NFATc1 controls the cytotoxicity of CD8+ T cells

NFAT nuclear translocation has been shown to be required for CD8+ T cell cytokine production in response to viral infection. Here the authors show NFATc1 controls the cytotoxicity and metabolic switching of activated CD8+ T cells required for optimal response to bacteria and tumor cells

Risk of urethral stricture recurrence increases over time after urethroplasty

ObjectiveTo report a single institutional experience with urethroplasty outcomes and success rates at long-term follow up. MethodsA retrospective review was carried out of all urethroplasties performed by a single surgeon from 2000 to 2010. A total of 347 patients underwent urethroplasty during this time period, of which 227 had minimum 1-year follow-up data available. Demographic, clinical, pathological and outcome data were reviewed. Recurrence was defined by patient reported urinary symptoms or need for subsequent intervention. Statistical analyses were carried out using SPSS statistical software. ResultsA total of 26% of all patients had a recurrence at a mean follow up of 62months (range 13-147months). The recurrence rate after anastomotic urethroplasty was 18%, as compared with 31% after substitution urethroplasty. Mean time to recurrence was 34months (range 5-87). On univariate analysis, use of abdominal skin graft, history of prior urethroplasty, lichen sclerosus and length of follow up were statistically significant predictors of recurrence. On multivariate analysis, only history of prior urethroplasty and length of follow-up time exceeding 48months were statistically significant predictors of recurrence. ConclusionsUrethroplasty for urethral stricture is the most durable treatment modality, regardless of surgical approach. However, there is an ongoing risk of recurrence with the passage of time. Patients should be counseled appropriately on the potential for late recurrence of stricture disease after urethroplasty

Impact of rigid and nonrigid registration on the determination of 18F-FDG PET-based tumour volume and standardized uptake value in patients with lung cancer

Purpose: Assessment of the metabolically active tumour tissue by FDG PET is evolving for use in the diagnosis of non-small-cell lung cancer (NSCLC), in the planning of radiotherapy, and in follow-up and response evaluation. For exact evaluation accurate registration of PET and CT data is required. The registration process is usually based on rigid algorithms; however, nonrigid algorithms are increasingly being used. The influence of the registration method on FDG PET-based standardized uptake value (SUVmax) and metabolic tumour volume (MTV) definition has not yet been evaluated. We compared intra- and interindividual differences in SUV and MTV between rigid- and nonrigid-registered PET and CT acquired during different breathing manoeuvres. Methods: The study group comprised 28 radiotherapy candidates with histologically proven NSCLC who underwent FDG PET acquisition and three CT acquisitions (expiration - EXP, inspiration - INS, mid-breath-hold - MID). All scans were re gistered with both a rigid (R) and a nonrigid (NR) procedure resulting in six fused datasets: R-INS, R-EXP, R-MID, NR-INS, NR-EXP and NR-MID. For the delineation of MTVs a contrast-oriented contouring algorithm developed in-house was used. To accelerate the delineation a semiautomatic software prototype was utilized. Results: Tumour mean SUVmax did not differ for R and NR registration (R 17.5±7, NR 17.4±7; p=0.2). The mean MTV was higher by 3±12 ml (p=0.02) in the NR group than in the R group, as was the mean tumour diameter (by 0. 1±0.2 cm; p<0.01). With respect to the three different breathing manoeuvres, there were no differences in MTV in the R group (p>0.7). In intraindividual comparison there were no significant differences in MTVs concerning the registration pairs R-EXP (68± 88 ml) vs. NR-EXP (69±85 ml) und R-MID (68±86 ml) vs. NR-MID (69±83 ml) (both p>0.4). However, the MTVs were larger after NR registration during inspiration (R-INS 68±82 vs. NR-INS 78±93 ml; p=0.02). Conclusion: The use

The role of membrane rafts in Lck transport, regulation and signalling in T-cells

Tyrosine phosphorylation is one of the key covalent modifications that occur in multicellular organisms. Since its discovery more than 30 years ago, tyrosine phosphorylation has come to be understood as a fundamentally important mechanism of signal transduction and regulation in all eukaryotic cells. The tyrosine kinase Lck (lymphocyte-specific protein tyrosine kinase) plays a crucial role in the T-cell response by transducing early activation signals triggered by TCR (T-cell receptor) engagement. These signals result in the phosphorylation of immunoreceptor tyrosinebased activation motifs present within the cytosolic tails of the TCR-associated CD3 subunits that, once phosphorylated, serve as scaffolds for the assembly of a large supramolecular signalling complex responsible for T-cell activation. The existence of membrane nano- or micro-domains or rafts as specialized platforms for protein transport and cell signalling has been proposed. The present review discusses the signals that target Lck to membrane rafts and the importance of these specialized membranes in the transport of Lck to the plasma membrane, the regulation of Lck activity and the phosphorylation of the TCR. © 2013 Biochemical Society.Ministerio de Economía y Competitividad, Spain (grant numbers BFU2012-32532 and CONSOLIDER COAT CSD2009-00016)Peer Reviewe

Evaluation and management of recurrent urinary tract infections in children: state of the art

Urinary tract infections (UTIs) represent an important cause of febrile illness in young children and can lead to renal scarring and kidney failure. However, diagnosis and treatment of recurrent UTI in children is an area of some controversy. Guidelines from the American Academy of Pediatrics, National Institute for Health and Clinical Excellence and European Society of Paediatric Radiology differ from each other in terms of the diagnostic algorithm to be followed. Treatment of vesicoureteral reflux and antibiotic prophylaxis for prevention of recurrent UTI are also areas of considerable debate. In this review, we collate and appraise recently published literature in order to formulate evidence-based guidance for the diagnosis and treatment of recurrent UTI in children

Apixaban versus Enoxaparin for Thromboprophylaxis in Medically Ill Patients

BACKGROUND: The efficacy and safety of prolonging prophylaxis for venous thromboembolism in medically ill patients beyond hospital discharge remain uncertain. We hypothesized that extended prophylaxis with apixaban would be safe and more effective than short-term prophylaxis with enoxaparin. METHODS: In this double-blind, double-dummy, placebo-controlled trial, we randomly assigned acutely ill patients who had congestive heart failure or respiratory failure or other medical disorders and at least one additional risk factor for venous thromboembolism and who were hospitalized with an expected stay of at least 3 days to receive apixaban, administered orally at a dose of 2.5 mg twice daily for 30 days, or enoxaparin, administered subcutaneously at a dose of 40 mg once daily for 6 to 14 days. The primary efficacy outcome was the 30-day composite of death related to venous thromboembolism, pulmonary embolism, symptomatic deep-vein thrombosis, or asymptomatic proximal-leg deep-vein thrombosis, as detected with the use of systematic bilateral compression ultrasonography on day 30. The primary safety outcome was bleeding. All efficacy and safety outcomes were independently adjudicated. RESULTS: A total of 6528 subjects underwent randomization, 4495 of whom could be evaluated for the primary efficacy outcome--2211 in the apixaban group and 2284 in the enoxaparin group. Among the patients who could be evaluated, 2.71% in the apixaban group (60 patients) and 3.06% in the enoxaparin group (70 patients) met the criteria for the primary efficacy outcome (relative risk with apixaban, 0.87; 95% confidence interval [CI], 0.62 to 1.23; P=0.44). By day 30, major bleeding had occurred in 0.47% of the patients in the apixaban group (15 of 3184 patients) and in 0.19% of the patients in the enoxaparin group (6 of 3217 patients) (relative risk, 2.58; 95% CI, 1.02 to 7.24; P=0.04). CONCLUSIONS: In medically ill patients, an extended course of thromboprophylaxis with apixaban was not superior to a shorter course with enoxaparin. Apixaban was associated with significantly more major bleeding events than was enoxaparin. (Funded by Bristol-Myers Squibb and Pfizer; ClinicalTrials.gov number, NCT00457002.)