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Background: Although there is growing recognition of the relevancy of informal caregivers there is scarce information on the contributory factors of caregiver burden in Parkinson's Disease (PD). Objective: To identify the main associated factors to caregivers' burden in people caring for a person with PD. Methods: We analyzed the data set from a multinational online survey the Parkinson's real‐world impact assesSMent (PRISM) focusing on medication use, comorbidities, health‐related quality of life, relationship changes and the use of healthcare and supportive care resources by people with PD and their carers. Structured questionnaires including the Parkinson's disease quality of life questionnaire (PDQ‐39), non‐motor symptoms questionnaire (NMSQuest) and the Questionnaire for impulsive‐compulsive disorder in Parkinson's disease (QUIP) were applied. Caregiver burden was assessed by the Zarit Burden Interview (ZBI). Results: In a cohort of 245 dyads (patient and respective caregiver), caregivers reported a mild to moderate burden. Carers' perception of PD impact in partnership, financial burden, hours of care, patient's age, hypersexuality and health‐related quality of life (HRQoL) were found to be significant contributory factors to caregiver burden. Taken together these variables explained 66.8% of the variance in the Interpretation of the ZBI total score. Conclusions: Caring for a person with PD entails substantial burden, particularly when the caregiver perceives greater changes in partnership dynamics, dedicates more time to caregiving tasks, has financial burden, and when the patient is older, reports worst HRQoL and has sexual compulsive urges. [ABSTRACT FROM AUTHOR]

In phenylketonuria (PKU), high phenylalanine (Phe) levels hamper neurodevelopment impairing executive function later in life. While the second has been more studied, fewer data exist on predictors of PKU patients' development in specific populations. To contribute to the field, we performed a retrospective analysis of predictors of neurodevelopment in PKU patients in a Portuguese cohort. We analyzed the retrospective data on the metabolic control of 89 patients, as their health and familial features. Griffith's Mental Development Scale performance at age 6 (GMDS6) was used to assess neurodevelopment. Our cohort included 14 GMDS6low and 75 GMDS6high patients. In a multivariate analysis, the better predictors of neurodevelopment were the metabolic control at age 3 and year of birth (n = 87, β0 = −121, β1 = −1.77, β2 = 0.06, LRchi2(2) = 13.61, Prob > chi2 = 0.001, Pseudo R2 = 0.1773). With this model, it was possible to define a safety cut‐off of 7.8 mg/dL for the Phe level at age 3 (sensitivity = 72.6%, specificity = 78.6%), confirming the safety of the cut‐off of 6 mg/dL already used in the clinical practice. Our study supports the relevance of metabolic control to predict the neurodevelopment of PKU patients, in the historical context of the disease management. [ABSTRACT FROM AUTHOR]

We describe the phenotype of 22 male patients (20 probands) carrying a hemizygous missense variant in MED12. The phenotypic spectrum is very broad ranging from nonspecific intellectual disability (ID) to the three well‐known syndromes: Opitz–Kaveggia syndrome, Lujan–Fryns syndrome, or Ohdo syndrome. The identified variants were randomly distributed throughout the gene (p = 0.993, χ2 test), but mostly outside the functional domains (p = 0.004; χ2 test). Statistical analyses did not show a correlation between the MED12‐related phenotypes and the locations of the variants (p = 0.295; Pearson correlation), nor the protein domain involved (p = 0.422; Pearson correlation). In conclusion, establishing a genotype–phenotype correlation in MED12‐related diseases remains challenging. Therefore, we think that patients with a causative MED12 variant are currently underdiagnosed due to the broad patients' clinical presentations. [ABSTRACT FROM AUTHOR]

Accurate prediction of the future performance and remaining useful lifetime of next‐generation solar cells such as organic photovoltaics (OPVs) is necessary to drive better designs of materials and ensure reliable system operation. Degradation is multifactorial and difficult to model deterministically; however, with the advent of machine learning, data from outdoor performance monitoring can be used for understanding the relative impact of stress factors and could provide a powerful method to interpret large quantities of outdoor data automatically. Here, we propose the use of artificial neural networks and regression models for forecasting OPV module performance and their degradation as a function of climatic conditions. We demonstrate their predictive capability for short‐term energy forecasting of OPV modules, showing that energy yield can be predicted if climatic conditions are known. In addition, the model has been extended so that the impact of climatic conditions on degradation can be predicted. The combined model has been validated on unseen OPV module data and is able to predict energy yield to within 4% accuracy. [ABSTRACT FROM AUTHOR]

Human life expectancy is increasing faster lately and, consequently, the number of patients with age‐related diseases such as type 2 diabetes (T2D) is rising every year. Cases of hyperinsulinemia have been extensively reported in elderly subjects and this alteration in blood insulin concentration is postulated to be a cause of insulin resistance, which in some cases triggers T2D onset. Thus, it is important to know the underlying mechanisms of age‐dependent hyperinsulinemia to find new strategies to prevent T2D in elderly subjects. Two processes control blood insulin concentration: Insulin secretion by the endocrine portion of the pancreas and insulin clearance, which occurs mainly in the liver by the action of the insulin‐degrading enzyme (IDE). Here, we demonstrated that 10‐month‐old mice (old) display increased body and fat pad weight, compared with 3‐month‐old mice (control), and these alterations were accompanied by glucose and insulin intolerance. We also confirm hyperinsulinemia in the old mice, which was related to increased insulin secretion but not to reduced insulin clearance. Although no changes in insulin clearance were observed, IDE activity was lower in the liver of old compared with the control mice. However, this decreased IDE activity was compensated by increased expression of IDE protein in the liver, thus explaining the similar insulin clearance observed in both groups. In conclusion, at the beginning of aging, 10‐month‐old mice do not display any alterations in insulin clearance. Therefore, hyperinsulinemia is initiated primarily due to a higher insulin secretion in the age‐related metabolic dysfunction in mice. Age‐related metabolic dysfunction decreased the activity of the main enzyme responsible for insulin degradation, the insulin‐degrading enzyme (IDE), in the liver of mice. Decreased IDE activity in the liver of these mice is compensated by increased IDE protein expression, which could explain the unchanged insulin clearance. Hyperinsulinemia is initiated primarily by increased insulin secretion but not by decreased insulin clearance in the age‐related metabolic dysfunction in mice. [ABSTRACT FROM AUTHOR]

The cellular cytoskeleton is involved with multiple biological processes and is tightly regulated by multiple proteins and effectors. Among these, the RhoGTPases family is one of the most important players. RhoGTPAses are, in turn, regulated by many other elements. In the past decade, one of those regulators, the RhoGAP Rho GTPase Activating Protein 21 (ARHGAP21), has been overlooked, despite being implied as having an important role on many of those processes. In this paper, we aimed to review the available literature regarding ARHGAP21 to highlight its importance and the mechanisms of action that have been found so far for this still unknown protein involved with cell adhesion, migration, Golgi regulation, cell trafficking, and even insulin secretion. [ABSTRACT FROM AUTHOR]

GTPase activating proteins (GAPs) are ubiquitously expressed, and their role in cellular adhesion and membrane traffic processes have been well described. TBC1D1, which is a Rab-GAP, is necessary for adequate glucose uptake by muscle cells, whereas increased TCGAP, which is a Rho-GAP, decreases GLUT4 translocation, and consequently glucose uptake in adipocytes. Here, we assessed the possible involvement of ARHGAP21, a Rho-GAP protein, in glucose homeostasis. For this purpose, wild type mice and ARHGAP21 transgenic whole-body gene-deficiency mice (heterozygous mice, expressing approximately 50% of ARHGAP21) were fed either chow (Ctl and Het) or high-fat diet (Ctl-HFD and Het-HFD). Het-HFD mice showed a reduction in white fat storage, reflected in a lower body weight gain. These mice also displayed an improvement in insulin sensitivity and glucose tolerance, which likely contributed to reduced insulin secretion and pancreatic beta cell area. The reduction of body weight was also observed in Het mice and this phenomenon was associated with an increase in brown adipose tissue and reduced muscle weight, without alteration in glucose-insulin homeostasis. In conclusion, the whole body ARHGAP21 reduction improved glucose homeostasis and protected against diet-induced obesity specifically in Het-HFD mice. However, the mechanism by which ARHGAP21 leads to these outcomes requires further investigation. [ABSTRACT FROM AUTHOR]

The Aristaless-related homeobox ( ARX) gene is implicated in intellectual disability with the most frequent pathogenic mutations leading to expansions of the first two polyalanine tracts. Here, we describe analysis of the ARX gene outlining the approaches in the Australian and Portuguese setting, using an integrated clinical and molecular strategy. We report variants in the ARX gene detected in 19 patients belonging to 17 families. Seven pathogenic variants, being expansion mutations in both polyalanine tract 1 and tract 2, were identifyed, including a novel mutation in polyalanine tract 1 that expands the first tract to 20 alanines. This precise number of alanines is sufficient to cause pathogenicity when expanded in polyalanine tract 2. Five cases presented a probably non-pathogenic variant, including the novel HGVS: c.441_455del, classified as unlikely disease causing, consistent with reports that suggest that in frame deletions in polyalanine stretches of ARX rarely cause intellectual disability. In addition, we identified five cases with a variant of unclear pathogenic significance. Owing to the inconsistent ARX variants description, publications were reviewed and ARX variant classifications were standardized and detailed unambiguously according to recommendations of the Human Genome Variation Society. In the absence of a pathognomonic clinical feature, we propose that molecular analysis of the ARX gene should be included in routine diagnostic practice in individuals with either nonsyndromic or syndromic intellectual disability. A definitive diagnosis of ARX-related disorders is crucial for an adequate clinical follow-up and accurate genetic counseling of at-risk family members. [ABSTRACT FROM AUTHOR]

Pitt-Hopkins syndrome (PTHS), characterized by severe intellectual disability and typical facial gestalt, is part of the clinical spectrum of Rett-like syndromes. TCF4, encoding a basic helix-loop-helix (bHLH) transcription factor, was identified as the disease-causing gene with de novo molecular defects. While PTHS appears to be a recognizable clinical entity, it seems to remain underdiagnosed, especially when facial gestalt is less typical. With the aim to facilitate the diagnosis of PTHS and to increase its rate and specificity, we have investigated 33 novel patients and defined a Clinical Diagnosis Score. Analysis of 112 individuals (79 previously reported and 33 novel patients) allowed us to delineate the TCF4 mutational spectrum, with 40% point mutations, 30% small deletions/insertions, and 30% deletions. Most of these were private mutations and generated premature stop codons. Missense mutations were localized in the bHLH domain, which is a mutational hotspot. No obvious difference was observed between patients harboring truncating, missense mutations, or deletions, further supporting TCF4 haploinsufficiency as the molecular mechanism underlying PTHS. In this study, we have summarized the current knowledge of TCF4 molecular pathology, reported all the mutations in the TCF4 database (), and present a novel and comprehensive diagnostic strategy for PTHS. Hum Mutat 33:64-72, 2012. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]