Neurogenesis within the hippocampus after chronic methylphenidate exposure.

Methylphenidate is a psychostimulant used to treat attention deficit hyperactivity disorder. Neurogenesis occurs throughout adulthood within the dentate gyrus of the hippocampus and can be altered by psychoactive medications; however, the impact of methylphenidate on neurogenesis is not fully understood. We investigated the effects of chronic low (1 mg/kg) and high (10 mg/kg) intraperitoneal doses of methylphenidate on neurogenesis in mouse hippocampus following 28 days and 56 days of treatment. Interestingly, methylphenidate, at both doses, increased neurogenesis. However, if methylphenidate treatment was not continued, the newly generated cells did not survive after 28 days. If treatment was continued, the newly generated neurons survived only in the mice receiving low-dose methylphenidate. To investigate the mechanism for this effect, we examined levels of proteins linked to cell proliferation in the hippocampus, including brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), vascular endothelial growth factor (VEGF), tropomyosin receptor kinase B (TrkB), and beta-catenin. BDNF or GDNF levels were not significantly different between groups. However, hippocampal VEGF, TrkB, and beta-catenin were significantly increased in mice receiving low-dose methylphenidate for 28 days compared to controls. Interestingly, high-dose methylphenidate significantly decreased beta-catenin after 28 days and decreased VEGF, beta-catenin, and TrkB after 56 days compared to controls. Thus, low-dose methylphenidate appears to increase cell proliferation and cell survival in the hippocampus, and these effects may be mediated by increase in VEGF, TrkB, and beta-catenin. While high dose methylphenidate may initially increase neuronal proliferation, newly generated neurons are unable to survive long-term, possibly due to decrease in VEGF, TrkB and beta-catenin.

A Novel Methodology for Extracting and Evaluating Therapeutic Movements in Game-Based Motion Capture Rehabilitation Systems.

Virtual rehabilitation yields outcomes that are at least as good as traditional care for improving upper limb function and the capacity to carry out activities of daily living. Due to the advent of low-cost gaming systems and patient preference for game-based therapies, video game technology will likely be increasingly utilized in physical therapy practice in the coming years. Gaming systems that incorporate low-cost motion capture technology often generate large datasets of therapeutic movements performed over the course of rehabilitation. An infrastructure has yet to be established, however, to enable efficient processing of large quantities of movement data that are collected outside of a controlled laboratory setting. In this paper, a methodology is presented for extracting and evaluating therapeutic movements from game-based rehabilitation that occurs in uncontrolled and unmonitored settings. By overcoming these challenges, meaningful kinematic analysis of rehabilitation trajectory within an individual becomes feasible. Moreover, this methodological approach provides a vehicle for analyzing large datasets generated in uncontrolled clinical settings to enable better predictions of rehabilitation potential and dose-response relationships for personalized medicine.

KCNC3(R420H), a K(+) channel mutation causative in spinocerebellar ataxia 13 displays aberrant intracellular trafficking.

Spinocerebellar ataxia 13 (SCA13) is an autosomal dominant disease resulting from mutations in KCNC3 (Kv3.3), a voltage-gated potassium channel. The KCNC3(R420H) mutation was first identified as causative for SCA13 in a four-generation Filipino kindred with over 20 affected individuals. Electrophysiological analyses in oocytes previously showed that this mutation did not lead to a functional channel and displayed a dominant negative phenotype. In an effort to identify the molecular basis of this allelic form of SCA13, we first determined that human KCNC3(WT) and KCNC3(R420H) display disparate post-translational modifications, and the mutant protein has reduced complex glycan adducts. Immunohistochemical analyses demonstrated that KCNC3(R420H) was not properly trafficking to the plasma membrane and surface biotinylation demonstrated that KCNC3(R420H) exhibited only 24% as much surface expression as KCNC3(WT). KCNC3(R420H) trafficked through the ER but was retained in the Golgi. KCNC3(R420H) expression results in altered Golgi and cellular morphology. Electron microscopy of KCNC3(R420H) localization further supports retention in the Golgi. These results are specific to the KCNC3(R420H) allele and provide new insight into the molecular basis of disease manifestation in SCA13.

A retrospective comparison of postoperative outcomes in ovariectomised jennies (Equus asinus) treated with phenylbutazone or flunixin meglumine.

BACKGROUND: Clinically, flunixin meglumine (FM) and phenylbutazone (PBZ) are preferentially selected for the treatment of visceral and musculoskeletal pain, respectively, in horses. In donkeys, there is no information to support or refute this conventional conjecture. OBJECTIVES: To compare postoperative outcomes in a group of jennies treated with intravenous FM or oral PBZ. ANIMALS: Fourteen jennies unilaterally ovariectomised by standing left flank laparotomy. STUDY DESIGN: Retrospective cohort study. METHODS: Data from medical records of ovariectomised jennies (case details, weight, non-steroidal anti-inflammatory drug [NSAID] protocol, surgery duration, operative sequence, anaesthesia protocol, physical examination findings and outcomes) were collected. From collated data, postoperative adverse events were defined as fever, tachycardia, tachypnea, inappetence, altered mentation, abnormal oral mucous membranes, bruxism, colic, incisional complications (i.e., drainage, oedema, peri-incisional emphysema and pain) and non-survival, then further divided into occurrence during the early (≤24 h) or late (>24 h) postoperative period for data analysis using R software. Chi-squared test was used to compare individual adverse events between groups (PBZ vs. FM) and moments (early vs. late). Significance was set at p ≤ 0.05. RESULTS: PBZ treatment (8/14) was associated with (odds ratio, 95% confidence interval) more total (2.93, 1.97-4.36), early (3.01, 1.87-4.84) and late (2.69, 1.28-5.63) adverse events than FM treatment (6/14). Tachycardia (37.83, 2.21-646.66), tachypnoea (0.29, 0.13-0.66), altered mentation (2.78, 1.01-7.67), altered mucous membranes (18.38, 1.04-325.23), incisional oedema (44.33, 2.60-754.5) and incisional pain (47.78, 2.81-811.61) were significantly different between groups. Early adverse events significantly different between groups included tachycardia (50.2, 2.9-877.0), altered mentation (3.33, 1.08-10.29) and incisional pain (21.0, 1.2-374.5), with late adverse events being tachypnea (0.07, 0.01-0.62), incisional oedema (32.92, 1.85-584.28) and incisional pain (28.92, 1.62-515.68). Colic (2/8) and non-survival (1/8) were rare events that only occurred in the PBZ cohort and could not be further evaluated for differences. MAIN LIMITATIONS: Small sample size; retrospective study; treatment bias; varied administration routes. CONCLUSIONS: Oral PBZ may be inappropriate to use following abdominal surgery in donkeys. CLINICAL RELEVANCE: More prospective and case-controlled studies are needed to evaluate the clinical efficacy of these two NSAIDs in donkeys.

Travelers' diarrhea: update on the incidence, etiology and risk in military and similar populations - 1990-2005 versus 2005-2015, does a decade make a difference?

BACKGROUND: Travelers' diarrhea remains a prevalent illness impacting individuals visiting developing countries, however most studies have focused on this disease in the context of short term travel. This study aims to determine the regional estimates of travelers' diarrhea incidence, pathogen-specific prevalence, and describe the morbidity associated with diarrheal disease among deployed military personnel and similar long term travelers. METHODS: We updated a prior systematic review to include publications between January 1990 and June 2015. Point estimates and confidence intervals of travelers' diarrhea and pathogen prevalence were combined in a random effects model and assessed for heterogeneity. Eighty-two studies were included in the analysis, including 29 new studies since the prior systematic review. RESULTS: Military personnel were evaluated in 69% of studies and non-military long term travelers in 34%, with a median duration of travel of 4.9 months, and travel predominantly to the Middle East, Southeast Asia, and Latin America and the Caribbean. Sixty-two percent of tested cases were due to bacterial pathogens, with enterotoxigenic E. coli (ETEC), enteroaggregative E. coli (EAEC), and Campylobacter predominating, and significant regional variability. The incidence of TD from studies with longitudinal data was 36.3 cases per 100 person-months, with the highest rates in Southeast Asia, Latin America and the Caribbean, and the Middle East, with higher estimates from those studies using self-reporting of disease. Morbidity remained significant, with 21% being incapacitated or placed sick in quarters (SIQ) by their illness, 15% requiring intravenous fluids, and 3% requiring hospitalization. CONCLUSIONS: In comparison to results from the prior systematic review, there were no significant differences in incidence, pathogen prevalence, or morbidity; however there was a trend toward improved care-seeking by sick individuals.

Chronic methylphenidate induces increased quinone production and subsequent depletion of the antioxidant glutathione in the striatum.

BACKGROUND: Methylphenidate (Ritalin®) is a psychostimulant used chronically to treat attention deficit hyperactivity disorder. Methylphenidate acts by preventing the reuptake of dopamine and norepinephrine, resulting in an increase in these neurotransmitters in the synaptic cleft. Excess dopamine can be autoxidized to a quinone that may lead to oxidative stress. The antioxidant, glutathione helps to protect the cell against quinones via conjugation reactions; however, depletion of glutathione may result from excess quinone formation. Chronic exposure to methylphenidate appears to sensitize dopaminergic neurons to the Parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We hypothesized that oxidative stress caused by the autooxidation of the excess dopamine renders dopaminergic neurons within the nigrostriatal pathway to be more sensitive to MPTP. METHODS: To test this hypothesis, male mice received chronic low or high doses of MPH and were exposed to saline or MPTP following a 1-week washout. Quinone formation in the striatum was examined via dot blot, and striatal GSH was quantified using a glutathione assay. RESULTS: Indeed, quinone formation increased with increasing doses of methylphenidate. Additionally, methylphenidate dose-dependently resulted in a depletion of glutathione, which was further depleted following MPTP treatment. CONCLUSIONS: Thus, the increased sensitivity of dopamine neurons to MPTP toxicity following chronic methylphenidate exposure may be due to quinone production and subsequent depletion of glutathione.

Targeted heat activation of HSP promoters in the skin of mammalian animals and humans.

The use of highly inducible HSP promoters for exerting spatial and/or temporal control over the expression of therapeutic transgenes has long been discussed. Localized and time-limited induction of the heat shock response may potentially also be of medical interest. However, such applications would require targeted delivery of heat doses capable of activating HSP promoters in tissues or organs of interest. Accessible areas, including the skin and tissues immediately underneath it, may be most readily targeted. A few applications for heat-directed or heat-controlled therapy in the skin might involve expression of proteins to restore or protect normal skin function, protein antigens for vaccination/immunotherapy, vaccine viruses or even systemically active proteins, e.g., cytokines and chemokines. A review of the literature relating to localized heat activation of HSP promoters and HSP genes in the skin revealed that a multitude of different technologies has been explored in small animal models. In contrast, we uncovered few publications that examine HSP promoter activation in human skin. None of these publications has a therapeutic focus. We present herein two, clinically relevant, developments of heating technologies that effectively activate HSP promoters in targeted regions of human skin. The first development advances a system that is capable of reliably activating HSP promoters in human scalp, in particular in hair follicles. The second development outlines a simple, robust, and inexpensive methodology for locally activating HSP promoters in small, defined skin areas.

Theoretical Explanation for Reduced Body Mass Index and Obesity Rates in Cannabis Users.

Introduction: Obesity is treatment-resistant, and is linked with a number of serious, chronic diseases. Adult obesity rates in the United States have tripled since the early 1960s. Recent reviews show that an increased ratio of omega-6 to omega-3 fatty acids contributes to obesity rates by increasing levels of the endocannabinoid signals AEA and 2-AG, overstimulating CB1R and leading to increased caloric intake, reduced metabolic rates, and weight gain. Cannabis, or THC, also stimulates CB1R and increases caloric intake during acute exposures. Goals: To establish the relationship between Cannabis use and body mass index, and to provide a theoretical explanation for this relationship. Results: The present meta-analysis reveals significantly reduced body mass index and rates of obesity in Cannabis users, in conjunction with increased caloric intake. Theoretical explanation: We provide for the first time a causative explanation for this paradox, in which rapid and long-lasting downregulation of CB1R following acute Cannabis consumption reduces energy storage and increases metabolic rates, thus reversing the impact on body mass index of elevated dietary omega-6/omega-3 ratios.

Travelers' Diarrhea: An Update on the Incidence, Etiology, and Risk in Military Deployments and Similar Travel Populations.

Travelers' diarrhea (TD) has historically been a common illness among visitors to developing nations. Although recent studies indicate decreasing incidence of TD among short-term travelers, a systematic review of illness among long-term travelers, including deployed military personnel, has not been conducted in more than 10 years. We conducted a literature search of studies published between 2005 and 2015 that evaluated TD in populations of deployed military personnel or similar long-term travelers (travel ≥1 month) to developing nations. Our literature search identified 28 studies for inclusion. We found that the incidence of TD remained high (10% clinical incidence, 30% self-reported incidence), with variability depending on region of travel and similar rates in both military and civilian long-term travelers. Bacteria (Escherichia coli, Campylobacter, Shigella, and Salmonella species) were the most commonly identified enteropathogens. Fifty percent of affected individuals experienced lost ability to work and 5% required hospitalization. This systematic review demonstrates that among deployed military personnel and long-term travelers, TD remains a prevalent disease that can significantly impact individual readiness for duty. These data demonstrate that to maintain operational readiness among deployed personnel, a focus on vigilance for disease and early treatment of cases is vital.

CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation.

Molecular chaperones, ubiquitin ligases and proteasome impairment have been implicated in several neurodegenerative diseases, including Alzheimer's and Parkinson's disease, which are characterized by accumulation of abnormal protein aggregates (e.g. tau and alpha-synuclein respectively). Here we report that CHIP, an ubiquitin ligase that interacts directly with Hsp70/90, induces ubiquitination of the microtubule associated protein, tau. CHIP also increases tau aggregation. Consistent with this observation, diverse of tau lesions in human postmortem tissue were found to be immunopositive for CHIP. Conversely, induction of Hsp70 through treatment with either geldanamycin or heat shock factor 1 leads to a decrease in tau steady-state levels and a selective reduction in detergent insoluble tau. Furthermore, 30-month-old mice overexpressing inducible Hsp70 show a significant reduction in tau levels. Together these data demonstrate that the Hsp70/CHIP chaperone system plays an important role in the regulation of tau turnover and the selective elimination of abnormal tau species. Hsp70/CHIP may therefore play an important role in the pathogenesis of tauopathies and also represents a potential therapeutic target.