Suppression of proximal T cell receptor signaling and lytic function in CD8+ tumor-infiltrating T cells

CD8(+) tumor-infiltrating lymphocytes (TIL) lack in vivo and in vitro lytic function due to a signaling deficit characterized by failure to flux calcium or activate tyrosine kinase activity upon contact with cognate tumor cells. Although CD3 zeta is phosphorylated by conjugation in vitro with cognate tumor cells, showing that TIL are triggered, PLC gamma-1, LAT, and ZAP70 are not activated and LFA-1 is not affinity-matured, and because p56(lck) is required for LFA-1 activation, this implies that the signaling blockade is very proximal. Here, we show that TIL signaling defects are transient, being reversed upon purification and brief culture in vitro, implying a fast-acting "switch". Biochemical analysis of purified nonlytic TIL shows that contact with tumor cells causes transient activation of p56(lck) ( approximately 10 s) which is rapidly inactivated. In contrast, tumor-induced activation of p56(lck) in lytic TIL is sustained coincident with downstream TCR signaling and lytic function. Shp-1 is robustly active in nonlytic TIL compared with lytic TIL, colocalizes with p56(lck) in nonlytic TIL, and inhibition of Shp-1 activity in lytic TIL in vitro blocks tumor-induced defective TIL cytolysis. Collectively, our data support the notion that contact of nonlytic TIL with tumor cells, and not with tumor-infiltrating myeloid-derived suppressor cells, causes activation of Shp-1 that rapidly dephosphorylates the p56(lck) activation motif (Y394), thus inhibiting effector phase functions.     

Smith-Lemli-Opitz syndrome: Biochemical before clinical diagnosis; early dietary management

Pursuit of a possible metabolic basis for an unrecognized pattern of multiple congenital anomalies in a newborn girl led to the detection of a huge elevation of plasma 7-dehy-drocholesterol at age 8 months. The biochemical findings and the evolving clinical picture led to the diagnosis of Smith-Lemli-Opitz syndrome at age 11 months. High cholesterol diet may have improved the rate of developmental progress. © 1994 Wiley-Liss, Inc.     

Evaluation of Pharmacokinetic Interaction between PA-824 and Midazolam in Healthy Adult Subjects

This study assessed the safety, tolerability, and pharmacokinetic interaction between PA-824, a novel antitubercular nitroimidazo-oxazine, and midazolam, a CYP3A4 substrate, in 14 healthy adult male and female subjects. The study followed up on observations in vitro that PA-824 caused weak and time-dependent inhibition of CYP3A4. Subjects received a single oral dose of midazolam (2 mg), followed by a 2-day washout. After the washout, all subjects received PA-824 (400 mg) once daily for 14 consecutive days. On day 14, all subjects received the final PA-824 dose coadministered with a 2-mg oral dose of midazolam. The pharmacokinetic endpoints AUC_0–t, AUC_0–∞, and C_max for midazolam and 1-hydroxy midazolam were compared between midazolam administered alone versus midazolam coadministered with PA-824. Statistical analysis demonstrated that the mean midazolam values of C_max, AUC_0–t, and AUC_0–∞ parameters were reduced by ca. 16, 15, and 15%, respectively, when PA-824 was coadministered with midazolam. The total exposure (AUC) of 1-hydroxy midazolam was 13 to 14% greater when coadministered with PA-824 compared to midazolam administered alone. The C_max of 1-hydroxy midazolam was similar between treatments. Based on these results, PA-824 does not inhibit or induce CYP3A4 to a clinically meaningful extent and is not likely to markedly affect the pharmacokinetics of CYP3A4 metabolized drugs.     

“We’ve Got Our Own Beliefs,Attitudes, Myths”: A Mixed Methods Assessment of Rural South African Health Care Workers' Knowledge of and Attitudes Towards PrEP Implementation

AIDS and Behavior - South Africa maintains the world’s largest HIV prevalence, accounting for 20.4% of people living with HIV internationally. HIV Pre-exposure prophylaxis (PrEP) has...     

Blond hair removal using ELOS systems.

OBJECTIVE: The aim of this study was to test blond hair removal using the ELOS system, which is optical energy and radio-frequency combined. METHODS: Seventeen patients with blond hair were randomly selected from the Department of Lasertherapy, Medical Centre Maastricht, The Netherlands. The mean age of the patients was 57.4 years. The mean energy used per patient was 23.2 J/cm2 and the mean radio-frequency was 18.6 J/cm2. RESULTS: A mean hair reduction of 57.4% was obtained with a mean of 8.5 treatments. There was a trend found between hair removal and the number of treatments. No correlation was found between the percentage of hair removal and age. Furthermore, there was no correlation between hair removal and the device's technical data. No major side effects were observed postoperatively. CONCLUSIONS: This study showed that ELOS can effectively be used for blond hair reduction.     

Emergency peripartum hysterectomy in a tertiary London hospital

Objective The objective was to review all emergency peripartum hysterectomies performed at a tertiary hospital in London, UK, and to identify the risk factors for emergency peripartum hysterectomy.Method A retrospective case control study. The cases consisted of all women who had emergency peripartum hysterectomy between 1 January 1993 and 31 December 2003. Controls were women who delivered immediately before and after the indexed case. Demographic data, medical and surgical histories, pregnancy, intrapartum and postpartum data were collected. Differences between cases and controls were compared with ², Fisher exact and Student t tests. Multiple logistic regression analysis was performed to identify independent risk factors for emergency peripartum hysterectomy.Results There were 15 cases of emergency peripartum hysterectomy in 31,079 deliveries, giving a rate of 0.48 per 1,000. Women who had emergency peripartum hysterectomy were significantly older (mean age 37 years vs. 29 years, P<0.001) and multiparous (P=0.02). More of the cases had a history of uterine surgery (67 vs. 30%, P=0.01), placenta praevia (60 vs. 3%, P<0.0001) and were delivered by caesarean section (86.7 vs. 30%, P=0.003). Eighty percent of the hysterectomies were performed in the daytime and all were done by consultants. Haemorrhage due to placenta praevia was the main indication for emergency peripartum hysterectomy (47%). Independent risk factors for emergency peripartum hysterectomy were older age (odds ratios [OR] 1.2, 95% confidence interval [95% CI] 1.2–1.6), multiparity (OR 2.6, 95% CI 1.3–10.2), history of previous caesarean section (OR 13.5, 95% CI 2.7–65.4), caesarean delivery in index pregnancy (OR 11.6, 95% CI 2.1–68.6) and caesarean delivery in index pregnancy for placenta praevia (OR 18, 95% CI 3.6–69).Conclusion Caesarean deliveries, especially repeat caesareans in women with placenta praevia, significantly increase the risk of emergency peripartum hysterectomy.     

Development of a Population Pharmacokinetic Model for Taranabant, a Cannibinoid-1 Receptor Inverse Agonist

Taranabant is a cannabinoid-1 receptor inverse agonist developed for the treatment of obesity. A population model was constructed to facilitate the estimation of pharmacokinetic parameters and to identify the influence of selected covariates. Data from 12 phase 1 studies and one phase 2 study were pooled from subjects administered single and multiple oral doses of taranabant ranging from 0.5 to 8 mg. A total of 6,834 taranabant plasma concentrations from 187 healthy and 385 obese subjects were used to develop the population model in NONMEM. A standard covariate analysis using forward selection (α = 0.05) and backward elimination (α = 0.001) was conducted. A three-compartment model with first-order absorption and elimination adequately described plasma taranabant concentrations. The population mean estimates for apparent clearance and apparent steady-state volume of distribution were 25.4 L/h and 2,578 L, respectively. Statistically significant covariate effects were modest in magnitude and not considered clinically relevant (the effects of body mass index (BMI) and creatinine clearance (CrCL) on apparent clearance; BMI, age, CrCL, and gender on apparent volume of the peripheral compartment and age on apparent intercompartmental clearance). The pharmacokinetic profile of taranabant can adequately be described by a three-compartment model with first-order absorption and elimination. Clinical dose adjustment based on covariates effects is not warranted.Key words: NONMEM, obesity, pharmacokinetics, population, taranabant