After infection with Borrelia species, the risk for developing Lyme disease varies significantly between individuals. Recognition of Borrelia by the immune system is mediated by pattern recognition receptors (PRRs), such as TLRs. While TLR2 is the main recognition receptor for Borrelia spp., little is known about the role of TLR1 and TLR6, which both can form functionally active heterodimers with TLR2. Here we investigated the recognition of Borrelia by both murine and human TLR1 and TLR6. Peritoneal macrophages from TLR1- and TLR6- gene deficient mice were isolated and exposed to Borrelia. Human PBMCs were stimulated with Borrelia with or without specific TLR1 and TLR6 blocking using specific antibodies. Finally, the functional consequences of TLR polymorphisms on Borrelia-induced cytokine production were assessed. Splenocytes isolated from both TLR1−/− and TLR6−/− mice displayed a distorted Th1/Th2 cytokine balance after stimulation with B.burgdorferi, while no differences in pro-inflammatory cytokine production were observed. In contrast, blockade of TLR1 with specific neutralizing antibodies led to decreased cytokine production by human PBMCs after exposure to B.burgdorferi. Blockade of human TLR6 did not lead to suppression of cytokine production. When PBMCs from healthy individuals bearing polymorphisms in TLR1 were exposed to B.burgdorferi, a remarkably decreased in vitro cytokine production was observed in comparison to wild-type controls. TLR6 polymorphisms lead to a minor modified cytokine production. This study indicates a dominant role for TLR1/TLR2 heterodimers in the induction of the early inflammatory response by Borrelia spirochetes in humans.

Most women who received a single 200-mg nevirapine dose still had detectable plasma concentrations of nevirapine after more than 2 weeks. This information is valuable for designing intervention studies to prevent the development of nevirapine resistance.

The product Teysuno™ (S-1) contains tegafur, a prodrug of 5-fluorouracil (5-FU), and two modulators of 5-FU metabolism, gimeracil and oteracil.The main clinical study in this application was a randomized controlled study comparing S-1 plus cisplatin with 5-FU plus cisplatin. In this study, median overall survival times of 8.6 months and 7.9 months for S-1 plus cisplatin and 5-FU plus cisplatin, respectively, were observed (hazard ratio, 0.92; 95% confidence interval, 0.80 -1.05). The Committee for Medicinal Products for Human Use of the European Medicines Agency concluded that S-1 in combination with cisplatin (75 mg/ m 2 ) was noninferior to 5-FU plus cisplatin (100 mg/m 2 ) in patients with advanced gastric cancer and adopted a positive opinion recommending the marketing authorization for this product for the treatment of advanced gastric cancer when given in combination with cisplatin. The recommended dose of S-1 is 25 mg/m 2 (expressed as tegafur content) twice a day, for 21 consecutive days followed by 7 days rest (one treatment cycle), in combination with 75 mg/m 2 cisplatin i.v. administered on day 1. This treatment cycle is repeated every 4 weeks.The most common side effects reported in the pivotal study were anemia, neutropenia, vomiting, diarrhea, abdominal pain, weight decrease, anorexia, and fatigue.The objective of this paper is to summarize the scientific review of the application leading to approval in the EU. The full scientific assessment report and the summary of product characteristics are available on the European Medicines Agency website (http://www.ema. europa.eu).

Interleukin-23 (IL-23

Objectives To investigate adherence to antiretroviral therapy over 48 weeks, to investigate the association between adherence and treatment-related symptoms and to investigate the impact of adherence on virological response over 48 weeks among established predictors of treatment success. Methods One-hundred-and-sixty HIV-1 infected protease inhibitor- and stavudine-naive patients participating in a trial of ritonavir/saquinavir versus ritonavir/saquinavir/ stavudine completed an adherence questionnaire and a symptom checklist at weeks 12, 24, 36 and 48. We calculated odds ratios between experienced symptoms and non-adherence. Regression models were used to determine predictors of HIV-1 RNA below 400 copies/ml at week 48, and of the area about the change from baseline over 48 weeks (ACFB) in serum HIV-1 RNA. Results The percentage of patients reporting missing medication, deviation from time schedule, and dietary prescriptions at separate time-points ranged from 12 to 15%, 32 to 35% and 17 to 22%, respectively. The percentage that changed their level of adherence during 48 weeks ranged from 29% for skipping medication to 48% for deviation from time-schedule. Experienced side-effects were associated with an increased likelihood of non-adherence. Not skipping medication was an independent predictor of both having a serum HIV-1 RNA below 400 copies/ml at week 48 and the ACFB over 48 weeks in serum HIV-1 RNA. Conclusions Adherence was an independent predictor of virological response over 48 weeks. The level of adherence is variable within patients over time. This suggests the need for continued adherence monitoring in all patients as part of standard medical practice.