Cerebellar c9RAN proteins associate with clinical and neuropathological characteristics of C9ORF72 repeat expansion carriers.

Clinical and neuropathological characteristics associated with G4C2 repeat expansions in chromosome 9 open reading frame 72 (C9ORF72), the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, are highly variable. To gain insight on the molecular basis for the heterogeneity among C9ORF72 mutation carriers, we evaluated associations between features of disease and levels of two abundantly expressed "c9RAN proteins" produced by repeat-associated non-ATG (RAN) translation of the expanded repeat. For these studies, we took a departure from traditional immunohistochemical approaches and instead employed immunoassays to quantitatively measure poly(GP) and poly(GA) levels in cerebellum, frontal cortex, motor cortex, and/or hippocampus from 55 C9ORF72 mutation carriers [12 patients with ALS, 24 with frontotemporal lobar degeneration (FTLD) and 19 with FTLD with motor neuron disease (FTLD-MND)]. We additionally investigated associations between levels of poly(GP) or poly(GA) and cognitive impairment in 15 C9ORF72 ALS patients for whom neuropsychological data were available. Among the neuroanatomical regions investigated, poly(GP) levels were highest in the cerebellum. In this same region, associations between poly(GP) and both neuropathological and clinical features were detected. Specifically, cerebellar poly(GP) levels were significantly lower in patients with ALS compared to patients with FTLD or FTLD-MND. Furthermore, cerebellar poly(GP) associated with cognitive score in our cohort of 15 patients. In the cerebellum, poly(GA) levels similarly trended lower in the ALS subgroup compared to FTLD or FTLD-MND subgroups, but no association between cerebellar poly(GA) and cognitive score was detected. Both cerebellar poly(GP) and poly(GA) associated with C9ORF72 variant 3 mRNA expression, but not variant 1 expression, repeat size, disease onset, or survival after onset. Overall, these data indicate that cerebellar abnormalities, as evidenced by poly(GP) accumulation, associate with neuropathological and clinical phenotypes, in particular cognitive impairment, of C9ORF72 mutation carriers

Uncoupling endosomal CLC chloride/proton exchange causes severe neurodegeneration

CLC chloride/proton exchangers may support acidification of endolysosomes and raise their luminal Cl− concentration. Disruption of endosomal ClC‐3 causes severe neurodegeneration. To assess the importance of ClC‐3 Cl−/H+ exchange, we now generate Clcn3unc/unc mice in which ClC‐3 is converted into a Cl− channel. Unlike Clcn3−/− mice, Clcn3unc/unc mice appear normal owing to compensation by ClC‐4 with which ClC‐3 forms heteromers. ClC‐4 protein levels are strongly reduced in Clcn3−/−, but not in Clcn3unc/unc mice because ClC‐3unc binds and stabilizes ClC‐4 like wild‐type ClC‐3. Although mice lacking ClC‐4 appear healthy, its absence in Clcn3unc/unc/Clcn4−/− mice entails even stronger neurodegeneration than observed in Clcn3−/− mice. A fraction of ClC‐3 is found on synaptic vesicles, but miniature postsynaptic currents and synaptic vesicle acidification are not affected in Clcn3unc/unc or Clcn3−/− mice before neurodegeneration sets in. Both, Cl−/H+‐exchange activity and the stabilizing effect on ClC‐4, are central to the biological function of ClC‐3

Utilización del catéter venoso central de inserción periférica en la Unidad de Cuidados Intensivos Neonatales del Instituto Nacional de Salud Del Niño Breña, 2017–2019

Introduction. Currently the birth rate worldwide is 18.8% and in Peru it is 10%. The main causes of neonatal mortality are preterm births, infections and congenital defects. The neonatal intensive care unit is the area that is responsible for the care of newborns in critical condition, obtaining an adequate central venous access route for their treatment is essential. Objective. To describe the use of the percutaneous peripheral insertion catheter in the Neonatal Intensive Care Unit of the Instituto Nacional de Salud del Niño Breña, period June 2017 - June 2019. Methods. The study was descriptive, observational, retrospective, cross-sectional. The intentional sample was made up of approximately 110 medical records of newborns who were hospitalized in the neonatal intensive care unit. The technique the observation and the instrument the checklist. Results. 51.8% were neonates with surgical pathology. Likewise, 36.4% had a gestational age less than or equal to 32 weeks, the most used vein was the basilica with 27.3%, 37.3% of the catheters were removed due to suspected Sepsis and the tips were sent for culture. Conclusions. The care in the procedure and maintenance of the percutaneous catheter was adequate, presenting a low number of complications.Introducción. Actualmente la tasa de nacimientos a nivel mundial es de 18,8% y en el Perú es de 10%. Las principales causas de mortalidad neonatal son los partos pre termino, infecciones y defectos congénitos. La unidad de cuidados intensivos neonatales es el área que se encarga de la atención de los recién nacidos en estado crítico, siendo indispensable la obtención de una vía de acceso venoso central adecuada para su tratamiento. Objetivo. Describir la utilización del catéter percutáneo de inserción periférica en la Unidad de Cuidados Intensivos Neonatales del Instituto Nacional de Salud del Niño Breña, periodo junio 2017 – junio 2019. Métodos. Estudio descriptivo, observacional, retrospectivo, transversal. La muestra fue intencional conformada aproximadamente por 110 historias clínicas de recién nacidos que estuvieron hospitalizados en la unidad de cuidados intensivos neonatales. La técnica la observación y el instrumento la lista de chequeo. Resultados. El 51,8% fueron neonatos con patología quirúrgica. Asimismo, el 36,4% tuvieron una edad gestacional menor o igual de 32 semanas, la vena más usada fue la basílica con un 27,3%, el 37.,3% de los catéteres fueron retirados por sospecha de sepsis y las puntas enviadas a cultivo. Conclusiones: El cuidado en el procedimiento y mantenimiento del catéter percutáneo fue el adecuado, presentándose un bajo número de complicaciones

Abnormal Expression Of Homeobox Genes And Transthyretin In C9Orf72 Expansion Carriers

Objective: We performed a genome-wide brain expression study to reveal the underpinnings of diseases linked to a repeat expansion in chromosome 9 open reading frame 72 (C9ORF72). Methods: The genome-wide expression profile was investigated in brain tissue obtained from C9ORF72 expansion carriers (n = 32), patients without this expansion (n = 30), and controls (n = 20). Using quantitative real-time PCR, findings were confirmed in our entire pathologic cohort of expansion carriers (n = 56) as well as nonexpansion carriers (n = 31) and controls (n = 20). Results: Our findings were most profound in the cerebellum, where we identified 40 differentially expressed genes, when comparing expansion carriers to patients without this expansion, including 22 genes that have a homeobox (e.g., HOX genes) and/or are located within the HOX gene cluster (top hit: homeobox A5 [HOXA5]). In addition to the upregulation of multiple homeobox genes that play a vital role in neuronal development, we noticed an upregulation of transthyretin (TTR), an extracellular protein that is thought to be involved in neuroprotection. Pathway analysis aligned with these findings and revealed enrichment for gene ontology processes involved in (anatomic) development (e.g., organ morphogenesis). Additional analyses uncovered that HOXA5 and TTR levels are associated with C9ORF72 variant 2 levels as well as with intron-containing transcript levels, and thus, disease-related changes in those transcripts may have triggered the upregulation of HOXA5 and TTR. Conclusions: In conclusion, our identification of genes involved in developmental processes and neuroprotection sheds light on potential compensatory mechanisms influencing the occurrence, presentation, and/or progression of C9ORF72-related diseases

Impact on the Quality of Life of an Educational Program for the Prevention of Work-Related Musculoskeletal Disorders: a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Work-related musculoskeletal disorders (WMSD) are a major cause for concern in public health and the main causes of sick leave. Treatments for WMSD have given disappointing results; prevention is the best strategy, but results of preventive measures have not been consistent. To the best of our knowledge there are few studies in literature that evaluated the impact of a specific program aimed at preventing WMSD on the quality of life of employed persons.</p> <p>Methods</p> <p>One hundred and one clerical and production workers in a steel trading company were enrolled in an open-label randomized controlled clinical trial (parallel groups) to compare the efficacy of an educational program for primary prevention of WMSD with control intervention. The primary outcome was a change in the physical functioning domain of the quality of life (QL) measured by Medical Outcomes Study Short Form 36 Health Survey (SF-36). The intervention group underwent six consecutive weekly sessions concerning specific orientations for the prevention of WMSD, while the control group received general health education in an identical schedule. The SF-36 and theses Work Limitation Questionnaire (WLQ) were evaluated at weeks zero, five and 26.</p> <p>Results</p> <p>Baseline characteristics of the interventions groups were comparable, and both groups comprised predominantly young healthy individuals. No significant differences in the variation of the SF-36 and WLQ between the groups were observed at weeks five and 26. However, both groups demonstrated improvement in some aspects of SF-36, suggesting that both educational interventions have beneficial impacts on QL.</p> <p>Conclusions</p> <p>A specific educational program aimed at the preventing of WMSD was comparable with general health orientation for the improvement of QL and work capacity in a sample of healthy workers during a six month period.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00981877">NCT00874718</a></p> <p>Trial Registration</p

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer.

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM -/- patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

Tracing a toad invasion: lack of mitochondrial DNA variation, haplotype origins, and potential distribution of introduced Duttaphrynus melanostictus in Madagascar

The black-spined toad, Duttaphrynus melanostictus, is widespread in South and South-East (SE) Asia, although recent molecular analyses have revealed that it represents a species complex (here called the D. melanostictus complex). Invasive populations of this toad have been detected in Madagascar since, at least, 2014. We here trace the origin of this introduction based on mitochondrial DNA sequences of 340 samples. All 102 specimens from Madagascar have identical sequences pointing to a single introduction event. Their haplotype corresponds to a lineage occurring in Cambodia, China, Laos, Thailand, Vietnam, and some locations of eastern Myanmar and northern Malaysia, here named the SE Asian lineage. Within this lineage, specimens from one location in Cambodia and three locations in Vietnam have the same haplotype as found in Madagascar. This includes Ho Chi Minh City, which has a major seaport and might have been the source for the introduction. Species distribution models suggest that the current range of the Madagascan invasive population is within the bioclimatic space occupied by the SE Asian lineage in its native range. The potential invasion zone in Madagascar is narrower than suggested by models from localities representing the full range of the D. melanostictus complex. Thus, an accurate taxonomy is essential for such inferences, but it remains uncertain if the toad might be able to spread beyond the potential suitable range because (1) knowledge on species-delimitation of the complex is insufficient, and (2) the native range in SE Asia might be influenced by historical biogeography or competition

Truncated stathmin-2 is a marker of TDP-43 pathology in frontotemporal dementia.

No treatment for frontotemporal dementia (FTD), the second most common type of early-onset dementia, is available, but therapeutics are being investigated to target the 2 main proteins associated with FTD pathological subtypes: TDP-43 (FTLD-TDP) and tau (FTLD-tau). Testing potential therapies in clinical trials is hampered by our inability to distinguish between patients with FTLD-TDP and FTLD-tau. Therefore, we evaluated truncated stathmin-2 (STMN2) as a proxy of TDP-43 pathology, given the reports that TDP-43 dysfunction causes truncated STMN2 accumulation. Truncated STMN2 accumulated in human induced pluripotent stem cell-derived neurons depleted of TDP-43, but not in those with pathogenic TARDBP mutations in the absence of TDP-43 aggregation or loss of nuclear protein. In RNA-Seq analyses of human brain samples from the NYGC ALS cohort, truncated STMN2 RNA was confined to tissues and disease subtypes marked by TDP-43 inclusions. Last, we validated that truncated STMN2 RNA was elevated in the frontal cortex of a cohort of patients with FTLD-TDP but not in controls or patients with progressive supranuclear palsy, a type of FTLD-tau. Further, in patients with FTLD-TDP, we observed significant associations of truncated STMN2 RNA with phosphorylated TDP-43 levels and an earlier age of disease onset. Overall, our data uncovered truncated STMN2 as a marker for TDP-43 dysfunction in FTD

Cost-effectiveness of healthy eating and/or physical activity promotion in pregnant women at increased risk of gestational diabetes mellitus

__Background:__ Gestational diabetes mellitus (GDM) is associated with perinatal health risks to both mother and offspring, and represents a large economic burden. The DALI study is a multicenter randomized controlled trial, undertaken to add to the knowledge base on the effectiveness of interventions for pregnant women at increased risk for GDM. The purpose of this study was to evaluate the cost-effectiveness of the healthy eating and/or physical activity promotion intervention compared to usual care among pregnant women at increased risk of GDM from a societal perspective. __Methods:__ An economic evaluation was performed alongside a European multicenter-randomized controlled trial. A total of 435 pregnant women at increased risk of GDM in primary and secondary care settings in nine European countries, were recruited and randomly allocated to a healthy eating and physical activity promotion intervention (HE + PA intervention), a healthy eating promotion intervention (HE intervention), or a physical activity promotion intervention (PA intervention). Main outcome measures were gestational weight gain, fasting glucose, insulin resistance (HOMA-IR), quality adjusted life years (QALYs), and societal costs. __Results:__ Between-group total cost and effect differences were not significant, besides significantly less gestational weight gain in the HE + PA group compared with the usual care group at 35-37 weeks ( 2.3;95%CI:-3.7;-0.9). Cost-effectiveness acceptability curves indicated that the HE + PA intervention was the preferred intervention strategy. At 35-37 weeks, it depends on the decision-makers' willingness to pay per kilogram reduction in gestational weight gain whether the HE + PA intervention is cost-effective for gestational weight gain, whereas it was not cost-effective for fasting glucose and HOMA-IR. After delivery, the HE + PA intervention was cost-effective for QALYs, which was predominantly caused by