aneurysm, are presented. Conclusions The c.537C>A and c.854A>G mutations affecting the CCD and the c.1154C>T mutation affecting the DBD of STAT1 are GOF. The c.820C>T mutation of STAT1 in patients with CMCD is recurrent due to a hotspot. Patients carrying GOF mutations of STAT1 may develop multiple intracranial aneurysms by hitherto unknown mechanisms.

We combine searches by the CDF and D0 Collaborations for the standard model Higgs boson with mass in the range 90-200 GeV/c(2) produced in the gluon-gluon fusion, WH, ZH, t (t) over barH, and vector boson fusion processes, and decaying in the H -> b (b) over bar, H -> W+W-, H -> ZZ, H -> tau(+)tau(-), and H -> gamma gamma modes. The data correspond to integrated luminosities of up to 10 fb(-1) and were collected at the Fermilab Tevatron in p (p) over bar collisions at root s = 1.96 TeV. The searches are also interpreted in the context of fermiophobic and fourth generation models. We observe a significant excess of events in the mass range between 115 and 140 GeV/c(2). The local significance corresponds to 3.0 standard deviations at m(H) = 125 GeV/c(2), consistent with the mass of the Higgs boson observed at the LHC, and we expect a local significance of 1.9 standard deviations. We separately combine searches for H -> b (b) over bar, H -> W+W-, H -> tau(+)tau(-), and H -> gamma gamma. The observed signal strengths in all channels are consistent with the presence of a standard model Higgs boson with a mass of 125 GeV/c(2).

We describe two gene-knockout (KO) strategies in Twanosoma brucei using Cre recombinase and IoxP sites. Due to the limited number of selection markers for T. brucei, it has been difficult to generate a mutant with two genes knocked out and impractical to simultaneously knockout more than two genes, deterring detailed studies of important cellular mechanisms. The first KO strategy described can overcome the marker problem by allowing continuous re-use of drug-resistance markers. The same KO vector can be used to make a conditional KO system, when a gene of interest is essential for cell viability. As a gene of interest is removed from its original chromosomal locus by the induction of Cre recombinase, deletion is complete and instantaneous. This makes it easier to identify primary effects rather than having secondary effects obscuring phenotypic assessment, as is often the case with RNAi silencing. (C) 2013 Elsevier B.V. All rights reserved.

Purpose To describe diverse medical students' perceptions of and interest in careers in academic medicine. Method In 2010, the authors invited students attending three national medical student conferences to respond to a survey and participate in six focus groups. The authors identified trends in data through bivariate analyses of the quantitative dataset and using a grounded theory approach in their analysis of focus group transcripts. Results The 601 survey respondents represented 103U.S. medical schools. The majority (72%) were in their first or second year; 34% were black and 17% were Hispanic. Many respondents (64%) expressed interest in careers in academic medicine; teaching and research were viewed as positive influences on that interest. However, black and Hispanic respondents felt they would have a harder time succeeding in academia. The 73 focus group participants (25% black, 29% Hispanic) described individual- and institutional-level challenges to academic medicine careers and offered recommendations. They desired deliberate and coordinated exposure to academic career paths, research training, clarification of the promotion process, mentorship, protected time for faculty to provide teaching and research training, and an enhanced infrastructure to support diversity and inclusion. Conclusions Medical students expressed an early interest in academic medicine but lacked clarity about the career path. Black and Hispanic students' perceptions of having greater difficulty succeeding in academia may be an obstacle to engaging them in the prospective pool of academicians. Strategic and dedicated institutional resources are needed to encourage racial and ethnic minority medical students to explore careers in academic medicine.

HIV-1 blocks apoptosis, programmed cell death, an innate defense of cells against viral invasion. However, apoptosis can be selectively reactivated in HIV-infected cells by chemical agents that interfere with HIV-1 gene expression. We studied two globally used medicines, the topical antifungal ciclopirox and the iron chelator deferiprone, for their effect on apoptosis in HIV-infected H9 cells and in peripheral blood mononuclear cells infected with clinical HIV-1 isolates. Both medicines activated apoptosis preferentially in HIV-infected cells, suggesting that the drugs mediate escape from the viral suppression of defensive apoptosis. In infected H9 cells, ciclopirox and deferiprone enhanced mitochondrial membrane depolarization, initiating the intrinsic pathway of apoptosis to execution, as evidenced by caspase-3 activation, poly(ADP-ribose) polymerase proteolysis, DNA degradation, and apoptotic cell morphology. In isolate-infected peripheral blood mononuclear cells, ciclopirox collapsed HIV-1 production to the limit of viral protein and RNA detection. Despite prolonged monotherapy, ciclopirox did not elicit breakthrough. No viral re-emergence was observed even 12 weeks after drug cessation, suggesting elimination of the proviral reservoir. Tests in mice predictive for cytotoxicity to human epithelia did not detect tissue damage or activation of apoptosis at a ciclopirox concentration that exceeded by orders of magnitude the concentration causing death of infected cells. We infer that ciclopirox and deferiprone act via therapeutic reclamation of apoptotic proficiency (TRAP) in HIV-infected cells and trigger their preferential elimination. Perturbations in viral protein expression suggest that the antiretroviral activity of both drugs stems from their ability to inhibit hydroxylation of cellular proteins essential for apoptosis and for viral infection, exemplified by eIF5A. Our findings identify ciclopirox and deferiprone as prototypes of selectively cytocidal antivirals that eliminate viral infection by destroying infected cells. A drug-based drug discovery program, based on these compounds, is warranted to determine the potential of such agents in clinical trials of HIV-infected patients.