Interleukin-13 Receptor α1-Dependent Responses in the Intestine Are Critical to Parasite Clearance

Nematode infection upregulates interleukin-4 (IL-4) and IL-13 and induces STAT6-dependent changes in gut function that promote worm clearance. IL-4 and IL-13 activate the type 2 IL-4 receptor (IL-4R), which contains the IL-13Rα1 and IL-4Rα chains. We used mice deficient in IL-13Rα1 (IL-13Rα1^−/−) to examine the contribution of IL-13 acting at the type 2 IL-4R to immune and functional responses to primary (Hb1) and secondary (Hb2) infections with the gastrointestinal nematode parasite Heligmosomoides bakeri. There were differences between strains in the IL-4 and IL-13 expression responses to Hb1 but not Hb2 infection. Following Hb2 infection, deficient mice had impaired worm expulsion and higher worm fecundity despite normal production of Th2-derived cytokines. The upregulation of IL-25 and IL-13Rα2 in Hb1- and Hb2-infected wild-type (WT) mice was absent in IL-13Rα1^−/− mice. Goblet cell numbers and resistin-like molecule beta (RELM-β) expression were attenuated significantly in IL-13Rα1^−/− mice following Hb2 infections. IL-13Rα1 contributes to the development of alternatively activated macrophages, but the type 1 IL-4R is also important. Hb1 infection had no effects on smooth muscle function or epithelial permeability in either strain, while the enhanced mucosal permeability and changes in smooth muscle function and morphology observed in response to Hb2 infection in WT mice were absent in IL-13Rα1^−/− mice. Notably, the contribution of claudin-2, which has been linked to IL-13, does not mediate the increased mucosal permeability following Hb2 infection. These results show that activation of IL-13Rα1 is critical for key aspects of the immune and functional responses to Hb2 infection that facilitate expulsion.     

Role of bevacizumab for the treatment of non-small-cell lung cancer

Advanced-stage non-small-cell lung cancer (NSCLC) is a lethal disease that is treated with combination chemotherapy. Although modest survival benefit has been documented with various platinum-based, two-drug combination chemotherapy regimens, an efficacy plateau has been reached. Bevacizumab, a monoclonal antibody against the vascular endothelial growth factor, is the first molecularly targeted agent that has demonstrated survival advantage when combined with chemotherapy for the treatment of advanced nonsquamous NSCLC. Improvements in all efficacy parameters, including response rate, progression-free survival and overall survival, were noted for advanced nonsquamous NSCLC patients when bevacizumab was added to the combination of carboplatin-paclitaxel compared with the same chemotherapy regimen alone. This has opened the door for expanding the role of bevacizumab in earlier stages of the disease with chemotherapy or radiotherapy. The anti-angiogenesis agents, including the monoclonal antibody and vascular endothelial growth factor tyrosine kinase inhibitors, will be among the most important drugs of the present decade. This article discusses the recent data with bevacizumab in NSCLC and its potential application at various stages of NSCLC.     

Pontine control of rapid eye movement sleep and fear memory

Aims

We often experience dreams of strong irrational and negative emotional contents with postural muscle paralysis during rapid eye movement (REM) sleep, but how REM sleep is generated and its function remain unclear. In this study, we investigate whether the dorsal pontine sub-laterodorsal tegmental nucleus (SLD) is necessary and sufficient for REM sleep and whether REM sleep elimination alters fear memory.

Methods

To investigate whether activation of SLD neurons is sufficient for REM sleep induction, we expressed channelrhodopsin-2 (ChR2) in SLD neurons by bilaterally injecting AAV1-hSyn-ChR2-YFP in rats. We next selectively ablated either glutamatergic or GABAergic neurons from the SLD in mice in order to identify the neuronal subset crucial for REM sleep. We finally  investigated the role of REM sleep in consolidation of fear memory using rat model with complete SLD lesions.

Results

We demonstrate the sufficiency of the SLD for REM sleep by showing that photo-activation of ChR2 transfected SLD neurons selectively promotes transitions from non-REM (NREM) sleep to REM sleep in rats. Diphtheria toxin-A (DTA) induced lesions of the SLD in rats or specific deletion of SLD glutamatergic neurons but not GABAergic neurons in mice completely abolish REM sleep, demonstrating the necessity of SLD glutamatergic neurons for REM sleep. We then show that REM sleep elimination by SLD lesions in rats significantly enhances contextual and cued fear memory consolidation by 2.5 and 1.0 folds, respectively, for at least 9 months. Conversely, fear conditioning and fear memory trigger doubled amounts of REM sleep in the following night, and chemo-activation of SLD neurons projecting to the medial septum (MS) selectively enhances hippocampal theta activity in REM sleep; this stimulation immediately after fear acquisition reduces contextual and cued fear memory consolidation by 60% and 30%, respectively.

Conclusion

SLD glutamatergic neurons generate REM sleep and REM sleep and SLD via the hippocampus particularly down-regulate contextual fear memory.     

Pre- and Post-Clerkship Knowledge,Perceptions, and Acceptability of Electroconvulsive Therapy (ECT) in 3rd Year Medical Students

To examine the impact of the third year psychiatry clerkship on medical students’ knowledge and opinion of ECT at University of Missouri-Columbia School of Medicine. Despite overwhelming evidence of ECT’s efficacy and safety for refractory affective illnesses, (among other conditions), it remains a misunderstood and underutilized intervention. Several studies indicate that ECT stigma and misinformation, unfortunately, does not spare the medical community. Medical students are an optimal group to study, as they are forming their perspectives on different specialties. Few studies have measured the effect of education programs (e.g., clerkships, lectures, observation of ECT) on medical students’ perspectives on ECT.     

Basal ganglia control of sleep–wake behavior and cortical activation

The basal ganglia (BG) are involved in numerous neurobiological processes that operate on the basis of wakefulness, including motor function, learning, emotion and addictive behaviors. We hypothesized that the BG might play an important role in the regulation of wakefulness. To test this prediction, we made cell body‐specific lesions in the striatum and globus pallidus (GP) using ibotenic acid. We found that rats with striatal (caudoputamen) lesions exhibited a 14.95% reduction in wakefulness and robust fragmentation of sleep–wake behavior, i.e. an increased number of state transitions and loss of ultra‐long wake bouts (> 120 min). These lesions also resulted in a reduction in the diurnal variation of sleep–wakefulness. On the other hand, lesions of the accumbens core resulted in a 26.72% increase in wakefulness and a reduction in non‐rapid eye movement (NREM) sleep bout duration. In addition, rats with accumbens core lesions exhibited excessive digging and scratching. GP lesions also produced a robust increase in wakefulness (45.52%), and frequent sleep–wake transitions and a concomitant decrease in NREM sleep bout duration. Lesions of the subthalamic nucleus or the substantia nigra reticular nucleus produced only minor changes in the amount of sleep–wakefulness and did not alter sleep architecture. Finally, power spectral analysis revealed that lesions of the striatum, accumbens and GP slowed down the cortical electroencephalogram. Collectively, our results suggest that the BG, via a cortico‐striato‐pallidal loop, are important neural circuitry regulating sleep–wake behaviors and cortical activation.