Anticipatory nausea in cyclical vomiting

BACKGROUND: Cyclical Vomiting Syndrome (CVS) is characterised by discrete, unexplained episodes of intense nausea and vomiting, and mainly affects children and adolescents. Comprehending Cyclical Vomiting Syndrome requires awareness of the severity of nausea experienced by patients. As a subjective symptom, nausea is easily overlooked, yet is the most distressing symptom for patients and causes many behavioural changes during attacks. CASE PRESENTATION: This first-hand account of one patient's experience of Cyclical Vomiting Syndrome shows how severe nausea contributed to the development of anticipatory nausea and vomiting (ANV), a conditioned response frequently observed in chemotherapy patients. This conditioning apparently worsened the course of the patient's disease. Anticipatory nausea and vomiting has not previously been recognised in Cyclical Vomiting Syndrome, however predictors of its occurrence in oncology patients indicate that it could complicate many cases. CONCLUSION: We suggest a model whereby untreated severe and prolonged nausea provokes anxiety about further cyclical vomiting attacks. This anxiety facilitates conditioning, thus increasing the range of triggers in a self-perpetuating manner. Effective management of the nausea-anxiety feedback loop can reduce the likelihood of anticipatory nausea and vomiting developing in other patients

Identity Formation in Adolescence: Change or Stability?

The aim of this five-wave longitudinal study of 923 early to middle adolescents (50.7% boys; 49.3% girls) and 390 middle to late adolescents (43.3% boys and 56.7% girls) is to provide a comprehensive view on change and stability in identity formation from ages 12 to 20. Several types of change and stability (i.e., mean-level change, rank-order stability, and profile similarity) were assessed for three dimensions of identity formation (i.e., commitment, in-depth exploration, and reconsideration), using adolescent self-report questionnaires. Results revealed changes in identity dimensions towards maturity, indicated by a decreasing tendency for reconsideration, increasingly more in-depth exploration, and increasingly more stable identity dimension profiles. Mean levels of commitment remained stable, and rank-order stability of commitment, in-depth exploration, and reconsideration did not change with age. Overall, girls were more mature with regard to identity formation in early adolescence, but boys had caught up with them by late adolescence. Taken together, our findings indicate that adolescent identity formation is guided by progressive changes in the way adolescents deal with commitments, rather than by changes in the commitments themselves

Neuromotor tolerability and behavioural characterisation of cannabidiolic acid, a phytocannabinoid with therapeutic potential for anticipatory nausea

Rationale: Anticipatory nausea (AN) is a poorly controlled side-effect experienced by chemotherapy patients. Currently, pharmacotherapy is restricted to benzodiazepine anxiolytics, which have limited efficacy, significant sedative effects, and induce dependency. The non-psychoactive phytocannabinoid, cannabidiolic acid (CBDA), has shown considerable efficacy in pre-clinical AN models, however determination of its neuromotor tolerability profile is crucial to justify clinical investigation. Provisional evidence for appetite-stimulating properties also requires detailed investigation. Objectives: To assess the tolerability of CBDA in locomotor activity, motor coordination and muscular strength tests, and additionally for ability to modulate feeding behaviours. Methods: Male Lister hooded rats administered CBDA (0.05-5 mg/kg; p.o.) were assessed in habituated open field (for locomotor activity), static beam and grip strength tests. A further study investigated whether these CBDA doses modulated normal feeding behaviour. Finally, evidence of anxiolytic-like effects in the habituated open field prompted testing of 5 mg/kg CBDA for anxiolytic-like activity in unhabituated open field, light/dark box and novelty-supressed feeding (NSF) tests. Results: CBDA had no adverse effects upon performance in any neuromotor tolerability test, however anxiolytic-like behaviour was observed in the habituated open field. Normal feeding behaviours were unaffected by any dose. CBDA (5 mg/kg) abolished the increased feeding latency in the NSF test induced by the 5-HT1AR antagonist, WAY-100,635, indicative of anxiolytic-like effects, but had no effect on anxiety-like behaviour in the novel open field or light/dark box. Conclusions: CBDA is very well tolerated and devoid of the sedative side-effect profile of benzodiazepines, justifying its clinical investigation as a novel AN treatment

Warm Body Temperature Facilitates Energy Efficient Cortical Action Potentials

The energy efficiency of neural signal transmission is important not only as a limiting factor in brain architecture, but it also influences the interpretation of functional brain imaging signals. Action potential generation in mammalian, versus invertebrate, axons is remarkably energy efficient. Here we demonstrate that this increase in energy efficiency is due largely to a warmer body temperature. Increases in temperature result in an exponential increase in energy efficiency for single action potentials by increasing the rate of Na+ channel inactivation, resulting in a marked reduction in overlap of the inward Na+, and outward K+, currents and a shortening of action potential duration. This increase in single spike efficiency is, however, counterbalanced by a temperature-dependent decrease in the amplitude and duration of the spike afterhyperpolarization, resulting in a nonlinear increase in the spike firing rate, particularly at temperatures above approximately 35°C. Interestingly, the total energy cost, as measured by the multiplication of total Na+ entry per spike and average firing rate in response to a constant input, reaches a global minimum between 37–42°C. Our results indicate that increases in temperature result in an unexpected increase in energy efficiency, especially near normal body temperature, thus allowing the brain to utilize an energy efficient neural code

Clofazimine Inhibits Human Kv1.3 Potassium Channel by Perturbing Calcium Oscillation in T Lymphocytes

The Kv1.3 potassium channel plays an essential role in effector memory T cells and has been implicated in several important autoimmune diseases including multiple sclerosis, psoriasis and type 1 diabetes. A number of potent small molecule inhibitors of Kv1.3 channel have been reported, some of which were found to be effective in various animal models of autoimmune diseases. We report herein the identification of clofazimine, a known anti-mycobacterial drug, as a novel inhibitor of human Kv1.3. Clofazimine was initially identified as an inhibitor of intracellular T cell receptor-mediated signaling leading to the transcriptional activation of human interleukin-2 gene in T cells from a screen of the Johns Hopkins Drug Library. A systematic mechanistic deconvolution revealed that clofazimine selectively blocked the Kv1.3 channel activity, perturbing the oscillation frequency of the calcium-release activated calcium channel, which in turn led to the inhibition of the calcineurin-NFAT signaling pathway. These effects of clofazimine provide the first line of experimental evidence in support of a causal relationship between Kv1.3 and calcium oscillation in human T cells. Furthermore, clofazimine was found to be effective in blocking human T cell-mediated skin graft rejection in an animal model in vivo. Together, these results suggest that clofazimine is a promising immunomodulatory drug candidate for treating a variety of autoimmune disorders

The disruption of proteostasis in neurodegenerative diseases

Cells count on surveillance systems to monitor and protect the cellular proteome which, besides being highly heterogeneous, is constantly being challenged by intrinsic and environmental factors. In this context, the proteostasis network (PN) is essential to achieve a stable and functional proteome. Disruption of the PN is associated with aging and can lead to and/or potentiate the occurrence of many neurodegenerative diseases (ND). This not only emphasizes the importance of the PN in health span and aging but also how its modulation can be a potential target for intervention and treatment of human diseases.info:eu-repo/semantics/publishedVersio