Diurnal fluctuation in the number of hypocretin/orexin and histamine producing: Implication for understanding and treating neuronal loss.

The loss of specific neuronal phenotypes, as determined by immunohistochemistry, has become a powerful tool for identifying the nature and cause of neurological diseases. Here we show that the number of neurons identified and quantified using this method misses a substantial percentage of extant neurons in a phenotype specific manner. In mice, 24% more hypocretin/orexin (Hcrt) neurons are seen in the night compared to the day, and an additional 17% are seen after inhibiting microtubule polymerization with colchicine. We see no such difference between the number of MCH (melanin concentrating hormone) neurons in dark, light or colchicine conditions, despite MCH and Hcrt both being hypothalamic peptide transmitters. Although the size of Hcrt neurons did not differ between light and dark, the size of MCH neurons was increased by 15% in the light phase. The number of neurons containing histidine decarboxylase (HDC), the histamine synthesizing enzyme, was 34% greater in the dark than in the light, but, like Hcrt, cell size did not differ. We did not find a significant difference in the number or the size of neurons expressing choline acetyltransferase (ChAT), the acetylcholine synthesizing enzyme, in the horizontal diagonal band (HBD) during the dark and light conditions. As expected, colchicine treatment did not increase the number of these neurons. Understanding the function and dynamics of transmitter production within "non-visible" phenotypically defined cells has fundamental implications for our understanding of brain plasticity

Enhancing Cellular Uptake of Magnetic Nanoparticles for Cancer Therapy via Nanoparticle Engineering & Sonoporation

Magnetic induction heating of iron oxide nanoparticles has been proposed as a method for noninvasive cancer treatment without the side effects of chemotherapy and ionizing radiation. At Kettering University we propose to improve the uptake of nanoparticles by cells through the use of nanoparticle engineering and ultrasonic fields

A Novel Long-Term ex vivo Model for Studying Vascular Calcification Pathogenesis: The Rat Isolated-Perfused Aorta

The investigation of vascular calcification and its underlying cellular and molecular pathways is of great interest in current research efforts. Therefore, suitable assays are needed to allow examination of the complex calcification process under controlled conditions. The current study describes a new ex vivo model of isolated-perfused rat aortic tissue with subsequent quantification and vessel staining to analyze the calcium content of the aortic wall. A rat aorta was perfused ex vivo with control and calcification media for 14 days, respectively. The calcification medium was luminally perfused and induced a significant increase in calcium deposition within the media of the vessel wall detected alongside the elastic laminae. Perfusion with control medium induced no calcification. In addition, the mRNA expression of the osteogenic marker bone morphogenetic protein 2 (BMP-2) increased in aortic tissue after perfusion, while SM22α as smooth muscle marker decreased. This newly developed ex vivo model of isolated-perfused rat aorta is suitable for vascular calcification studies testing inducers and inhibitors of vessel calcification and studying signaling pathways within calcification progression

Natural Sleep and Its Seasonal Variations in Three Pre-Industrial Societies

How did humans sleep before the modern era? Because the tools to measure sleep under natural conditions were developed long after the invention of the electric devices suspected of delaying and reducing sleep, we investigated sleep in three preindustrial societies[1–3]. We find that all three show similar sleep organization, suggesting that they express core human sleep patterns, likely characteristic of pre-modern era Homo sapiens. Sleep periods, the times from onset to offset, averaged 6.9–8.5-h, with sleep durations of 5.7–7.1-h, amounts near the low end of those industrial societies[4–7]. There was a difference of nearly 1-h between summer and winter sleep. Daily variation in sleep duration was strongly linked to time of onset, rather than offset. None of these groups began sleep near sunset, onset occurring, on average, 3.3-h after sunset. Awakening was usually before sunrise. The sleep period consistently occurred during the nighttime period of falling environmental temperature, was not interrupted by extended periods of waking and terminated, with vasoconstriction, near the nadir of daily ambient temperature. The daily cycle of temperature change, largely eliminated from modern sleep environments, may be a potent natural regulator of sleep. Light exposure, was maximal in the morning greatly decreasing at noon, indicating that all three groups seek shade at midday and that light activation of the suprachiasmatic nucleus is maximal in the morning. Napping occurred on \u3c7% of days in winter and \u3c22% of days in summer. Mimicking aspects of the natural environment might be effective in treating certain modern sleep disorders

Statement of the Third International Exercise-Associated Hyponatremia Consensus Development Conference, Carlsbad, California, 2015

The third International Exercise-Associated Hyponatremia (EAH) Consensus Development Conference convened in Carlsbad, California in February 2015 with a panel of 17 international experts. The delegates represented 4 countries and 9 medical and scientific sub-specialties pertaining to athletic training, exercise physiology, sports medicine, water/sodium metabolism, and body fluid homeostasis. The primary goal of the panel was to review the existing data on EAH and update the 2008 Consensus Statement.1 This document serves to replace the second International EAH Consensus Development Conference Statement and launch an educational campaign designed to address the morbidity and mortality associated with a preventable and treatable fluid imbalance. The following statement is a summary of the data synthesized by the 2015 EAH Consensus Panel and represents an evolution of the most current knowledge on EAH. This document will summarize the most current information on the prevalence, etiology, diagnosis, treatment and prevention of EAH for medical personnel, athletes, athletic trainers, and the greater public. The EAH Consensus Panel strove to clearly articulate what we agreed upon, did not agree upon, and did not know, including minority viewpoints that were supported by clinical experience and experimental data. Further updates will be necessary to both: (1) remain current with our understanding and (2) critically assess the effectiveness of our present recommendations. Suggestions for future research and educational strategies to reduce the incidence and prevalence of EAH are provided at the end of the document as well as areas of controversy that remain in this topic. [excerpt

Effects of Apremilast, an Oral Inhibitor of Phosphodiesterase 4, in a Randomized Trial of Patients With Active Ulcerative Colitis

Background & Aims New oral therapeutic agents are needed for patients with ulcerative colitis (UC) who are unresponsive or intolerant to conventional therapy. Methods We performed a double-blind, phase 2 trial of adults with active UC for 3 months or more who were naive to biologic therapy or had been failed by, could not tolerate, or had contraindications to conventional therapies. The study was performed at 61 sites in 14 countries (screening from January 2015 through May 2017). Patients were randomly assigned to groups given apremilast 30 mg (n = 57), apremilast 40 mg (n = 55), or placebo (n = 58) twice daily for 12 weeks; patients were then randomly assigned to groups that received apremilast, 30 or 40 mg twice daily, for an additional 40 weeks. Endoscopies were performed and biopsies were collected during the screening phase, at week 12, and at week 52. Blood and fecal samples were also collected and analyzed throughout the study. The primary endpoint was clinical remission at week 12, defined as a total Mayo score of 2 or less, with no individual subscore above 1. Results Clinical remission was achieved at week 12 by 31.6% of patients in the 30 mg apremilast group and 12.1% of patients in the placebo group (P = .01). However, only 21.8% of patients in the 40 mg apremilast group achieved clinical remission at week 12 (P = .27 compared with placebo). Differences in clinical remission between the 30 mg and 40 mg apremilast groups were associated with differences in endoscopic improvement. Both apremilast groups had similar improvements from baseline in Mayo score components (stool frequency score, rectal bleeding score, physician's global assessment). The 30 mg and 40 mg apremilast groups had greater median percent reductions in C-reactive protein (measured by a high-sensitivity blood test) and fecal calprotectin through week 12 than the placebo group. At week 52, clinical remission was achieved by 40.4% of patients initially assigned to the apremilast 30 mg group and 32.7% of patients initially assigned to the apremilast 40 mg group. The most frequent apremilast-associated adverse events were headache and nausea. Conclusions Although the primary endpoint of clinical remission was not met in this phase 2 trial, a greater proportion of patients with active UC who received apremilast (30 mg or 40 mg) had improvements in clinical and endoscopic features, and markers of inflammation, at 12 weeks. Clinical remission was maintained to week 52 in up to 40% of patients who continued apremilast until that time point. ClinicalTrials.gov no: NCT0228941

Spin-ice physics in cadmium cyanide

Spin-ices are frustrated magnets that support a particularly rich variety of emergent physics. Typically, it is the interplay of magnetic dipole interactions, spin anisotropy, and geometric frustration on the pyrochlore lattice that drives spin-ice formation. The relevant physics occurs at temperatures commensurate with the magnetic interaction strength, which for most systems is 1–5 K. Here, we show that non-magnetic cadmium cyanide, Cd(CN)2, exhibits analogous behaviour to magnetic spin-ices, but does so on a temperature scale that is nearly two orders of magnitude greater. The electric dipole moments of cyanide ions in Cd(CN)2 assume the role of magnetic pseudospins, with the difference in energy scale reflecting the increased strength of electric vs magnetic dipolar interactions. As a result, spin-ice physics influences the structural behaviour of Cd(CN)2 even at room temperature.ISSN:2041-172