bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rotating savings and credit association, its members' diversity, and higher‐level functional capacity: A 3‐year prospective study from the Japan Gerontological Evaluation Study
Authors: Sato Koryu , Kondo Naoki , Kondo Katsunori 
Published: November 2019

AimA rotating savings and credit association – an informal local microfinance group – provides community‐dwelling older adults with cohesive social capital. This study examined whether participation in mujin, a traditional Japanese rotating savings and credit association, affected the maintenance of higher‐level functional capacity in older adults.MethodsWe studied 10 991 older adults living in 24 municipalities in Japan who were aged ≥65 years, and physically and cognitively independent. We carried out a baseline survey in 2013 and a follow‐up survey in 2016. Higher‐level functional capacity, consisting of instrumental activities of daily living, intellectual activity and social role, was assessed using the Tokyo Metropolitan Institute of Gerontology Index of Competence. To address potential reverse causation, we used stabilized inverse probability weights to balance characteristics at baseline between mujin participants and non‐participants.ResultsIn our analytic sample, 406 out of 10 991 older adults (3.7%) participated in mujin at the baseline. Our weighted logistic regression showed that mujin participants were more likely to maintain higher‐level functional capacity (i.e. full marks in the Tokyo Metropolitan Institute of Gerontology Index of Competence) 3 years later compared with non‐participants (odds ratio 1.75, 95% confidence interval 1.29–2.39). Furthermore, independent social role functioning and intellectual activity were associated with participation in mujin for an equal number of both sexes, as well as people of high social standing.ConclusionsThe present study suggests that rotating savings and credit associations can help older adults maintain their independence in a higher‐level functional capacity. Furthermore, the members' diversity might add to these beneficial effects. Geriatr Gerontol Int 2019; 19: 1268–1274.
Promotion of oxidative stress is associated with mitochondrial dysfunction and muscle atrophy in aging mice
Authors: Kadoguchi Tomoyasu , Shimada Kazunori , Miyazaki Tetsuro , Kitamura Kenichi , Kunimoto Mitsuhiro , Aikawa Tatsuro , Sugita Yurina , Ouchi Shohei , Shiozawa Tomoyuki , Yokoyama‐Nishitani Miho , Fukao Kosuke , Miyosawa Katsutoshi , Isoda Kikuo , Daida Hiroyuki 
Published: November 2019

AimWe examined the changes in oxidative stress, mitochondrial function and muscle atrophy during aging in mice.MethodsWe used 6‐, 12‐ and 24‐month (6 M, 12 M and 24 M)‐old C57BL/6J mice. Skeletal muscles were removed from the lower limb and used for quantitative real‐time polymerase chain reaction, immunoblotting and histological analyses.ResultsThe muscle weight and myocyte cross‐sectional area were significantly decreased in the 12 M and 24 M mice compared with those of the 6 M mice. The levels of the oxidative stress markers, nicotinamide adenine dinucleotide phosphate oxidase 2, nicotinamide adenine dinucleotide phosphate oxidase 4, mitochondrial 4‐hydroxy‐2‐nonenal and 3‐nitrotyrosine, were significantly higher in the 24 M mice compared with those of the 6 M mice. Furthermore, the 24 M mice had lower levels of mitochondrial markers, peroxisome proliferator‐activated receptor gamma coactivator 1 (PGC)‐α, peroxisome proliferator‐activated receptor gamma coactivator‐1β, sirtuin‐1, adenosine triphosphate synthase mitochondria F1 complex α subunit 1 and mitochondrial cytochrome c oxidase 1. The ubiquitin–proteasome pathway genes muscle ring finger‐1 and atrogin‐1 were significantly upregulated in the 12 M and 24 M mice, and protein synthesis markers (phosphorylated‐Akt and ‐p70 ribosomal S6 kinase) were significantly lower in the 24 M mice compared with the 6 M mice (all P < 0.05).ConclusionsThese findings have important implications for the mechanisms that underlie sarcopenia and frailty processes. Geriatr Gerontol Int 2020; 20: 78–84.
Wearing Off Effect of OnabotulinumtoxinA Near the End of Treatment Cycle for Chronic Migraine: A 4‐Year Clinical Experience
Authors: Khan Fawad A. , Mohammed Alaa E. , Poongkunran Mugilan , Chimakurthy Anilkumar , Pepper Michael 
Published: November 2019

IntroductionThe injection interval for onabotulinumtoxinA (BoNTA) in the management of chronic migraine (CM) is 12 weeks (78‐84 days). The aim of this study was to review patient‐reported wearing off effect (WOE) of the therapeutic benefit of BoNTA near the end of the treatment cycle. We intended to describe the demographics of patients at baseline and compare groups of patients with multiple episodes of WOE.MethodsWe conducted a retrospective review of patients with CM who received uninterrupted BoNTA therapy from January 2014 to March 2018. The data from patient‐reported WOE (worsening headache variables and neck pain) that occurred during the 4 weeks (28 days) prior to the scheduled re‐injection of BoNTA for treatment cycles with injection interval ≤13 weeks and without obvious confounding factors were reviewed.ResultsWe identified 98 eligible patients and analyzed 471 treatment cycles. Forty‐three unique patients reported at least 1 occurrence of WOE. About 24/43 patients reported 1 WOE event and 19/43 patients reported ≥2 WOE events. Between the 2 groups, anxiety disorder and opioid use for headache were statistically significantly different. In the former group, the median interquartile range (IQR) dose of BoNTA was 165 (155, 175) units and the median IQR duration of the antinociceptive effect of BoNTA was 66.5 (63, 71.5) days. In the latter group, the median IQR dose of BoNTA was 167 (155, 173.3) units and the median IQR duration of the antinociceptive effect of BoNTA was 65.3 (62.5, 68.8) days. Up to 32% of these patients reported an increase in the use of abortive therapies to manage the symptoms of WOE.DiscussionThe primary goal of BoNTA in the treatment of CM is to mitigate the development of central sensitization. Since the 12‐week injection paradigm may not provide sustained antinociceptive effect in all patients, it may account for the failure of response to BoNTA. Repeated occurrences of the WOE can potentially lead to medication overuse and impact quality of life.
Development of a Prospective Real‐World Data Clinical Registry of Children and Adolescents With Migraine
Authors: Hornik Christoph P. , Gelfand Amy A. , Szperka Christina L. , Pezzuto Tara , Utevsky Amanda , Kessel Shirley , McCune Susan , Alexander John J. , Benjamin Daniel K. , Cohen‐Wolkowiez Michael 
Published: November 2019

ObjectiveTo develop a multicenter, multistakeholder, prospective clinical registry of children and adolescents with migraine to support the collection of real‐world data of sufficient quality to support regulatory submissions and provide site‐based infrastructure support for future clinical trials.BackgroundAs new migraine treatments come to market, pediatric efficacy and safety trials of these agents are needed. A clinical registry is an ideal regulatory strategy to provide both real‐world data and site infrastructure to execute these trials.DesignMulticenter, multistakeholder, prospective real‐world data clinical registry of children and adolescents, 4‐17 years of age, diagnosed with migraine with or without aura. Participants will be followed for up to 12 months at 3‐month intervals, with interval recording of clinical data at study sites and self‐reported data via mobile health application, as well as biobanking. We developed electronic case report forms that incorporated routinely collected clinical data with National Institute of Neurological Disorders and Stroke Headache Common Data Elements (Version 2.0). All data are captured in a 21 CFR Part 11 – compliant electronic data capture system – augmented by a real‐time, web‐based, and customizable data visualization platform. We engaged vendors to provide ancillary biobanking, patient data entry, and data visualization services.ResultsWe used an iterative and highly collaborative multistakeholder approach to design and implement a streamlined registry protocol with input from all participating US sites. At each design and implementation step, we received input from therapeutic area experts, the US Food and Drug Administration (FDA), the National Institutes of Health, patient and parent advocates, health technology partners, drug developers, and site‐based clinical investigators. The registry is governed by a multistakeholder steering committee with representation from sites, industry partners, patient advocates, and a member from the FDA (non‐voting with respect to steering committee matters). The multistakeholder and site‐driven approach to registry design and execution was highly efficient and resulted in the first patient enrolled within 6 months of concept development.ConclusionsBy ensuring regulatory compliant implementation of the registry, we created both a source of real‐world data and a multisite platform for the conduct of future clinical trials that can be submitted to regulatory authorities to support inclusion of pediatric data in approved drug labeling. A highly collaborative approach with broad stakeholder engagement at all stages of the registry development was a key to our operational success.
Preserving US microbe collections sparks future discoveries
Authors: Boundy-Mills K. , McCluskey K. , Elia P. , Glaeser J.A. , Lindner D.L. , Nobles D.R. , Normanly J. , Ochoa-Corona F.M. , Scott J.A. , Ward T.J. , Webb K.M. , Webster K. , Wertz J.E. 
Published: November 2019

SummaryCollections of micro-organisms are a crucial element of life science research infrastructure but are vulnerable to loss and damage caused by natural or man-made disasters, the untimely death or retirement of personnel, or the loss of research funding. Preservation of biological collections has risen in priority due to a new appreciation for discoveries linked to preserved specimens, emerging hurdles to international collecting and decreased funding for new collecting. While many historic collections have been lost, several have been preserved, some with dramatic rescue stories. Rescued microbes have been used for discoveries in areas of health, biotechnology and basic life science. Suggestions for long-term planning for microbial stocks are listed, as well as inducements for long-term preservation.
Role of VEGFR‐1 in melanoma acquired resistance to the BRAF inhibitor vemurafenib
Authors: Atzori Maria Grazia , Ceci Claudia , Ruffini Federica , Trapani Mauro , Barbaccia Maria Luisa , Tentori Lucio , D'Atri Stefania , Lacal Pedro Miguel , Graziani Grazia 
Published: November 2019

AbstractThe vascular endothelial growth factor receptor‐1 (VEGFR‐1) is a tyrosine kinase receptor frequently expressed in melanoma. Its activation by VEGF‐A or placental growth factor (PlGF) promotes tumour cell survival, migration and invasiveness. Moreover, VEGFR‐1 stimulation contributes to pathological angiogenesis and induces recruitment of tumour‐associated macrophages. Since melanoma acquired resistance to BRAF inhibitors (BRAFi) has been associated with activation of pro‐angiogenic pathways, we have investigated VEGFR‐1 involvement in vemurafenib resistance. Results indicate that human melanoma cells rendered resistant to vemurafenib secrete greater amounts of VEGF‐A and express higher VEGFR‐1 levels compared with their BRAFi‐sensitive counterparts. Transient VEGFR‐1 silencing in susceptible melanoma cells delays resistance development, whereas in resistant cells it increases sensitivity to the BRAFi. Consistently, enforced VEGFR‐1 expression, by stable gene transfection in receptor‐negative melanoma cells, markedly reduces sensitivity to vemurafenib. Moreover, melanoma cells expressing VEGFR‐1 are more invasive than VEGFR‐1 deficient cells and receptor blockade by a specific monoclonal antibody (D16F7 mAb) reduces extracellular matrix invasion triggered by VEGF‐A and PlGF. These data suggest that VEGFR‐1 up‐regulation might contribute to melanoma progression and spreading after acquisition of a drug‐resistant phenotype. Thus, VEGFR‐1 inhibition with D16F7 mAb might be a suitable adjunct therapy for VEGFR‐1 positive tumours with acquired resistance to vemurafenib.
Achieving the composite end‐point of glycated hemoglobin <7.0% without weight gain or hypoglycemia with once‐weekly dulaglutide in Chinese patients with type 2 diabetes: A post‐hoc analysis
Authors: Xiao Xinhua , Wang Changjiang , Lai Xiaoyang , Zhang Bin , Gu Liqun , Hou Jianing , Zhou Zhiguang 
Published: November 2019

AbstractAims/IntroductionTo assess the effect of dulaglutide (DU) 1.5/0.75 mg in comparison with glimepiride (GLIM) or insulin glargine (GLAR) on the composite end‐point in Chinese type 2 diabetes patients.Materials and MethodsPost‐hoc analyses of two randomized phase III trials (NCT01644500 and NCT01648582) were carried out using Fisher’s exact test. The primary composite end‐point was the number of patients reaching glycated hemoglobin (HbA1c) <7.0%, without weight gain and hypoglycemia. Secondary composite end‐points included the number of patients reaching HbA1c <7.0% without weight gain and HbA1c <7.0% without hypoglycemia.ResultsData of 1,147 Chinese type 2 diabetes patients were analyzed (NCT01644500 = 556; NCT01648582 = 591). In each analyzed trial, 40–48% of patients received DU (1.5 mg), 30–39% of patients received DU (0.75 mg) and 15–20% of patients on active comparators (GLIM/GLAR) reached the primary composite end‐point at week 26 (P < 0.001 for DU vs GLIM/GLAR). At 52 weeks, 26% of patients that received DU (1.5 mg), 23% of patients that received DU (0.75 mg) and 7% of patients that received GLAR attained the primary composite end‐point (P < 0.001 for DU vs GLAR). A similar trend of results was found for secondary composite end‐points.ConclusionsDulaglutide is found to be an effective therapeutic alternative for Chinese type 2 diabetes patients. Compared with GLIM/GLAR, significantly greater proportions of patients on DU attained the HbA1c target of <7.0% without weight gain or hypoglycemia.
Late recurrence of melanoma after 10 years – Is the course of the disease different from early recurrences?
Authors: Sarac E. , Wilhelmi J. , Thomas I. , Leiter U. , Keim U. , Eigentler T.K. , Garbe C. , Amaral T. 
Published: November 2019

AbstractBackgroundIt is known that melanoma can metastasize and recur many years after the first diagnosis. Although predictive and prognostic factors for melanoma are well defined, there is still insufficient information about the factors affecting the recurrence period and the effect of the recurrence time to survival.ObjectivesThis study investigates the course of melanoma to show prognostic factors comparing early and late recurrence patients. The main objective is to uncover the effect of the recurrence time on the progression of the disease.MethodsIn this retrospective study, late recurrence (LR) was defined as melanoma recurrence 10 years after the first diagnosis and early recurrence (ER) was defined as recurrence within 10 years. Gender, age, localization of primary tumour, time to first metastasis, survival rates, histological subtype, stage, tumour thickness, invasion level, ulceration and regression of the primary melanoma were documented. Survival curves were evaluated using the Kaplan–Meier and compared with the log‐rank test. Multivariate Cox proportional hazard models were used to identify significant independent prognostic factors for melanoma‐specific survival (MSS).ResultsA total of 1537 melanoma patients were analysed. Early metastasis was developed in 1438 patients (93.6%), and 99 patients (6.4%) developed late metastasis. Late recurrence patients were younger (P < 0.001) and had fewer ulcerated (P = 0.005), fewer head/neck localized (P = 0.009) and thinner (P < 0.001) melanomas than ER patients. The MSS time (mean ± SD) was nearly identical for LR (31 ± 4.4 months 95% CI [22.3–39.7]) and ER (32 ± 1.9 months [28.3–35.7]). Multivariate regression analysis revealed male gender (hazard ratio [HR = 1.4, P < 0.001), truncal tumour localization (HR = 1.7, P < 0.001), tumour thickness (HR = 1.4, P < 0.045) and ulceration (HR = 1.3, P < 0.008) as significant independent prognostic factors for MSS.ConclusionAlthough ER and LR patients are found to have different clinicopathologic features, the time of the first recurrence after diagnosis do not seem to have an effect on the survival.
Intravenous lipid emulsion modifies synaptic transmission in hippocampal CA1 pyramidal neurons after bupivacaine‐induced central nervous system toxicity
Authors: Nie Hao , Bai Zhixia , Li Zhenzhou , Yan Li , Chen Xue‐Xin 
Published: November 2019

AbstractLocal anesthetics can cause severe toxicity when absorbed systemically. Rapid intravenous administration of lipid emulsion (LE) is the standard of care for severe local anesthetic systemic toxicity which can cause cardiovascular and central nervous system (CNS) injury. The biological mechanism by which LE alleviates CNS toxicity remains unknown and understudied. Previous research has suggested that local anesthetics cause an imbalance of excitatory and inhibitory transmission in the brain. Therefore, this study aimed to observe the effect of LE on glutamate‐ and GABA‐induced currents in CA1 pyramidal neurons after bupivacaine‐induced CNS toxicity. We further characterized post‐synaptic modifications in these cells to try to elucidate the mechanism by which LE mediates bupivacaine‐induced CNS toxicity. Sprague–Dawley rats received intravenous bupivacaine (1 mg kg−1 min−1) in either normal saline or LE (or LE without bupivacaine) for 5 min. An acute brain slice preparation and a combination of whole‐cell patch clamp techniques and whole‐cell recordings were used to characterize action potential properties, miniature excitatory, and inhibitory post‐synaptic currents, and post‐synaptic modifications of excitatory and inhibitory transmission in CA1 hippocampal pyramidal neurons. The expression level of GABAA receptors were assessed with western blotting, whereas H&E and TUNEL staining were used to assess cytoarchitecture and apoptosis levels respectively. Bupivacaine treatment significantly increased the number of observed action potentials, whereas significantly decreasing rheobase, the first interspike interval (ISI), and hyperpolarization‐activated cation currents (Ih) in CA1 pyramidal neurons. LE treatment significantly reduced the frequency of miniature inhibitory post‐synaptic currents and enhanced GABA‐induced paired pulse ratio with 50 ms interval stimulation in bupivacaine‐treated rats. Regulation of GABAA levels is a promising mechanism by which LE may ameliorate CNS toxicity after systemic absorption of bupivacaine.
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Insulin‐induced hypoglycaemia suppresses pulsatile luteinising hormone secretion and arcuate Kiss1 cell activation in female mice
Authors: McCosh Richard B. , Kreisman Michael J. , Tian Katherine , Ho Bryan S. , Thackray Varykina G. , Breen Kellie M. 
Published: November 2019

AbstractStress suppresses pulsatile luteinising hormone (LH) secretion in a variety of species, although the mechanism underlying this inhibition of reproductive function remains unclear. Metabolic stress, particularly hypoglycaemia, is a clinically‐relevant stress type that is modelled with bolus insulin injection (insulin‐induced hypoglycaemia). The present study utilised ovariectomised C57BL/6 mice to test the hypothesis that acute hypoglycaemia suppresses pulsatile LH secretion via central mechanisms. Pulsatile LH secretion was measured in 90‐minute sampling periods immediately prior to and following i.p. injection of saline or insulin. The secretion of LH was not altered over time in fed animals or acutely fasted (5 hours) animals following an i.p. saline injection. By contrast, insulin elicited a robust suppression of pulsatile LH secretion in fasted animals, preventing LH pulses in five of six mice. To identify the neuroendocrine site of impairment, a kisspeptin challenge was performed in saline or insulin pre‐treated animals in a cross‐over design. LH secretion in response to exogenous kisspeptin was not different between animals pre‐treated with saline or insulin, indicating normal gonadotrophin‐releasing hormone cell and pituitary responses during acute hypoglycaemia. Based on this finding, the effect of insulin‐induced hypoglycaemia on arcuate kisspeptin (Kiss1) cell function was determined using c‐Fos as a marker of neuronal activation. Insulin caused a significant suppression in the percentage of Kiss1 cells in the arcuate nucleus that contained c‐Fos compared to saline‐injected controls. Taken together, these data support the hypothesis that insulin‐induced hypoglycaemia suppresses pulsatile LH secretion in the female mouse via predominantly central mechanisms, which culminates in the suppression of the arcuate Kiss1 population.
Perinatal compromise contributes to programming of GABAergic and glutamatergic systems leading to long‐term effects on offspring behaviour
Authors: Shaw Julia C. , Crombie Gabrielle K. , Zakar Tamas , Palliser Hannah K. , Hirst Jonathan J. 
Published: November 2019

AbstractExtensive evidence now shows that adversity during the perinatal period is a significant risk factor for the development of neurodevelopmental disorders long after the causative event. Despite stemming from a variety of causes, perinatal compromise appears to have similar effects on the developing brain, thereby resulting in behavioural disorders of a similar nature. These behavioural disorders occur in a sex‐dependent manner, with males affected more by externalising behaviours such as attention deficit hyperactivity disorder (ADHD) and females by internalising behaviours such as anxiety. Regardless of the causative event or the sex of the offspring, these disorders may begin in childhood or adolescence but extend into adulthood. A mechanism by which adverse events in the perinatal period impact later in life behaviour has been shown to be the changing epigenetic landscape. Methylation of the GAD1/GAD67 gene, which encodes the key glutamate‐to‐GABA‐synthesising enzyme glutamate decarboxylase 1, resulting in increased levels of glutamate, is one epigenetic mechanism that may account for a tendency towards excitation in disorders such as ADHD. Exposure of the fetus or the neonate to high levels of cortisol may be the mediator between perinatal compromise and poor behavioural outcomes because evidence suggests that increased glucocorticoid exposure triggers widespread changes in the epigenetic landscape. This review summarises the current evidence and recent literature about the impact of various perinatal insults on the epigenome and the common mechanisms that may explain the similarity of behavioural outcomes occurring following diverse perinatal compromise.