Integration of beta-Catenin, Sirtuin, and FOXO Signaling Protects from Mutant Huntingtin Toxicity

One of the current challenges of neurodegenerative disease research is to determine whether signaling pathways that are essential to cellular homeostasis might contribute to neuronal survival and modulate the pathogenic process in human disease. In Caenorhabditis elegans, sir-2.1/SIRT1 overexpression protects neurons from the early phases of expanded polyglutamine (polyQ) toxicity, and this protection requires the longevity-promoting factor daf-16/FOXO. Here, we show that this neuroprotective effect also requires the DAF-16/FOXO partner bar-1/beta-catenin and putative DAF-16-regulated gene ucp-4, the sole mitochondrial uncoupling protein (UCP) in nematodes. These results fit with a previously proposed mechanism in which the beta-catenin FOXO and SIRT1 proteins may together regulate gene expression and cell survival. Knockdown of beta-catenin enhanced the vulnerability to cell death of mutant-huntingtin striatal cells derived from the HdhQ111 knock-in mice. In addition, this effect was compensated by SIRT1 overexpression and accompanied by the modulation of neuronal UCP expression levels, further highlighting a cross-talk between beta-catenin and SIRT1 in the modulation of mutant polyQ cytoxicity. Taken together, these results suggest that integration of beta-catenin, sirtuin and FOXO signaling protects from the early phases of mutant huntingtin toxicity

The Grizzly, April 25, 1995

Coming Soon: The New Wismer • Two Suspects Apprehended for Oklahoma City Bombing • Mathematics Awareness Week • Clare Zeberkiewicz Awarded UPS Scholarship • Spring Fling • A Midnight Jog • Dr. Clark Responds to Core Concerns • Recycling at Ursinus • Travel Opportunities Offer Escape from Ursinus Campus • New House to Focus on Unity and Diversity • Rape Aggression Defense Teaches Valuable Self-Defense Techniques • Alpha Kappa Delta to Form • The Costa Rica Experience • Don\u27t miss the Concert Band and Jazz Ensemble • Comedian Rich Ramirez Delivers • Politics Comes to Ursinus • Sammartino Named Player of the Week • Baseball Team Ties Record for Wins • Lacrosse Team Stays Alive for Playoff Bid • Men\u27s Tennis Team on a Roll • Track Teams Gear Up for Conference Meet • All-Sports Reception Set for May 1 • Volleyball Team Seeks Players • Cosgrove Named First Team All-American • Women\u27s Tennis • Champions! Softball Team Shares Centennial Title • Softball Team Plays HR Derbyhttps://digitalcommons.ursinus.edu/grizzlynews/1360/thumbnail.jp

Delayed Achilles tendon rupture presentation: Non-operative management may be the SMART choice

IntroductionThis biomechanical study aims to assess the function of patients who were treated non-operatively for delayed diagnosis Achilles tendon rupture. Patients were treated using the Swansea Morriston Achilles Rupture Treatment protocol (SMART), which is a physiotherapy led non-operative treatment program.Methods19 patients (16 M:3F) were enrolled and prospectively assessed using ARS/ATRS (PROMS), Ankle ROM and isokinetic peak torque for plantarflexion of the ankle. MRI scans of both the injured and uninjured TA were performed to compare both AP diameter and length.ResultsBoth ATRS and ARS improved between short and long-term follow-up. The mean difference in plantar torque between the injured and uninjured leg was 21.9%. There was no significant difference in ankle plantarflexion or dorsiflexion. There was no significant difference in length of the injured and uninjured TA on MRI. 3 patients failed the SMART protocol requiring surgical fixation.DiscussionThe SMART protocol can be an effective method of treatment even in younger and active patients especially if delay to treatment is less than 12 weeks. It may still be preferable for patients with a large gap size or high functional demand to elect for surgical intervention, but clinicians should consider the SMART protocol as an alternative to surgery and discuss it with some patients as a viable alternative.KeywordsTendoachillesConservativeChronicDelayedAbbreviationsTATendoachillesSMARTSwansea Morriston Achilles Rupture Treatmen

Efficacy of vinblastine in central nervous system Langerhans cell histiocytosis: a nationwide retrospective study

<p>Abstract</p> <p>Background</p> <p>Vinblastine (VBL) is the standard treatment for systemic Langerhans cell histiocytosis (LCH), but little is known about its efficacy in central nervous system (CNS) mass lesions.</p> <p>Methods</p> <p>A retrospective chart review was conducted. Twenty patients from the French LCH Study Group register met the inclusion criteria. In brief, they had CNS mass lesions, had been treated with VBL, and were evaluable for radiologic response.</p> <p>Results</p> <p>The median age at diagnosis of LCH was 11.5 years (range: 1-50). Intravenous VBL 6 mg/m²was given in a 6-week induction treatment, followed by a maintenance treatment. The median total duration was 12 months (range: 3-30). Eleven patients received steroids concomitantly. Fifteen patients achieved an objective response; five had a complete response (CR: 25%), ten had a partial response (PR: 50%), four had stable disease (SD: 20%) and one patient progressed (PD: 5%). Of interest, four out of the six patients who received VBL without concomitant steroids achieved an objective response. With a median follow-up of 6.8 years, the 5-year event-free and overall survival was 61% and 84%, respectively. VBL was well-tolerated and there were no patient withdrawals due to adverse events.</p> <p>Conclusion</p> <p>VBL, with or without steroids, could potentially be a useful therapeutic option in LCH with CNS mass lesions, especially for those with inoperable lesions or multiple lesions. Prospective clinical trials are warranted for the evaluation of VBL in this indication.</p

Outcome domains and outcome measures used in studies assessing the effectiveness of interventions to manage non-respiratory sleep disturbances in children with neurodisabilities: a systematic review

Objectives: To assess whether a core outcome set is required for studies evaluating the effectiveness of interventions for non-respiratory sleep disturbances in children with neurodisabilities. Design: Survey of outcome measures used in primary studies identified by a systematic review. Data sources: ASSIA; CENTRAL; Cochrane Database of Systematic Reviews; Conference Proceedings Citation Index; CINAHL; DARE; Embase; HMIC; MEDLINE; MEDLINE In-Process; PsycINFO; Science Citation Index; Social Care Online; Social Policy & Practice; ClinicalTrials.gov; WHO International Clinical Trials Registry Platform (ICTRP); and the UK Clinical Trials Gateway were searched up to February 2017. Eligibility criteria: Studies evaluating pharmacological or non-pharmacological interventions for children (≤ 18 years old) with a neurodisability and experiencing non-respiratory sleep disturbance. Data extraction and synthesis: Outcomes related to child and parent sleep-related outcomes; measures of perceived parenting confidence, efficacy or understanding of sleep management; child-related quality of life, daytime behaviour and cognition; parent/carer outcomes; and adverse events were listed from each study and categorised into domains. Results: Thirty-nine studies (13 melatonin and 26 non-pharmacological) assessed five core outcome areas: child sleep, other child outcomes, parent outcomes, adverse events and process measures. There were 54 different measures of child related sleep across five domains: global measures; sleep initiation; maintenance; scheduling; and other outcomes. The most commonly reported measure in melatonin studies was total sleep time (n=12; 92%); and for non-pharmacological studies was the parent-reported Child Sleep Habits Questionnaire (CSHQ; 58%), both classified as global measures. Fifteen non-pharmacological (58%) and four pharmacological studies (31%) reported child outcomes other than sleep. The domains assessed (using 29 different measures) were child behaviour, quality of life, ADHD symptoms, cognition, school-related, and other. One pharmacological and 14 non-pharmacological (54%) studies reported parent outcomes (17 different measures). Eleven melatonin studies (85%) recorded adverse events, with variation in how data were collected and reported. One non-pharmacological study reported an explicit method of collecting on adverse events. Several process measures were reported, related to adherence, feasibility of delivery, acceptability and experiences of receiving the intervention. Conclusions: There is a lack of consistency between studies in the outcome measures used to assess the effectiveness of interventions for non-respiratory sleep disturbances in children with neurodisabilities. A minimum core outcome set, with international consensus, should be developed in consultation with parents, children and young people, and those involved in supporting families. Registration number systematic review PROSPERO (CRD42016034067

Oral Melatonin for Non-Respiratory Sleep Disturbance in Children with Neurodisabilities: Systematic Review and Meta-Analyses

Aim: To evaluate the effectiveness of pharmacological interventions for managing non-respiratory sleep disturbances in children with neurodisabilities. Method: We performed a systematic review and meta-analyses of randomized controlled trials (RCTs). We searched 16 databases, grey literature, and reference lists of included papers up to February 2017. Data were extracted and assessed for quality by two researchers (B.B., C.M., G.S., A.S., A.P.). Results: Thirteen trials were included, all evaluating oral melatonin. All except one were at high or unclear risk of bias. There was a statistically significant increase in diary-reported total sleep time for melatonin compared with placebo (pooled mean difference 29.6min, 95% confidence interval [CI] 6.9–52.4, p=0.01). Statistical heterogeneity was high (97%). For the single RCT with low risk of bias, the unadjusted mean difference in total sleep time was 13.2 minutes (95% CI −13.3 to 39.7) favouring melatonin, while the mean difference adjusted for baseline total sleep time was statistically significant (22.4min, 95% CI 0.5–44.3, p=0.04). Adverse event profile suggested that melatonin was well-tolerated. Interpretation: There is a paucity of evidence on managing sleep disturbances in children with neurodisabilities, and it is mostly of limited scope and poor quality. There is evidence of the benefit and safety of melatonin compared with placebo, although the extent of this benefit is unclear. What this paper adds: Melatonin for the management of non-respiratory sleep disturbances in children with neurodisabilities was well tolerated with minimal adverse effects. The extent of benefit and which children might benefit most from melatonin use is uncertain. Benefit may be greatest in those with autism spectrum disorder; however, this finding should be interpreted with caution

Using a personalized DVD to prescribe an exercise program to older people post-hip fracture enhances adherence to the exercises: A feasibility study

Optimum recovery from hip fracture has been linked to the provision of effective rehabilitation, but levels of adherence vary among older patients. In this feasibility study a novel personalized DVD was designed for four participants, which delivered a 5 week tailored home exercise program (HEP), with the participant being videoed completing their exercises. Treatment fidelity of the DVD HEP was evaluated, including participants' perceptions of and response to the DVD-HEP, which was explored using diaries and interviews and analyzed thematically. Secondary outcome measures including exercise adherence and self-efficacy for exercise were analyzed using descriptive statistics. Levels of adherence to the HEP were 1.2-3.5 times more than the minimum prescribed dose and participants demonstrated higher levels of self-efficacy for exercise. Adherence was found to be enhanced by physical improvement, positive self-reflection about engagement in the DVD-HEP, the format of the DVD, and increased self-efficacy. Personalized DVDs may be a feasible method of promoting adherence to home exercise programs among older patients

Dew condensation on desert beetle skin

Some tenebrionind beetles inhabiting the Namib desert are known for using their body to collect water droplets from wind-blown fogs. We aim to determine whether dew water collection is also possible for desert insects. For this purpose, we investigated the infra-red emissivity, and the wetting and structural properties, of the surface of the elytra of a preserved specimen of Physasterna cribripes (Tenebrionidæ) beetle, where the macro-structure appears as a series of “bumps”, with “valleys” between them. Dew formation experiments were carried out in a condensation chamber. The surface properties (infra-red emissivity, wetting properties) were dominated by the wax at the elytra surface and, to a lower extent, its micro-structure. We performed scanning electron microscope on histological sections and determined the infra-red emissivity using a scanning pyrometer. The emissivity measured (0.95 ± 0.07 between 8–14 μm) was close to the black body value. Dew formation occurred on the insect’s elytra, which can be explained by these surface properties. From the surface coverage of the condensed drops it was found that dew forms primarily in the valleys between the bumps. The difference in droplet nucleation rate between bumps and valleys can be attributed to the hexagonal microstructure on the surface of the valleys, whereas the surface of the bumps is smooth. The drops can slide when they reach a critical size, and be collected at the insect’s mouth

The Wnt Receptor Ryk Reduces Neuronal and Cell Survival Capacity by Repressing FOXO Activity During the Early Phases of Mutant Huntingtin Pathogenicity

The Wnt receptor Ryk is an evolutionary-conserved protein important during neuronal differentiation through several mechanisms, including γ-secretase cleavage and nuclear translocation of its intracellular domain (Ryk-ICD). Although the Wnt pathway may be neuroprotective, the role of Ryk in neurodegenerative disease remains unknown. We found that Ryk is up-regulated in neurons expressing mutant huntingtin (HTT) in several models of Huntington's disease (HD). Further investigation in Caenorhabditis elegans and mouse striatal cell models of HD provided a model in which the early-stage increase of Ryk promotes neuronal dysfunction by repressing the neuroprotective activity of the longevity-promoting factor FOXO through a noncanonical mechanism that implicates the Ryk-ICD fragment and its binding to the FOXO co-factor β-catenin. The Ryk-ICD fragment suppressed neuroprotection by lin-18/Ryk loss-of-function in expanded-polyQ nematodes, repressed FOXO transcriptional activity, and abolished β-catenin protection of mutant htt striatal cells against cell death vulnerability. Additionally, Ryk-ICD was increased in the nucleus of mutant htt cells, and reducing γ-secretase PS1 levels compensated for the cytotoxicity of full-length Ryk in these cells. These findings reveal that the Ryk-ICD pathway may impair FOXO protective activity in mutant polyglutamine neurons, suggesting that neurons are unable to efficiently maintain function and resist disease from the earliest phases of the pathogenic process in HD. © 2014 Tourette et al

Eff ectiveness of one dose of oral cholera vaccine in response to an outbreak: a case-cohort study

Background Oral cholera vaccines represent a new eff ective tool to fi ght cholera and are licensed as two-dose regimens with 2–4 weeks between doses. Evidence from previous studies suggests that a single dose of oral cholera vaccine might provide substantial direct protection against cholera. During a cholera outbreak in May, 2015, in Juba, South Sudan, the Ministry of Health, Médecins Sans Frontières, and partners engaged in the fi rst fi eld deployment of a single dose of oral cholera vaccine to enhance the outbreak response. We did a vaccine eff ectiveness study in conjunction with this large public health intervention. Methods We did a case-cohort study, combining information on the vaccination status and disease outcomes from a random cohort recruited from throughout the city of Juba with that from all the cases detected. Eligible cases were those aged 1 year or older on the fi rst day of the vaccination campaign who sought care for diarrhoea at all three cholera treatment centres and seven rehydration posts throughout Juba. Confi rmed cases were suspected cases who tested positive to PCR for Vibrio cholerae O1. We estimated the short-term protection (direct and indirect) conferred by one dose of cholera vaccine (Shanchol, Shantha Biotechnics, Hyderabad, India). Findings Between Aug 9, 2015, and Sept 29, 2015, we enrolled 87 individuals with suspected cholera, and an 898-person cohort from throughout Juba. Of the 87 individuals with suspected cholera, 34 were classifi ed as cholera positive, 52 as cholera negative, and one had indeterminate results. Of the 858 cohort members who completed a follow-up visit, none developed clinical cholera during follow-up. The unadjusted single-dose vaccine eff ectiveness was 80·2% (95% CI 61·5–100·0) and after adjusting for potential confounders was 87·3% (70·2–100·0). Interpretation One dose of Shanchol was eff ective in preventing medically attended cholera in this study. These results support the use of a single-dose strategy in outbreaks in similar epidemiological settings