Imatinib mesylate selectively impairs expansion of memory cytotoxic T cells without affecting the control of primary viral infections

Imatinib mesylate (imatinib) is a potent inhibitor of defined tyrosine kinases (TKs) and is effective in the treatment of malignancies characterized by constitutive activation of these TKs such as chronic myeloid leukemia and gastrointestinal stromal tumors. TKs also play an important role in T-cell receptor (TCR) signal transduction. Inhibitory as well as stimulating effects of imatinib on T cells and dendritic cells have been described. Here, we analyzed the effects of imatinib treatment on antiviral immune responses in vivo. Primary cytotoxic T-cell (CTL) responses were not impaired in imatinib-treated mice after infection with lymphocytic choriomeningitis virus (LCMV) or after immunization with a tumor cell line expressing LCMV glycoprotein (LCMV-GP). Similarly, neutralizing antibody responses to vesicular stomatitis virus (VSV) were not affected. In contrast, secondary expansion of LCMV-specific memory CTLs was reduced in vitro and in vivo, resulting in impaired protection against reinfection. In addition, imatinib treatment delayed the onset of diabetes in a CTL-induced diabetes model. In summary, imatinib treatment in vivo selectively inhibits the expansion of antigen-experienced memory CTLs without affecting primary T- or B-cell responses. Therefore, imatinib may be efficacious in the suppression of CTL-mediated immunopathology in autoimmune diseases without the risk of acquiring viral infections.

Policy of routine titanium miniplate removal after maxillofacial trauma

PURPOSE: The literature shows that hardware removal rates after the fixation of maxillofacial fractures with miniplates are not insignificant. The aim of the present survey was to clarify the policies of Finnish oral and maxillofacial consultants for the removal of titanium miniplates after the treatment of facial fractures in adults. Additional aims were to clarify the factors influencing plate removal policy in general, and the reasons for routine plate removal in particular. MATERIALS AND METHODS: Twenty-six consultant oral and maxillofacial surgeons responded to a questionnaire about miniplate removal policy after treating 5 types of simple, noncomminuted fractures. RESULTS: Overall, routine plate removal was uncommon. However, 12 consultants (46.2%) routinely removed the plate after treating mandibular angle fractures, and simultaneously extracted the third molar because of an increased risk of infection. Most respondents (88.5%) stated that clinical experience guided their plate-removal policy. A policy of routine plate removal was most infrequent among the consultants who had the most experience. CONCLUSIONS: The literature provides no definitive answer to the question of whether routine removal of miniplates could or should be indicated, and in what situations. Considering the fairly significant frequency of plate-related complications in general and infection-related complications in particular, long-term follow-up after treatment is indicated.

Double-pulse transcranial magnetic stimulation over the frontal eye field facilitates triggering of memory-guided saccades.

The study investigated the influence of double-pulse transcranial magnetic stimulation (dTMS) on memory-guided saccade triggering. Double pulses with interstimulus intervals (ISIs) of 35, 50, 65 or 80 ms were applied over the right frontal eye field (FEF) and as control over the occipital cortex. A significant dTMS effect was found exclusively for contralateral saccades; latency of memory-guided saccades was reduced after FEF stimulation with an ISI of 50 ms compared to latency without stimulation. This effect proved to be specific for the ISI of 50 ms over the FEF because control stimulation with the same ISI over the occipital cortex had no significant effect on latency of memory-guided saccades. The results of our study showed that, by using an appropriate ISI, dTMS is able to facilitate contralateral saccade triggering by stimulating the FEF. This suggests that TMS interferes specifically with saccade triggering mechanisms, probably by acting on presaccadic neurons of the FEF.

Interlinked dual-time feedback loops can enhance robustness to stochasticity and persistence of memory.

Multiple interlinked positive feedback loops shape the stimulus responses of various biochemical systems, such as the cell cycle or intracellular Ca2+ release. Recent studies with simplified models have identified two advantages of coupling fast and slow feedback loops. This dual-time structure enables a fast response while enhancing resistances of responses and bistability to stimulus noise. We now find that (1) the dual-time structure similarly confers resistance to internal noise due to molecule number fluctuations, and (2) model variants with altered coupling, which better represent some specific biochemical systems, share all the above advantages. We also develop a similar bistable model with coupling of a fast autoactivation loop to a slow loop. This model's topology was suggested by positive feedback proposed to play a role in long-term synaptic potentiation (LTP). The advantages of fast response and noise resistance are also present in this autoactivation model. Empirically, LTP develops resistance to reversal over approximately 1h . The model suggests this resistance may result from increased amounts of synaptic kinases involved in positive feedback.

A model of late long-term potentiation simulates aspects of memory maintenance.

Late long-term potentiation (L-LTP) denotes long-lasting strengthening of synapses between neurons. L-LTP appears essential for the formation of long-term memory, with memories at least partly encoded by patterns of strengthened synapses. How memories are preserved for months or years, despite molecular turnover, is not well understood. Ongoing recurrent neuronal activity, during memory recall or during sleep, has been hypothesized to preferentially potentiate strong synapses, preserving memories. This hypothesis has not been evaluated in the context of a mathematical model representing ongoing activity and biochemical pathways important for L-LTP. In this study, ongoing activity was incorporated into two such models - a reduced model that represents some of the essential biochemical processes, and a more detailed published model. The reduced model represents synaptic tagging and gene induction simply and intuitively, and the detailed model adds activation of essential kinases by Ca(2+). Ongoing activity was modeled as continual brief elevations of Ca(2+). In each model, two stable states of synaptic strength/weight resulted. Positive feedback between synaptic weight and the amplitude of ongoing Ca(2+) transients underlies this bistability. A tetanic or theta-burst stimulus switches a model synapse from a low basal weight to a high weight that is stabilized by ongoing activity. Bistability was robust to parameter variations in both models. Simulations illustrated that prolonged periods of decreased activity reset synaptic strengths to low values, suggesting a plausible forgetting mechanism. However, episodic activity with shorter inactive intervals maintained strong synapses. Both models support experimental predictions. Tests of these predictions are expected to further understanding of how neuronal activity is coupled to maintenance of synaptic strength. Further investigations that examine the dynamics of activity and synaptic maintenance can be expected to help in understanding how memories are preserved for up to a lifetime in animals including humans.

Introduction of a New Policy of no Nighttime Appendectomies: Impact on Appendiceal Perforation Rates and Postoperative Morbidity

Background Working hour limitations and tight health care budgets have posed significant challenges to emergency surgical services. Since 1 January 2010, surgical interventions at Berne University Hospital between 23:00 and 08:00 h have been restricted to patients with an expected serious adverse outcome if not operated on within 6 h. This study was designed to assess the safety of this new policy that restricts nighttime appendectomies (AEs). Methods The patients that underwent AE from 1 January 2010 to 31 December 2011 (“2010-2011 group”) were compared retrospectively with patients that underwent AE before introduction of the new policy (1 January 2006–31 December 2009; “2006-2009 group”). Results Overall, 390 patients were analyzed. There were 255 patients in the 2006–2009 group and 135 patients in the 2010–2011 group. Patients’ demographics did not differ statistically between the two study groups; however, 45.9 % of the 2006–2009 group and 18.5 % of the 2010–2011 group were operated between 23:00 and 08:00 h (p < 0.001). The rates of appendiceal perforations and surgical site infections did not differ statistically between the 2006–2009 group and the 2010–2011 group (20 vs. 18.5 %, p = 0.725 and 2 vs. 0 %, p = 0.102). Additionally, no difference was found for the hospital length of stay (3.9 ± 7.4 vs. 3.4 ± 6.0 days, p = 0.586). However, the proportion of patients with an in-hospital delay of >12 h was significantly greater in the 2010–2011 group than in the 2006–2009 group [55.6 vs. 43.5 %, p = 0.024, odds ratio (95 % confidence interval 1.62 (1.1–2.47)]. Conclusions Restricting AEs from 23:00 to 08:00 h does not increase the perforation rates and occurrence of clinical outcomes. Therefore, these results suggest that appendicitis may be managed safely in a semielective manner.

Trade versus Culture : The Policy of Cultural Exception and the World Trade Organization

This chapter is a contribution to the Palgrave Handbook of European Media Policy (co-edited by Pauwels, Donders & Loisen). It is the chapter’s purpose to examine the proponents of the cultural exception policy, their strategies and demands, and to explore how they came to be reflected in the law and policy of the World Trade Organization (WTO). The chapter also looks at the current state of affairs, as although WTO law has not undergone any substantial amendments since its entry into force in 1995, the media landscape has in the meantime been truly transformed, in some aspects in a revolutionary manner. The broader picture of global governance has not remained still either, with new and emergent powers, changing mechanisms of rule-making and taking.