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PurposeMore than half of the familial cutaneous melanomas have unknown genetic predisposition. This study aims at characterizing a novel melanoma susceptibility gene.MethodsWe performed exome and targeted sequencing in melanoma-prone families without any known melanoma susceptibility genes. We analyzed the expression of candidate gene DENND5A in melanoma samples in relation to pigmentation and UV signature. Functional studies were carried out using microscopic approaches and zebrafish model.ResultsWe identified a novel DENND5A truncating variant that segregated with melanoma in a Swedish family and 2 additional rare DENND5A variants, 1 of which segregated with the disease in an American family. We found that DENND5A is significantly enriched in pigmented melanoma tissue. Our functional studies show that loss of DENND5A function leads to decrease in melanin content in vitro and pigmentation defects in vivo. Mechanistically, harboring the truncating variant or being suppressed leads to DENND5A losing its interaction with SNX1 and its ability to transport the SNX1-associated vesicles from melanosomes. Consequently, untethered SNX1-premelanosome protein and redundant tyrosinase are redirected to lysosomal degradation by default, causing decrease in melanin content.ConclusionOur findings provide evidence of a physiological role of DENND5A in the skin context and link its variants to melanoma susceptibility.  相似文献   
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People with epilepsy have a three‐fold increased risk of dying prematurely, and a significant proportion is due to sudden cardiac death or acute myocardial infarctions. The causes of increased cardiovascular morbidity and mortality in epilepsy are manifold and include acute or remote effects of epileptic seizures, the longstanding epilepsy itself or antiseizure treatments. Seizure‐related cardiac arrhythmias are common and comprise bradyarrhythmia and asystole, atrial fibrillation and ventricular tachycardia. The most frequent clinically relevant seizure‐related arrhythmia is ictal asystole that may require implantation of a cardiac pacemaker, whereas seizure‐related ventricular tachycardias are only rarely reported. Takotsubo cardiomyopathy and myocardial infarction are rare complications and predominantly described in association with tonic‐clonic seizures. Epilepsy‐related cardiac complications include a disturbed cardiac autonomic nervous system and acquired dysfunction of the heart (recently defined as ‘epileptic heart’), probably contributing to the abnormalities of cardiac repolarisation and elevated risk of sudden cardiac death in people with epilepsy. If successful, the use of antiseizure medication prevents seizure‐related cardiac arrhythmias and remote cardiac complications. However, enzyme‐inducing antiseizure medications have a negative impact on cardiovascular risk factors, which may further be aggravated by weight gain linked to specific antiseizure drugs. Given the severe consequences of cardiac risks, the aim of this educational review is to explain the many facets of cardiac complications and their underlying causes, and to enable the reader to recognize and manage these risks with the goal to mitigate the cardiac risks in people with epilepsy. Features of syncope are explained in detail, as syncope of all origins can be mistaken as epileptic seizures in people with or without epilepsy, and ictal syncope (i.e. seizure‐induced syncope) can easily be ignored.  相似文献   
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Clinical Epileptology - Ziel dieser Praxisleitlinie ist es, die Häufigkeit von plötzlichen unerwarteten Todesfällen bei Epilepsie (SUDEP) in verschiedenen Epilepsiepopulationen zu...  相似文献   
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Hillermann  T.  Homburg  K.  Rainer  M.  Budde  U. 《Der Anaesthesist》2022,71(4):299-302
Die Anaesthesiologie - Eine junge Patientin erleidet während der Anlage einer axillären Plexusblockade einen generalisierten Krampfanfall. Die Mechanismen, im Wesentlichen die vermutlich...  相似文献   
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The Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) was developed and validated to weigh the burden of pretransplantation comorbidities and estimate their impact on post-transplantation risks of nonrelapse mortality (NRM). Recently, the HCT-CI was augmented by the addition of both age and the values of 3 markers: ferritin, albumin, and platelet count. So far, research involving The HCT-CI has been limited almost exclusively to recipients of allogeneic hematopoietic cell transplantation (HCT) from HLA-matched grafts. To this end, we sought to investigate the discriminative capacity of an augmented comorbidity/age index among 724 recipients of allogeneic HCT from HLA-mismatched (n = 345), haploidentical (n = 117), and umbilical cord blood (UCB; n = 262) grafts between 2000 and 2013. In the overall cohort, the augmented comorbidity/age index had a higher c-statistic estimate for prediction of NRM compared with the original HCT-CI (.63 versus .59). Findings were similar for recipients of HLA-mismatched (.62 versus .59), haploidentical (.60 versus .54), or UCB grafts (.65 versus .61). Compared with patients with an HCT-CI score ≥4, those with a score <4 had a higher survival rate among recipients of HLA-mismatched (55% versus 39%; P < .0008), HLA-haploidentical (58% versus 38%; P = .01), or UCB (67% versus 48%; P = .004) grafts. Our results demonstrate the utility of the augmented comorbidity/age index as a valid prognostic tool among recipients of allogeneic HCT from alternative graft sources.  相似文献   
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Both pulmonary rehabilitation (PR) and chronic obstructive pulmonary disease (COPD) are generic terms and it increasingly becomes clear that rehabilitation programmes need to be tailored to the complexity and circumstances of the individual patient. Indeed, PR is described as a comprehensive, individualized intervention based on thorough assessment of identifiable treatable traits. The current review summarizes ongoing developments regarding additional interventions and tools to facilitate PR and improve outcomes in patients with a chronic respiratory disease.  相似文献   
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