ATM-dependent DNA damage surveillance in T-cell development and leukemogenesis: the DSB connection

Summary:  The immune system is capable of recognizing and eliminating an enormous array of pathogens due to the extremely diverse antigen receptor repertoire of T and B lymphocytes. However, the development of lymphocytes bearing receptors with unique specificities requires the generation of programmed double strand breaks (DSBs) coupled with bursts of proliferation, rendering lymphocytes susceptible to mutations contributing to oncogenic transformation. Consequently, mechanisms responsible for monitoring global genomic integrity must be activated during lymphocyte development to limit the oncogenic potential of antigen receptor locus recombination. Mutations in ATM (ataxia-telangiectasia mutated), a kinase that coordinates DSB monitoring and the response to DNA damage, result in impaired T-cell development and predispose to T-cell leukemia. Here, we review recent evidence providing insight into the mechanisms by which ATM promotes normal lymphocyte development and protects from neoplastic transformation.     

The Impact of Community Diversity and Consolidated Inequality on Dropping Out of High School

Abstract: Data from the National Education Longitudinal Study were combined with census data at the zip code level to examine the impact of neighborhood racial and ethnic diversity and consolidated inequality, in addition to individual, family, and school factors, on the likelihood of dropping out of high school. Results indicate that while the effects for diversity and consolidated inequality did not support the stated hypotheses, main effects for family risk and prior academic achievement were significant and in the stated direction. Also, when controlling for individual, family, school, and neighborhood characteristics, African Americans were less likely than White students to drop out of school. Implications for contextual effects research and educational outcomes are discussed.     

Pharmacokinetics of Moxifloxacin in Rabbits After Intravenous,Subcutaneous and a Long‐acting Poloxamer 407 Gel Formulation Administration

The pharmacokinetics (PK) of moxifloxacin in healthy white New Zealand rabbits was studied following intravenous (IV) and subcutaneous (SC) administration routes as well as a SC long‐acting poloxamer 407 gel formulation (SC‐P407). Moxifloxacin concentrations were determined by high‐performance liquid chromatography assay with fluorescence detection. Mean half‐life for IV, SC and SC‐P407 routes was 2.15, 5.41 and 11.09 h. Clearance value after IV dosing was 0.78 l/kg/h. After SC administration, the mean absolute bioavailability was 117% and the C_max was 1.61 ± 0.49 mg/l. After SC‐P407 administration, the bioavailability was 44% and the C_max 1.83 was ±0.62 mg/l. No adverse effects were observed in any of the rabbits following IV, SC and SC‐P407 administration of moxifloxacin. Minimal inhibitory concentrations of moxifloxacin against different strains of Staphylococcus aureus from different european countries were used to compute the main pharmacodynamic (PD) surrogate markers of efficacy. The high tolerability of this SC‐P407 formulation and the favourable PK behaviour such as the long half‐life, acceptable bioavailability and excellent PK–PD ratios achieved indicate that it is likely to be effective in rabbits.     

Diabetes mellitus is strongly associated with tuberculosis in Indonesia.

SETTING: Diabetes mellitus is a known risk factor for tuberculosis (TB), but no studies have been reported from South-East Asia, which has a high burden of TB and a rapidly growing prevalence of diabetes. OBJECTIVE: To examine if and to what extent diabetes is associated with an increased risk of TB in an urban setting in Indonesia. DESIGN: Case-control study comparing the prevalence of diabetes mellitus (fasting blood glucose level >126 mg/dl) among newly diagnosed pulmonary TB patients and matched neighbourhood controls. RESULTS: Patients and control subjects had a similar age (median 30 years) and sex distribution (52% male), but malnutrition was more common among TB patients (median body mass index 17.7 vs. 21.5 kg/m2). HIV infection was uncommon (1.5% of patients). Diabetes mellitus was present in 60 of 454 TB patients (13.2%) and 18 of 556 (3.2%) control subjects (OR 4.7; 95%CI 2.7-8.1). Adjustment for possible confounding factors did not reduce the risk estimates. Following anti-tuberculosis treatment, hyperglycaemia reverted in a minority (3.7%) of TB patients. CONCLUSION: Diabetes mellitus is strongly associated with TB in young and non-obese subjects in an urban setting in Indonesia. This may have implications for TB control and patient care in this region.