Sensing the invisible: differential sensitivity of visual cortex and amygdala to traumatic context

To what extent does emotional traumatic context affect sensory processing in the brain? A striking example of emotional impact on sensation is manifested in posttraumatic stress disorder (PTSD), in which a severe emotional trauma produces recurrent and vivid unpleasant sensory recollections. Here we report on an fMRI study exploring the sensory processing of trauma-related pictures in the visual cortex and amygdala in respect to PTSD. The impact of traumatic experience on brain responses was tested in relation to stimuli content and its level of recognition in a parametric factorial design. Twenty combat veterans, 10 with and 10 without PTSD, viewed backward-masked images of combat and noncombat content, presented at below, near, and above recognition thresholds. The response to combat content evoked more activation in the visual cortex in PTSD subjects than in non-PTSD subjects, only when images were presented at below recognition threshold. By contrast, the amygdala demonstrated increased activation in PTSD subjects irrespective of content and recognition threshold of the images. These intriguing findings are compatible with the notion that in PTSD, emotional traumatic experience could modify visual processing already at the preattentive level. On the other hand, lack of content specificity in the amygdala point to a possible predisposed mechanism for pathological processing of traumatic experience. The differential sensitivity of the amygdala and visual cortex to traumatic context implies distinct roles of limbic and sensory regions in the registration and recollection of emotional experience in the brain.     

Chronotherapy using corticosteroids for multiple sclerosis relapses

Background

The activity of the immune system displays a circadian rhythm. In diseases characterised by aberrant immune activity, chronotherapy (a treatment regimen tailored to diurnal body rhythms) may increase the efficiency, safety and tolerability of drugs.

Aim

To compare the outcomes of intravenous corticosteroid administration during the day or night, for treatment of acute multiple sclerosis relapses.

Methods

17 patients with multiple sclerosis were included in the study. Clinical assessment of disability was performed at trial entry, and at days 7 and 30 from the initiation of treatment. Adverse events and preference of night‐time versus daytime treatment were assessed at the end of the treatment course.

Results

After night‐time treatment, clinical recovery was significantly (p<0.001) enhanced and the mean number of side effects was significantly (p = 0.007) lower. Furthermore, most patients expressed a preference for night‐time versus daytime treatment.

Conclusions

The study suggests a potential benefit for implementation of chronotherapy using steroid treatment for acute multiple sclerosis relapse, with implications for other immune‐mediated disorders.Diurnal rhythm is a characteristic of the immune system, displaying periodicity in the activity of both its humoral and cellular arms. Among the recognised humoral mediators that exhibit a circadian pattern is cortisol, a key circulating glucocorticoid with potent endogenous immunosuppressant activity, which imposes diurnal variation on a broad spectrum of immune functions.¹ Accordingly, periods of enhanced immune reactivity coincide with or follow the early morning nadir in plasma cortisol. For example, the interferon (IFN)γ:interleukin (IL) 10 (proinflammatory:anti‐inflammatory cytokines) ratio peaks during the early morning and correlates negatively with plasma cortisol levels.² At the cellular level, diurnal rhythms are also seen in natural killer cell activity, the CD4:CD8 ratio and the absolute number of circulating T cells.³Recognition of the importance of diurnal patterns has led to the development of the innovative area of chronotherapy, the application of chronobiological principles to therapeutics. Recently, this strategy of chronotherapy has been successfully implemented in therapeutics of asthma, cancer, gastrointestinal and cardiovascular diseases.^4,5Multiple sclerosis, a chronic inflammatory disease of the central nervous system, is associated with seasonal variation of cytokine secretion and lesion activity in affected individuals,⁶ as well as with diurnal variations in symptoms.⁷ In the past decade, new horizons have opened in treatments for multiple sclerosis; nonetheless, patients treated with immunomodulators still continue to experience relapses, albeit at a lower rate.^8,9,10 These acute multiple sclerosis‐related exacerbations are commonly treated with glucocorticoids, specifically, high‐dose methylprednisolone.¹¹This study was designed to examine the clinical effect of intravenous corticosteroids administered at night time compared with daytime, for treatment of the acute multiple sclerosis relapse, and presents the possible benefits of the chronotherapy approach for patients with multiple sclerosis.     

Nap and melatonin-induced changes in hippocampal activation and their role in verbal memory consolidation

Overnight sleep contributes to memory consolidation; even a short nap improves memory performance. Such improvement has been linked to hippocampal activity during sleep. Melatonin has been shown to affect the human hippocampus and to induce 'sleep like' changes in brain activation. We therefore conducted and compared two functional magnetic resonance imaging studies: the first study assessed the effect of a 2-hr mid-day nap versus an equal amount of wakefulness on a verbal memory task (unrelated word pair association); the second assessed the effect of melatonin versus placebo (both conditions without nap) on a similar task. We report that following a nap relative to wakefulness, successful retrieval-related activation in the parahippocampus is decreased. A smaller decrease is seen in wakefulness with melatonin but not placebo. In parallel, an improvement in verbal memory recall was found after a nap compared with wakefulness but not with melatonin during wakefulness compared with placebo. Our findings demonstrate effects of melatonin that resemble those of sleep on verbal memory processing in the hippocampus thus suggesting that melatonin, like sleep, can initiate offline plastic changes underlying memory consolidation; they also suggest that concomitant rest without interferences is necessary for enhanced performance.     

Endothelial potential of human embryonic stem cells

Growing interest in using endothelial cells for therapeutic purposes has led to exploring human embryonic stem cells as a potential source for endothelial progenitor cells. Embryonic stem cells are advantageous when compared with other endothelial cell origins, due to their high proliferation capability, pluripotency, and low immunogenity. However, there are many challenges and obstacles to overcome before the vision of using embryonic endothelial progenitor cells in the clinic can be realized. Among these obstacles is the development of a productive method of isolating endothelial cells from human embryonic stem cells and elucidating their differentiation pathway. This review will focus on the endothelial potential of human embryonic stem cells that is described in current studies, with respect to the differentiation of human embryonic stem cells to endothelial cells, their isolation, and their characterization.     

Molecular impacts of rapamycin-based drug combinations: combining rapamycin with gemcitabine or imatinib mesylate (Gleevec) in a human leiomyosarcoma model

Drug combinations may provide a therapeutic benefit in treating cancer patients. However when considering a drug combination, it is important to assess how the molecular impact of the combination relates to the effects manifested by each drug alone and whether or not it varies depending on the tumor type. In this study, we have analyzed the molecular impact on a human leiomyosarcoma cell line (SK-LMS-1) of a combination consisting of the mTOR inhibitor rapamycin and either the anti-metabolite drug gemcitabine (Gemzar) or the protein tyrosine kinase inhibitor imatinib mesylate (Gleevec, STI571). We show that imatinib mesylate depolarizes the mitochondrial membrane potential (DeltaPhim) and inhibits protein tyrosine phosphorylation, but displays only minor effects on cell proliferation when added alone or in combin-ation with rapamycin. Gemcitabine or rapamycin, when added alone, inhibit protein tyrosine phosphorylation as well as phosphorylation of the MAP kinases ERK1/2. Both drugs also affect the cell cycle, arresting the cells at the S or G1 phase respectively. Rapamycin elevates significantly DeltaPhim but produces only a moderate effect on cell growth. Gemcitabine inhibits considerably cell growth but exerts no effect on DeltaPhim. Combining gemcitabine and rapamycin produces a major effect on the cell cycle, elevates the DeltaPhim even further and maintains the molecular impacts exerted by each single drug. Therefore, consistent with our clinical observation, these results suggest that combining gemcitabine and rapamycin may be beneficial in treating leiomyosarcoma patients.     

Molecular-based diagnosis of <Emphasis Type="Italic">Clostridium difficile</Emphasis> infection is associated with reduced mortality

Polymerase chain reaction (PCR) for the diagnosis of Clostridium difficile infection (CDI) might result in overdiagnosis. The clinical outcomes of symptomatic CDI patients diagnosed by PCR remain uncertain. We aimed to determine whether patients whose diagnosis of CDI was based on PCR had different characteristics and clinical outcomes than those diagnosed by toxin immunoassay. Consecutive CDI patients, hospitalized at Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel, between January 2013 and January 2016, were identified retrospectively and included in the study. Diagnosis of CDI was based on PCR or diagnosis by immunoassay for C. difficile toxin. The main outcome was 30- and 90-day all-cause mortality. The PCR group included 165 patients and the immunoassay group included 157 patients. In comparison to the immunoassay group, patients in the PCR group were more likely to be younger, to be independent, to undergo previous abdominal surgery, and to use laxatives. The 30-day mortality rate in the PCR group was significantly lower than that in the immunoassay group, 29/165 (18%) vs 49/157 (31%), respectively; p?=?0.028. On multivariate analysis, PCR diagnosis was associated with reduced mortality, OR 0.48 (95% CI 0.26–0.88). PCR-based diagnosis of CDI is associated with reduced all-cause mortality rates. Further studies are needed to determine the management of patients with discrepant immunoassay and PCR diagnosis of CDI.