Poly ADP-ribose signaling is dysregulated in Huntington disease.

Huntington disease (HD) is a genetic neurodegenerative disease caused by cytosine, adenine, guanine (CAG) expansion in the Huntingtin (HTT) gene, translating to an expanded polyglutamine tract in the HTT protein. Age at disease onset correlates to CAG repeat length but varies by decades between individuals with identical repeat lengths. Genome-wide association studies link HD modification to DNA repair and mitochondrial health pathways. Clinical studies show elevated DNA damage in HD, even at the premanifest stage. A major DNA repair node influencing neurodegenerative disease is the PARP pathway. Accumulation of poly adenosine diphosphate (ADP)-ribose (PAR) has been implicated in Alzheimer and Parkinson diseases, as well as cerebellar ataxia. We report that HD mutation carriers have lower cerebrospinal fluid PAR levels than healthy controls, starting at the premanifest stage. Human HD induced pluripotent stem cell-derived neurons and patient-derived fibroblasts have diminished PAR response in the context of elevated DNA damage. We have defined a PAR-binding motif in HTT, detected HTT complexed with PARylated proteins in human cells during stress, and localized HTT to mitotic chromosomes upon inhibition of PAR degradation. Direct HTT PAR binding was measured by fluorescence polarization and visualized by atomic force microscopy at the single molecule level. While wild-type and mutant HTT did not differ in their PAR binding ability, purified wild-type HTT protein increased in vitro PARP1 activity while mutant HTT did not. These results provide insight into an early molecular mechanism of HD, suggesting possible targets for the design of early preventive therapies.

Adaptive laboratory evolution in a novel parallel shaken pH-auxostat.

Adaptive laboratory evolution (ALE) is a widely used microbial strain development and optimization method. ALE experiments, to select for faster-growing strains, are commonly performed as serial batch cultivations in shake flasks, serum bottles, or microtiter plates or as continuous cultivations in bioreactors on a laboratory scale. To combine the advantages of higher throughput in parallel shaken cultures with continuous fermentations for conducting ALE experiments, a new Continuous parallel shaken pH-auxostat (CPA) was developed. The CPA consists of six autonomous parallel shaken cylindrical reactors, equipped with real-time pH control of the culture medium. The noninvasive pH measurement and control are realized by biocompatible pH sensor spots and a programmable pump module, to adjust the dilution rate of fresh medium for each reactor separately. Two different strains of the methylotrophic yeast Ogataea polymorpha were used as microbial model systems for parallel chemostat and pH-auxostat cultivations. During cultivation, the medium is acidified by the microbial activity of the yeast. For pH-auxostat cultivations, the growth-dependent acidification triggers the addition of fresh feed medium into the reactors, leading to a pH increase and thereby to the control of the pH to a predetermined set value. By controlling the pH to a predetermined set value, the dilution rate of the continuous cultivation is adjusted to values close to the washout point, in the range of the maximum specific growth rate of the yeast. The pH control was optimized by conducting a step-response experiment and obtaining tuned PI controller parameters by the Chien-Hrones-Reswick (CHR) PID tuning method. Two pH-auxostat cultivations were performed with two different O. polymorpha strains at high dilution rates for up to 18 days. As a result, up to 4.8-fold faster-growing strains were selected. The increased specific maximum growth rates of the selected strains were confirmed in subsequent batch cultivations.

High Charge Density in Peptide Dendrimers is Required to Destabilize Membranes: Insights into Endosome Evasion.

Peptide dendrimers are a type of branched, symmetric, and topologically well-defined molecule that have already been used as delivery systems for nucleic acid transfection. Several of the most promising sequences showed high efficiency in many key steps of transfection, namely, binding siRNA, entering cells, and evading the endosome. However, small changes to the peptide dendrimers, such as in the hydrophobic core, the amino acid chirality, or the total available charges, led to significantly different experimental results with unclear mechanistic insights. In this work, we built a computational model of several of those peptide dendrimers (MH18, MH13, and MH47) and some of their variants to study the molecular details of the structure and function of these molecules. We performed CpHMD simulations in the aqueous phase and in interaction with a lipid bilayer to assess how conformation and protonation are affected by pH in different environments. We found that while the different peptide dendrimer sequences lead to no substantial structural differences in the aqueous phase, the total charge and, more importantly, the total charge density are key for the capacity of the dendrimer to interact and destabilize the membrane. These dendrimers become highly charged when the pH changes from 7.5 to 4.5, and the presence of a high charge density, which is decreased for MH47 that has four fewer titratable lysines, is essential to trigger membrane destabilization. These findings are in excellent agreement with the experimental data and help us to understand the high efficiency of some dendrimers and why the dendrimer MH47 is unable to complete the transfection process. This evidence provides further understanding of the mode of action of these peptide dendrimers and will be pivotal for the future design of new sequences with improved transfection capabilities.

Examining the Effects of a 24-Week Exercise Program on Functional Capacity, Cognitive Capacity, and Quality of Life in Individuals With Intellectual and Developmental Disabilities.

This study investigated the effects of two physical exercise programs for adults with intellectual and developmental disabilities. Twenty-one participants were assigned to an indoor group (IG, n = 7; 24-week gym intervention with machine), an outdoor group (OG, n = 7; 24-week outdoor intervention with low-cost materials) or a control group. The outcomes assessed included quality of life, dementia, and functional capacity. The IG significantly improved physical well-being compared with the control group (p = .017). There were no significant differences in dementia score between groups and moments. Postintervention, the IG showed improvements compared with the control group for the 30-s sit-to-stand test (p = .03), timed up-and-go (p = .00), and 6-min-walk test (p = .033) and between moments in the IG for 30-s sit-to-stand test (pre ≠ post; p = .007) and 6-min-walk test (pre ≠ post; p = .007). Outdoor interventions appeared effective for physical well-being, while indoor interventions using weight-training machines benefited functional capacity. No significant effects were observed for dementia/cognitive decline.

FK506 impairs neutrophil migration that results in increased polymicrobial sepsis susceptibility.

OBJECTIVE: This study aimed to investigate the effects of FK506 on experimental sepsis immunopathology. It investigated the effect of FK506 on leukocyte recruitment to the site of infection, systemic cytokine production, and organ injury in mice with sepsis. METHODS: Using a murine cecal ligation and puncture (CLP) peritonitis model, the experiments were performed with wild-type (WT) mice and mice deficient in the gene Nfat1 (Nfat1-/-) in the C57BL/6 background. Animals were treated with 2.0 mg/kg of FK506, subcutaneously, 1 h before the sepsis model, twice a day (12 h/12 h). The number of bacteria colony forming units (CFU) was manually counted. The number of neutrophils in the lungs was estimated by the myeloperoxidase (MPO) assay. The expression of CXCR2 in neutrophils was determined using flow cytometry analysis. The expression of inflammatory cytokines in macrophage was determined using ELISA. The direct effect of FK506 on CXCR2 internalization was evaluated using HEK-293T cells after CXCL2 stimulation by the BRET method. RESULTS: FK506 treatment potentiated the failure of neutrophil migration into the peritoneal cavity, resulting in bacteremia and an exacerbated systemic inflammatory response, which led to higher organ damage and mortality rates. Failed neutrophil migration was associated with elevated CXCL2 chemokine plasma levels and lower expression of the CXCR2 receptor on circulating neutrophils compared with non-treated CLP-induced septic mice. FK506 did not directly affect CXCL2-induced CXCR2 internalization by transfected HEK-293 cells or mice neutrophils, despite increasing CXCL2 release by LPS-treated macrophages. Finally, the CLP-induced response of Nfat1-/- mice was similar to those observed in the Nfat1+/+ genotype, suggesting that the FK506 effect is not dependent on the NFAT1 pathway. CONCLUSION: Our data indicate that the increased susceptibility to infection of FK506-treated mice is associated with failed neutrophil migration due to the reduced membrane availability of CXCR2 receptors in response to exacerbated levels of circulating CXCL2.

Interfacial Dynamics and Growth Modes of ß2-Microglobulin Dimers.

Protein aggregation is a complex process, strongly dependent on environmental conditions and highly structurally heterogeneous, both at the final level of fibril structure and intermediate level of oligomerization. Since the first step in aggregation is the formation of a dimer, it is important to clarify how certain properties of the latter (e.g., stability or interface geometry) may play a role in self-association. Here, we report a simple model that represents the dimer's interfacial region by two angles and combine it with a simple computational method to investigate how modulations of the interfacial region occurring on the ns-µs time scale change the dimer's growth mode. To illustrate the proposed methodology, we consider 15 different dimer configurations of the ß2m D76N mutant protein equilibrated with long Molecular Dynamics simulations and identify which interfaces lead to limited and unlimited growth modes, having, therefore, different aggregation profiles. We found that despite the highly dynamic nature of the starting configurations, most polymeric growth modes tend to be conserved within the studied time scale. The proposed methodology performs remarkably well taking into consideration the nonspherical morphology of the ß2m dimers, which exhibit unstructured termini detached from the protein's core, and the relatively weak binding affinities of their interfaces, which are stabilized by nonspecific apolar interactions. The proposed methodology is general and can be applied to any protein for which a dimer structure has been experimentally determined or computationally predicted.

Acclimatization of Sweet Potatoes Under in vitro Application of Diatomaceous Earth.

Diatomaceous earth is an organic naturally occurring material rich in silicon. This silicon source can be used in organic agriculture, it also has a great potential of use in the acclimatization of crops. However, there are no reports of the effects of diatomaceous earth supplementation on the micropropagation of sweet potato. Thus, the objective of this study was to evaluate the effects of different concentrations of diatomaceous earth applied in vitro on the growth, physiology and anatomy of sweet potato cv. 'Brazlândia Branca' after acclimatization. Four concentrations of diatomaceous earth. After 30 days of in vitro growth, the plants were transferred to a greenhouse for acclimatization. After 45 days, leaf number, shoot and root length, fresh and dry shoot and root mass, gas exchange, chlorophyll content, root and leaf anatomy. The experimental design was completely randomized. The supplementation of diatomaceous earth in the in vitro cultivation had beneficial effects, increasing the accumulation of mass, improving the photosynthetic apparatus and promoting favorable anatomical characteristics during the acclimatization of the sweet potato plants. In addition, the use of diatomaceous earth achieved adequate seedling development, with higher seedling quality and resistance to biotic and abiotic effects than attained with control treatment.

Effects of a 24-Week Low-Cost Multicomponent Exercise Program on Health-Related Functional Fitness in the Community-Dwelling Aged and Older Adults.

Background and Objectives: This study aimed to examine the effects of a low-cost multicomponent exercise program on health-related functional fitness in the community-dwelling aged and older adults. As a second objective, this study compared the exercise program between aged adults (<65 years) and those considered elderly (≥65 years). Materials and Methods: Forty-eight participants were included in the exercise program, and their mean age was 64.73 years (±5.93 years). The Senior Fitness Tests were performed by each participant. A dynamometer was used to assess hand grip strength, and body composition was assessed considering the body mass index. Paired-sample t test was used to compare data at baseline and after the exercise program, considering the total sample. Afterwards, a 2 × 2 analysis of variance was used to examine differences within and between groups. Results: Statistically significant improvements in the chair stand (t = -14.06; p < 0.001; d = 0.42), arm curl (t = -12.10; p < 0.001; d = 0.58), 2 min step test (t = -9.41; p < 0.001; d = 0.24), timed up and go test (t = 5.60; p < 0.001; d = 0.19), and hand grip strength (t = -3.33; p < 0.001; d = 0.15) were observed. There were also significant differences in the back scratch (t = -6.68; p < 0.001; d = 0.18) and chair sit and reach test (t = 5.04; p < 0.001; d = 0.05), as well as body mass index (p < 0.05). No significant differences were found between groups (p > 0.05). Conclusion: This study provides evidence that a 24-week low-cost community-based exercise program can improve functional fitness in aged and in older adults. The exercise program supplied the necessary data to construct further randomized controlled trials that can be performed in the community in an environmentally sustainable fashion and applied, not only to the elderly, but also to those transitioning to this age group.

Motivational Correlates, Satisfaction with Life, and Physical Activity in Older Adults: A Structural Equation Analysis.

Background: Motivation is a crucial factor in predicting health-related outcomes, and understanding the determinants of motivation can provide valuable insights into how to improve health behaviors and outcomes in older adults. In this study, we aimed to investigate the associations between intrinsic and extrinsic exercise motivation, basic psychological needs, satisfaction with life, and physical activity among the elderly population. Methods: The sample consisted of 268 older adults (59 male, 209 female) aged 65-90 years old (Mage = 68.11, SD = 6.95). All participants reported that they were exercising, on average, 1.65 days (SD = 0.51) per week. Factor analysis was conducted using a two-step approach. First, a confirmatory factor analysis and then a structural equation model considering all variables under analysis was performed. Results: the structural model displayed acceptable fit to the data: χ2/df = 3.093; CFI = 0.913; TLI = 0.908; SRMR = 0.071; RMSEA 0.079 [0.066, 0.092]. Significant direct effects were found as theoretically proposed, namely: (a) intrinsic motivation were positively and significantly associated with basic psychological need satisfaction (p < 0.001); (b) extrinsic motivation were negatively but not significantly associated with basic psychological needs (p < 0.001); and (c) basic psychological need satisfaction were positively and significantly associated with satisfaction with life (p < 0.001) and physical activity (p < 0.001). Conclusions: Intrinsic motivation and basic psychological needs play a crucial role in shaping exercise behavior and overall well-being. By understanding these motivation and needs, exercise and health professionals can work towards fulfilling them and achieving a greater sense of satisfaction in the life of the elderly and promote exercise adherence.

Neurofilament Light Protein as a Potential Blood Biomarker for Huntington's Disease in Children.

BACKGROUND: Juvenile-onset Huntington's disease (JOHD) is a rare and particularly devastating form of Huntington's disease (HD) for which clinical diagnosis is challenging and robust outcome measures are lacking. Neurofilament light protein (NfL) in plasma has emerged as a prognostic biomarker for adult-onset HD. METHODS: We performed a retrospective analysis of samples and data collected between 2009 and 2020 from the Kids-HD and Kids-JHD studies. Plasma samples from children and young adults with JOHD, premanifest HD (preHD) mutation carriers, and age-matched controls were used to quantify plasma NfL concentrations using ultrasensitive immunoassay. RESULTS: We report elevated plasma NfL concentrations in JOHD and premanifest HD mutation-carrying children. In pediatric HD mutation carriers who were within 20 years of their predicted onset and patients with JOHD, plasma NfL level was associated with caudate and putamen volumes. CONCLUSIONS: Quantifying plasma NfL concentration may assist clinical diagnosis and therapeutic trial design in the pediatric population. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

An MDS Evidence-Based Review on Treatments for Huntington's Disease.

BACKGROUND: Huntington's disease (HD) is a rare neurodegenerative disorder with protean clinical manifestations. Its management is challenging, consisting mainly of off-label treatments. OBJECTIVES: The International Parkinson and Movement Disorder Society commissioned a task force to review and evaluate the evidence of available therapies for HD gene expansion carriers. METHODS: We followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Eligible randomized controlled trials were identified via an electronic search of the CENTRAL, MEDLINE, and EMBASE databases. All eligible trials that evaluated one or more of 33 predetermined clinical questions were included. Risk of bias was evaluated using the Cochrane Risk of Bias tool. A framework was adapted to allow for efficacy and safety conclusions to be drawn from the balance between the GRADE level of evidence and the importance of the benefit/harm of the intervention. RESULTS: Twenty-two eligible studies involving 17 interventions were included, providing data to address 8 clinical questions. These data supported a likely effect of deutetrabenazine on motor impairment, chorea, and dystonia and of tetrabenazine on chorea. The data did not support a disease-modifying effect for premanifest and manifest HD. There was no eligible evidence to support the use of specific treatments for depression, psychosis, irritability, apathy, or suicidality. Similarly, no evidence was eligible to support the use of physiotherapy, occupational therapy, exercise, dietary, or surgical treatments. CONCLUSIONS: Data for therapeutic interventions in HD are limited and support only the use of VMAT2 inhibitors for specific motor symptoms. © 2021 International Parkinson and Movement Disorder Society.

Natural history and burden of Huntington's disease in the UK: A population-based cohort study.

BACKGROUND: Huntington's disease (HD) is a rare neurodegenerative disease that presents with progressive psychological, cognitive and motor impairment. These diverse symptoms place a high burden on the patient, families and the healthcare systems they rely on. This study aimed to describe the epidemiology and clinical burden in individuals with HD compared with controls from the general population. METHODS: This cohort study utilised data from general practitioner medical records to estimate the prevalence and incidence of HD between January 2000 and December 2018. A cohort of incident HD cases were matched 1:3 to controls from the general population, in whom common clinical diagnoses, medications and healthcare interventions were compared at the time of first recorded diagnosis and at a time close to death. Incidence rates of common diagnoses and mortality were compared with matched controls in the time following HD diagnosis. RESULTS: Prevalence of HD increased between 2000 and 2018, whilst incidence remained stable. Prevalence of psychiatric diagnoses and symptomatic treatments were higher in HD cases than controls. A higher relative risk of psychotic disorders, depression, insomnia, dementia, weight loss, pneumonia and falls was observed in HD cases. Risk of death was >4 times higher in HD, with a median survival of ~12 years from first recorded diagnosis. CONCLUSIONS: This study demonstrates the significant and progressive clinical burden in individuals with HD up to 18 years after first recorded diagnosis.

Set to fail: Affective dynamics in a resistance training program designed to reach muscle concentric failure.

Grounded in hedonic assumptions, evidence suggests that people tend to engage in activities they consider pleasurable and enjoyable, while trying to avoid pain and displeasure. This suggests that the dynamic between positive and negative affect can influence current behavior and the intentions to continue performing. Regarding resistance training (RT), research focusing on how to promote a better affective response is still scarce and much needed. Given existing limitations and theoretical suggestions, a RT program was developed and applied to recreational exercisers in a quasi-experimental design aiming to (1) explore the affective response dynamic through an assessment after the last set of each exercise; and (2) analyze possible differences of preference and tolerance profiles in affective variables (core affect and enjoyment). For that purpose, 43 participants (21 male and 22 female; Mage  = 34.69 ± 6.71 years; Mexperience  = 8.32 ± 4.54 years; MBMI  = 24.26 ± 2.64 kg/m2 ) accepted to participate in this study. Descriptive statistics, correlational, and group comparisons analyses were performed to provide evidence for proposed objectives. The present study showed that measures of affective valence/arousal applied immediately after a set represents a feasible and ecologically valid approach to tap core affect. Results presented evidence that recreationally trained exercisers in a common RT program would need a minimum of one measurement to assess the affective response. However, additional assessments could refine the understanding of exercise pleasurable experience. Results also suggest that exercisers with distinct profiles of preference/tolerance depicted differentiated patterns for the affective response, possibly justifying a distinct approach when promoting affective regulation.

A Remote Digital Monitoring Platform to Assess Cognitive and Motor Symptoms in Huntington Disease: Cross-sectional Validation Study.

BACKGROUND: Remote monitoring of Huntington disease (HD) signs and symptoms using digital technologies may enhance early clinical diagnosis and tracking of disease progression, guide treatment decisions, and monitor response to disease-modifying agents. Several recent studies in neurodegenerative diseases have demonstrated the feasibility of digital symptom monitoring. OBJECTIVE: The aim of this study was to evaluate a novel smartwatch- and smartphone-based digital monitoring platform to remotely monitor signs and symptoms of HD. METHODS: This analysis aimed to determine the feasibility and reliability of the Roche HD Digital Monitoring Platform over a 4-week period and cross-sectional validity over a 2-week interval. Key criteria assessed were feasibility, evaluated by adherence and quality control failure rates; test-retest reliability; known-groups validity; and convergent validity of sensor-based measures with existing clinical measures. Data from 3 studies were used: the predrug screening phase of an open-label extension study evaluating tominersen (NCT03342053) and 2 untreated cohorts-the HD Natural History Study (NCT03664804) and the Digital-HD study. Across these studies, controls (n=20) and individuals with premanifest (n=20) or manifest (n=179) HD completed 6 motor and 2 cognitive tests at home and in the clinic. RESULTS: Participants in the open-label extension study, the HD Natural History Study, and the Digital-HD study completed 89.95% (1164/1294), 72.01% (2025/2812), and 68.98% (1454/2108) of the active tests, respectively. All sensor-based features showed good to excellent test-retest reliability (intraclass correlation coefficient 0.89-0.98) and generally low quality control failure rates. Good overall convergent validity of sensor-derived features to Unified HD Rating Scale outcomes and good overall known-groups validity among controls, premanifest, and manifest participants were observed. Among participants with manifest HD, the digital cognitive tests demonstrated the strongest correlations with analogous in-clinic tests (Pearson correlation coefficient 0.79-0.90). CONCLUSIONS: These results show the potential of the HD Digital Monitoring Platform to provide reliable, valid, continuous remote monitoring of HD symptoms, facilitating the evaluation of novel treatments and enhanced clinical monitoring and care for individuals with HD.

Kynurenine pathway metabolites in cerebrospinal fluid and blood as potential biomarkers in Huntington's disease.

Converging lines of evidence from several models, and post-mortem human brain tissue studies, support the involvement of the kynurenine pathway (KP) in Huntington's disease (HD) pathogenesis. Quantifying KP metabolites in HD biofluids is desirable, both to study pathobiology and as a potential source of biomarkers to quantify pathway dysfunction and evaluate the biochemical impact of therapeutic interventions targeting its components. In a prospective single-site controlled cohort study with standardised collection of cerebrospinal fluid (CSF), blood, phenotypic and imaging data, we used high-performance liquid-chromatography to measure the levels of KP metabolites-tryptophan, kynurenine, kynurenic acid, 3-hydroxykynurenine, anthranilic acid and quinolinic acid-in CSF and plasma of 80 participants (20 healthy controls, 20 premanifest HD and 40 manifest HD). We investigated short-term stability, intergroup differences, associations with clinical and imaging measures and derived sample-size calculation for future studies. Overall, KP metabolites in CSF and plasma were stable over 6 weeks, displayed no significant group differences and were not associated with clinical or imaging measures. We conclude that the studied metabolites are readily and reliably quantifiable in both biofluids in controls and HD gene expansion carriers. However, we found little evidence to support a substantial derangement of the KP in HD, at least to the extent that it is reflected by the levels of the metabolites in patient-derived biofluids.

Growth and renal function dynamics of renal oncocytomas in patients on active surveillance.

OBJECTIVES: To study the natural history of renal oncocytomas and address indications for intervention by determining how growth is associated with renal function over time, the reasons for surgery and ablation, and disease-specific survival. PATIENTS AND METHODS: The study was conducted in a retrospective cohort of consecutive patients with renal oncocytoma on active surveillance reviewed at the Specialist Centre for Kidney Cancer at the Royal Free London NHS Foundation Trust (2012 to 2019). Comparison between groups was performed using Mann-Whitney U-tests and chi-squared tests. A mixed-effects model with a random intercept for patient was used to study the longitudinal association between tumour size and estimated glomerular filtration rate (eGFR). RESULTS: Longitudinal data from 98 patients with 101 lesions were analysed. Most patients were men (68.3%) and the median (interquartile range [IQR]) age was 69 (13) years. The median (IQR) follow-up was 29 (26) months. Most lesions were small renal masses, and 24% measured over 4 cm. Over half (64.4%) grew at a median (IQR) rate of 2 (4) mm per year. No association was observed between tumour size and eGFR over time (P = 0.871). Nine lesions (8.9%) were subsequently treated. Two deaths were reported, neither were related to the diagnosis of renal oncocytoma. CONCLUSION: Natural history data from the largest active surveillance cohort of renal oncocytomas to date show that renal function does not seem to be negatively impacted by growing oncocytomas, and confirms clinical outcomes are excellent after a median follow-up of over 2 years. Active surveillance should be considered the 'gold standard' management of renal oncocytomas up to 7cm.

Botulinum toxin type A versus anticholinergics for cervical dystonia.

BACKGROUND: This is an update of a Cochrane Review first published in 2005. Cervical dystonia is the most common form of focal dystonia and is a highly disabling movement disorder, characterised by involuntary, usually painful, head posturing. Currently, botulinum toxin type A (BtA) is considered the first line therapy for this condition. Before BtA, anticholinergics were the most widely accepted treatment. OBJECTIVES: To compare the efficacy, safety, and tolerability of BtA versus anticholinergic drugs in adults with cervical dystonia. SEARCH METHODS: We searched the Cochrane Movement Disorders' Trials Register to June 2003, screened reference lists of articles and conference proceedings to September 2018, and searched CENTRAL, MEDLINE, and Embase, with no language restrictions, to July 2020. SELECTION CRITERIA: Double-blind, parallel, randomised trials (RCTs) of BtA versus anticholinergic drugs in adults with cervical dystonia. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed records, selected included studies, extracted data using a paper pro forma, and evaluated the risk of bias and quality of the evidence. We resolved disagreements by consensus or by consulting a third review author. If enough data had been available, we were to perform meta-analyses using a random-effects model for the comparison of BtA versus anticholinergic drugs to estimate pooled effects and corresponding 95% confidence intervals (95% CI). The primary efficacy outcome was improvement in cervical dystonia-specific impairment. The primary safety outcome was the proportion of participants with any adverse event. MAIN RESULTS: We included one RCT of moderate overall risk of bias (as multiple domains were at unclear risk of bias), which included 66 BtA-naive participants with cervical dystonia. Two doses of BtA (Dysport; week 0 and 8; mean dose 262 to 292 U) were compared with daily trihexyphenidyl (up to 24 mg daily). The trial was sponsored by the BtA producer. BtA reduced cervical dystonia severity by an average of 2.5 points (95% CI 0.68 to 4.32) on the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) severity subscale 12 weeks after injection, compared to trihexyphenidyl. More participants reported adverse events in the trihexyphenidyl treatment group (76 events), compared with the BtA group (31 events); however, the difference in dropouts due to adverse events was inconclusive between groups. There was a decreased risk of dry mouth, and memory problems with BtA, but the differences were inconclusive between groups for the other reported side effects (blurred vision, dizziness, depression, fatigue, pain at injection site, dysphagia, and neck weakness). AUTHORS' CONCLUSIONS: We found very low-certainty evidence that BtA is more effective, better tolerated, and safer than trihexyphenidyl. We found no information on a dose-response relationship with BtA, differences between BtA formulations or different anticholinergics, the utility of electromyography-guided injections, or the duration of treatment effect.

Trainer-exerciser relationship: The congruency effect on exerciser psychological needs using response surface analysis.

Perceptions of fitness trainers' need-supportive and need-thwarting behaviors have been shown to impact exercisers' psychological need satisfaction and frustration. Currently, it is unknown whether an agreement or disagreement between exercisers' and fitness trainers' reported perceptions of these behaviors leads to the satisfaction and/or frustration of psychological needs. Based on self-determination theory, the present study examined the effect of congruency between fitness trainers' and exercisers' perceptions of need-supportive and need-thwarting interpersonal behaviors on basic psychological need satisfaction and frustration. A sample of 130 fitness trainers (43 females; Mage  = 31.58 ± 7.65) and a total of 640 gym exercisers (350 females; Mage  = 34.23 ± 11.59) participated in this study. Findings suggested that the majority of fitness trainers tended to over-report their use of need-supportive behavior and under-report their need-thwarting behaviors. Results showed that when there was congruency between fitness trainers' reported use and exercisers' perception of interpersonal behaviors, basic need satisfaction tended to increase. This effect was greater for exercisers that rated their respective fitness trainer high on relatedness support. Fitness trainers should be self-aware of their interpersonal behaviors when engaging with exercisers and interventions based on self-determination theory could serve as a promising avenue to improve the quality of exercisers' experience.

Computational Analysis of the Interactions between the S100B Extracellular Chaperone and Its Amyloid ß Peptide Client.

S100B is an astrocytic extracellular Ca2+-binding protein implicated in Alzheimer's disease, whose role as a holdase-type chaperone delaying Aß42 aggregation and toxicity was recently uncovered. Here, we employ computational biology approaches to dissect the structural details and dynamics of the interaction between S100B and Aß42. Driven by previous structural data, we used the Aß25-35 segment, which recapitulates key aspects of S100B activity, as a starting guide for the analysis. We used Haddock to establish a preferred binding mode, which was studied with the full length Aß using long (1 µs) molecular dynamics (MD) simulations to investigate the structural dynamics and obtain representative interaction complexes. From the analysis, Aß-Lys28 emerged as a key candidate for stabilizing interactions with the S100B binding cleft, in particular involving a triad composed of Met79, Thr82 and Glu86. Binding constant calculations concluded that coulombic interactions, presumably implicating the Lys28(Aß)/Glu86(S100B) pair, are very relevant for the holdase-type chaperone activity. To confirm this experimentally, we examined the inhibitory effect of S100B over Aß aggregation at high ionic strength. In agreement with the computational predictions, we observed that electrostatic perturbation of the Aß-S100B interaction decreases anti-aggregation activity. Altogether, these findings unveil features relevant in the definition of selectivity of the S100B chaperone, with implications in Alzheimer's disease.

Differences between Portuguese and Brazilian Patients with Fibromyalgia Syndrome: Exploring the Associations across Age, Time of Diagnosis, and Fatigue-Related Symptoms.

Background and Objectives: The current literature demonstrates that different cultures have different perceptions of the symptoms of Fibromyalgia Syndrome (FM). The aim of the study was to explore the differences between Brazilian and Portuguese patients with FM in their fatigue experience and to measure the differences in the perception of fatigue according to age and duration of diagnosis. Materials and Methods: In total, 209 Portuguese women aged between 21 and 75 years old (M = 47.44; SD = 10.73) and 429 Brazilian women aged between 18 and 77 years old (M = 46.51; SD = 9.24) were recruited to participate in the present study. Participants filled out the items in the Multidimensional Daily Fatigue-Fibromyalgia-17 Diary (MDF-Fibro-17), a specific tool to measure the level of five components of FM-related fatigue. Results: The results showed a greater perception of all of the components of fatigue in the Brazilian sample. No significant differences were found related to the age and duration of FM diagnosis. Conclusions: Overall, there are significant differences in fatigue symptoms between Portuguese and Brazilian women with FM, suggesting that cultural and geographical differences should be considered when describing fatigue-related symptoms in women with FM.