Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond.

Cells have a number of mechanisms to maintain protein homeostasis, including proteasome-mediated degradation of ubiquitinated proteins and autophagy, a regulated process of ‘self-eating’ where the contents of entire organelles can be recycled for other uses. The unfolded protein response prevents protein overload in the secretory pathway. In the past decade, it has become clear that these fundamental cellular processes also help contain inflammation though degrading pro-inflammatory protein complexes such as the NLRP3 inflammasome. Signaling pathways such as the UPR can also be co-opted by toll-like receptor and mitochondrial reactive oxygen species signaling to induce inflammatory responses. Mutations that alter key inflammatory proteins, such as NLRP3 or TNFR1, can overcome normal protein homeostasis mechanisms, resulting in autoinflammatory diseases. Conversely, Mendelian defects in the proteasome cause protein accumulation, which can trigger interferon-dependent autoinflammatory disease. In non-Mendelian inflammatory diseases, polymorphisms in genes affecting the UPR or autophagy pathways can contribute to disease, and in diseases not formerly considered inflammatory such as neurodegenerative conditions and type 2 diabetes, there is increasing evidence that cell intrinsic or environmental alterations in protein homeostasis may contribute to pathogenesis

Comparison Between the Methods of Adjustment and Constant Stimuli for the Estimation of Redirection Detection Thresholds

International audienc

Cooling via one hand improves physical performance in heat-sensitive individuals with Multiple Sclerosis: A preliminary study

<p>Abstract</p> <p>Background</p> <p>Many individuals afflicted with multiple sclerosis (MS) experience a transient worsening of symptoms when body temperature increases due to ambient conditions or physical activity. Resulting symptom exacerbations can limit performance. We hypothesized that extraction of heat from the body through the subcutaneous retia venosa that underlie the palmar surfaces of the hands would reduce exercise-related heat stress and thereby increase the physical performance capacity of heat-sensitive individuals with MS.</p> <p>Methods</p> <p>Ten ambulatory MS patients completed one or more randomized paired trials of walking on a treadmill in a temperate environment with and without cooling. Stop criteria were symptom exacerbation and subjective fatigue. The cooling treatment entailed inserting one hand into a rigid chamber through an elastic sleeve that formed an airtight seal around the wrist. A small vacuum pump created a -40 mm Hg subatmospheric pressure enviinside the chamber where the palmar surface of the hand rested on a metal surface maintained at 18–22°C. During the treatment trials, the device was suspended from above the treadmill on a bungee cord so the subjects could comfortably keep a hand in the device without having to bear its weight while walking on the treadmill.</p> <p>Results</p> <p>When the trials were grouped by treatment only, cooling treatment increased exercise durations by 33% (43.6 ± 17.1 min with treatment vs. 32.8 ± 10.9 min. without treatment, mean ± SD, p < 5.0·10^-6, paired t-test, n = 26). When the average values were calculated for the subjects who performed multiple trials before the treatment group results were compared, cooling treatment increased exercise duration by 35% (42.8 ± 16.4 min with treatment vs. 31.7 ± 9.8 min. without treatment, mean ± SD, p < 0.003, paired t-test, n = 10).</p> <p>Conclusion</p> <p>These preliminary results suggest that utilization of the heat transfer capacity of the non-hairy skin surfaces can enable temperature-sensitive individuals with MS to extend participation in day-to-day physical activities despite thermally stressful conditions. However, systematic longitudinal studies in larger cohorts of MS patients with specific deficits and levels of disability conducted under a variety of test conditions are needed to confirm these preliminary findings.</p

Could valerian have been the first anticonvulsant?

To assess the available evidence for the belief that valerian, highly recommended in the past for treating epilepsy, possessed real anticonvulsant effectiveness.Review of available literature.In 1592, Fabio Colonna, in his botanical classic Phytobasanos, reported that taking powdered valerian root cured his own epilepsy. Subsequent reports of valerian's anticonvulsant effectiveness appeared. By the late 18th and early 19th centuries, it was often regarded as the best available treatment for the disorder. Valerian preparations yield isovaleric acid, a substance analogous to valproic acid and likely to possess anticonvulsant properties, as isovaleramide does. In favorable circumstances, high valerian doses can be calculated to have sometimes provided potentially effective amounts of anticonvulsant substance for epilepsy patients.Valerian probably did possess the potential for an anticonvulsant effect, but the uncertain chemical composition and content of valerian preparations, and their odor and taste, made it unlikely that they could ever prove satisfactory in widespread use