Genetic basis of neurodevelopmental disorders in 103 Jordanian families

We recruited 103 families from Jordan with neurodevelopmental disorders (NDD) and patterns of inheritance mostly suggestive of autosomal recessive inheritance. In each family, we investigated at least one affected individual using exome sequencing and an in-house diagnostic variant interpretation pipeline including a search for copy number variation. This approach led us to identify the likely molecular defect in established disease genes in 37 families. We could identify 25 pathogenic nonsense and 11 missense variants as well as 3 pathogenic copy number variants and 1 repeat expansion. Notably, 11 of the disease-causal variants occurred de novo. In addition, we prioritized a homozygous frameshift variant in PUS3 in two sisters with intellectual disability. To our knowledge, PUS3 has been postulated only recently as a candidate disease gene for intellectual disability in a single family with three affected siblings. Our findings provide additional evidence to establish loss of PUS3 function as a cause of intellectual disability.     

The sympathetic nervous system in acute kidney injury

Acute kidney injury (AKI) is frequently accompanied by activation of the sympathetic nervous system (SNS). This may result from pre‐exisiting chronic diseases associated with sympathetic activation prior to AKI or it may be induced by stressors that ultimately lead to AKI such as endotoxins and arterial hypotension in circulatory shock. Conversely, sympathetic activation may also result from acute renal injury. Focusing on studies in experimental renal ischaemia and reperfusion (IR), this review summarizes the current knowledge on how the SNS is activated in IR‐induced AKI and on the consequences of sympathetic activation for the development of acute renal damage. Experimental studies show beneficial effects of sympathoinhibitory interventions on renal structure and function in response to IR. However, few clinical trials obtained in scenarios that correspond to experimental IR, namely major elective surgery, showed that peri‐operative treatment with centrally acting sympatholytics reduced the incidence of AKI. Apparently, discrepant findings on how sympathetic activation influences renal responses to acute IR‐induced injury are discussed and future areas of research in this field are identified.     

Superior vena cava graft infection in thoracic surgery: a retrospective study of the French EPITHOR database

 Open in a separate windowOBJECTIVESTo report our experience on the management of superior vena cava graft infection.METHODSBetween 2001 and 2018, patients with superior vena cava synthetic graft or patch reconstruction after resection of intrathoracic tumours or benign disease were selected retrospectively from the French EPITHOR database and participating thoracic centres. Our study population includes patients with superior vena cava graft infection, defined according to the MAGIC consensus. Superior vena cava synthetic grafts in an empyema or mediastinitis were considered as infected.RESULTSOf 111 eligible patients, superior vena cava graft infection occurred in 12 (11.9%) patients with a polytetrafluoroethylene graft secondary to contiguous contamination. Management consisted of either conservative treatment with chest tube drainage and antibiotics (n = 3) or a surgical graft-sparing strategy (n = 9). Recurrence of infection appears in 6 patients. Graft removal was performed in 2 patients among the 5 reoperated patients. The operative mortality rate was 25%.CONCLUSIONSSuperior vena cava graft infection may develop as a surgical site infection secondary to early mediastinitis or empyema. Graft removal is not always mandatory but should be considered in late or recurrent graft infection or in infections caused by aggressive microorganisms (virulent or multidrug resistant bacteria or fungi).     

Value of indocyanine green pelvic lymph node mapping in the surgical approach of cervical cancer

Lymph node metastasis is a significant predictive factor for disease recurrence and survival in cervical cancer patients and relevant for therapeutic strategies. We evaluated the clinical value of indocyanine green (ICG) by measuring the sensitivity and negative predictive value of sentinel lymph node mapping compared with the gold standard of complete lymphadenectomy in detecting lymph node metastases for cervical cancer. We utilized the near-infrared imaging agent ICG to detect tumor-infested lymph nodes in the pelvis analogue to a classical sentinel lymph node procedure by analyzing data from 20 patients who had undergone surgery for cervical cancer at our institution. A laparoscopic lymph node mapping procedure by means of ICG, followed by a complete pelvic lymphadenectomy with or without paraaortic lymphadenectomy was done in all patients. Histological examination identified seven patients with tumor-positive pelvic nodes, whereas mapping with ICG identified only five of these patients. Detection rate of positive nodes by ICG mapping and false negative rate was 71.4% and 28.6%, respectively; bilateral detection rate was 83.3%. One of the two false negative patients additionally suffered from deep infiltrating endometriosis. Our results indicate that ICG can identify the relevant pelvic nodes independent of tumor size, provided bilateral detection is achieved and additional, related diseases are excluded. This trial is registered within the German Clinical Trial Register (DRKS-ID: DRKS00014692).     

Therapeutische Interventionen bei peri- und postmenopausalen Beschwerden

Die S3-Leitlinie „Peri- und Postmenopause – Diagnostik und Therapie“ beinhaltet Handlungsanweisungen und Empfehlungen für die Hormonersatztherapie (HRT) zur Behandlung klimakterischer Beschwerden, die von etwa 50 % der perimenopausalen Frauen und bei 30–80 % der postmenopausalen Frauen angegeben werden. Eine HRT mit Östrogenen (ET) oder Östrogenen und Gestagenen (EPT) wird als symptomatische Therapie zur Behandlung von klimakterischen Beschwerden mit klinisch relevanter Beeinträchtigung der Lebensqualität eingesetzt. Alternativ können auch Isoflavone, Cimicifuga-Präparate, Serotonin- bzw. Serotonin-Noradrenalin-Wiederaufnahmehemmer, Clonidin, Gabapentin oder kognitive Verhaltenstherapie angewendet werden. Im vorliegenden Artikel werden Effektivität und Sicherheit sowie Nebenwirkungen und systemische Wirkungen dieser unterschiedlichen Therapieformen entsprechend den Vorgaben der S3-Leitlinie „Peri- und Postmenopause – Diagnostik und Therapie“ dargestellt.     

S3-Leitlinie Peri- und Postmenopause – Diagnostik und Interventionen

Die Gynäkologie -     

Hormonersatztherapie und vaskuläres Risiko

Gynäkologische Endokrinologie - Auch die neue Version der AWMF-S3-Leitlinie „Peri- und Postmenopause – Diagnostik und Interventionen“ der Deutschen Gesellschaft für...     

Next-generation sequencing in X-linked intellectual disability

X-linked intellectual disability (XLID) is a genetically heterogeneous disorder with more than 100 genes known to date. Most genes are responsible for a small proportion of patients only, which has hitherto hampered the systematic screening of large patient cohorts. We performed targeted enrichment and next-generation sequencing of 107 XLID genes in a cohort of 150 male patients. Hundred patients had sporadic intellectual disability, and 50 patients had a family history suggestive of XLID. We also analysed a sporadic female patient with severe ID and epilepsy because she had strongly skewed X-inactivation. Target enrichment and high parallel sequencing allowed a diagnostic coverage of >10 reads for ~96% of all coding bases of the XLID genes at a mean coverage of 124 reads. We found 18 pathogenic variants in 13 XLID genes (AP1S2, ATRX, CUL4B, DLG3, IQSEC2, KDM5C, MED12, OPHN1, SLC9A6, SMC1A, UBE2A, UPF3B and ZDHHC9) among the 150 male patients. Thirteen pathogenic variants were present in the group of 50 familial patients (26%), and 5 pathogenic variants among the 100 sporadic patients (5%). Systematic gene dosage analysis for low coverage exons detected one pathogenic hemizygous deletion. An IQSEC2 nonsense variant was detected in the female ID patient, providing further evidence for a role of this gene in encephalopathy in females. Skewed X-inactivation was more frequently observed in mothers with pathogenic variants compared with those without known X-linked defects. The mutation rate in the cohort of sporadic patients corroborates previous estimates of 5–10% for X-chromosomal defects in male ID patients.