The endoplasmic reticulum-associated degradation pathway is responsible for the translocation of misfolded proteins across the endoplasmic reticulum membrane into the cytosol for subsequent ...degradation by the proteasome. To define the phenotype associated with a novel inherited disorder of cytosolic endoplasmic reticulum-associated degradation pathway dysfunction, we studied a series of eight patients with deficiency of N-glycanase 1.
Whole-genome, whole-exome, or standard Sanger sequencing techniques were employed. Retrospective chart reviews were performed in order to obtain clinical data.
All patients had global developmental delay, a movement disorder, and hypotonia. Other common findings included hypolacrima or alacrima (7/8), elevated liver transaminases (6/7), microcephaly (6/8), diminished reflexes (6/8), hepatocyte cytoplasmic storage material or vacuolization (5/6), and seizures (4/8). The nonsense mutation c.1201A>T (p.R401X) was the most common deleterious allele.
NGLY1 deficiency is a novel autosomal recessive disorder of the endoplasmic reticulum-associated degradation pathway associated with neurological dysfunction, abnormal tear production, and liver disease. The majority of patients detected to date carry a specific nonsense mutation that appears to be associated with severe disease. The phenotypic spectrum is likely to enlarge as cases with a broader range of mutations are detected.
Objectives:
Lower urinary tract symptoms (LUTS), which are often caused by benign prostatic hypertrophy (BPH), and sexual dysfunction are common in older men, with an overall prevalence of >50% in ...men aged ≥50 years. Men with LUTS have been reported to experience sexual dysfunction, including ejaculatory loss, painful ejaculation, and erectile dysfunction. This study was conducted to investigate the relationship between LUTS and sexual problems in aging men.
Methods:
A large-scale, multinational survey was conducted in the US and six European countries to systematically investigate the relationship between LUTS and sexual dysfunction in older men. Detailed questionnaires were mailed to a national representative sample of men aged 50 to 80 years in each country. Selection was made on the basis of age, occupation, geographic region, and population density. LUTS and sexual function were assessed by validated symptom scales, including the International Prostate Symptom Score, the Danish Prostatic Symptom Score, and the International Index of Erectile Function. Subjects also completed a health and demographics questionnaire.
Results:
A total of 34,800 surveys were mailed out, 14,254 were completed and returned, and 12,815 were deemed evaluable and included in the analysis. Results were consistent from one country to another. Although 90% of the men had LUTS, only 19% had sought medical help for urinary problems and only 11% were medically treated. Sexual activity was reported by 83% of the sample, with 71% reporting at least one episode of sexual activity during the previous 4 weeks. Sexual disorders and their bothersomeness were strongly related to both age and severity of LUTS. The relationship between sexual problems and LUTS is independent of comorbidities such as diabetes, hypertension, cardiac disease, and hypercholesterolemia.
Conclusions:
Sexual activity is common in a majority of men over age 50 and is an important component of overall quality of life. The presence and severity of LUTS are independent risk factors for sexual dysfunction in older men. These results highlight the clinical importance of evaluating LUTS in patients with sexual dysfunction, and the need to consider sexual issues in the management of patients with benign prostatic hypertrophy.
Delayed cerebral ischemia (DCI) is the most common and disabling complication among patients admitted to the hospital for subarachnoid hemorrhage (SAH). Clinical and radiographic methods often fail ...to detect DCI early enough to avert irreversible injury. We assessed the clinical feasibility of implementing a continuous EEG (cEEG) ischemia monitoring service for early DCI detection as part of an institutional guideline. An institutional neuromonitoring guideline was designed by an interdisciplinary team of neurocritical care, clinical neurophysiology, and neurosurgery physicians and nursing staff and cEEG technologists. The interdisciplinary team focused on (1) selection criteria of high-risk patients, (2) minimization of safety concerns related to prolonged monitoring, (3) technical selection of quantitative and qualitative neurophysiologic parameters based on expert consensus and review of the literature, (4) a structured interpretation and reporting methodology, prompting direct patient evaluation and iterative neurocritical care, and (5) a two-layered quality assurance process including structured clinician interviews assessing events of neurologic worsening and an adjudicated consensus review of neuroimaging and medical records. The resulting guideline's clinical feasibility was then prospectively evaluated. The institutional SAH monitoring guideline used transcranial Doppler ultrasound and cEEG monitoring for vasospasm and ischemia monitoring in patients with either Fisher group 3 or Hunt-Hess grade IV or V SAH. Safety criteria focused on prevention of skin breakdown and agitation. Technical components included monitoring of transcranial Doppler ultrasound velocities and cEEG features, including quantitative alpha:delta ratio and percent alpha variability, qualitative evidence of new focal slowing, late-onset epileptiform activity, or overall worsening of background. Structured cEEG reports were introduced including verbal communication for findings concerning neurologic decline. The guideline was successfully implemented over 27 months, during which neurocritical care physicians referred 71 SAH patients for combined transcranial Doppler ultrasound and cEEG monitoring. The quality assurance process determined a DCI rate of 48% among the monitored population, more than 90% of which occurred during the duration of cEEG monitoring (mean 6.9 days) beginning 2.7 days after symptom onset. An institutional guideline implementing cEEG for SAH ischemia monitoring and reporting is feasible to implement and efficiently identify patients at high baseline risk of DCI during the period of monitoring.
Genomic resources for the domestic dog have improved with the widespread adoption of a 173k SNP array platform and updated reference genome. SNP arrays of this density are sufficient for detecting ...genetic associations within breeds but are underpowered for finding associations across multiple breeds or in mixed-breed dogs, where linkage disequilibrium rapidly decays between markers, even though such studies would hold particular promise for mapping complex diseases and traits. Here we introduce an imputation reference panel, consisting of 365 diverse, whole-genome sequenced dogs and wolves, which increases the number of markers that can be queried in genome-wide association studies approximately 130-fold. Using previously genotyped dogs, we show the utility of this reference panel in identifying potentially novel associations, including a locus on CFA20 significantly associated with cranial cruciate ligament disease, and fine-mapping for canine body size and blood phenotypes, even when causal loci are not in strong linkage disequilibrium with any single array marker. This reference panel resource will improve future genome-wide association studies for canine complex diseases and other phenotypes.
Abstract Objective To synthesize the best available evidence regarding the impact of nonsurgical interventions on persistent symptoms after mild traumatic brain injury (MTBI). Data Sources MEDLINE ...and other databases were searched (2001–2012) with terms including “rehabilitation.” Inclusion criteria were original, peer-reviewed research published in English and other languages. References were also identified from the bibliographies of eligible articles. Study Selection Controlled trials and cohort and case-control studies were selected according to predefined criteria. Studies had to have a minimum of 30 MTBI cases and assess nonsurgical interventions using clinically relevant outcomes such as self-rated recovery. Data Extraction Eligible studies were critically appraised using a modification of the Scottish Intercollegiate Guidelines Network (SIGN) criteria. Two reviewers independently reviewed each study and extracted data from the admissible studies into evidence tables. Data Synthesis The evidence was synthesized qualitatively according to the modified SIGN criteria. Recommendations were linked to the evidence tables using a best-evidence synthesis. After 77,914 records were screened, only 2 of 7 studies related to nonsurgical interventions were found to have a low risk of bias. One studied the effect of a scheduled telephone intervention offering counseling and education on outcome and found a significantly better outcome for symptoms (6.6 difference in adjusted mean symptom score; 95% confidence interval, 1.2–12.0), but no difference in general health outcome at 6 months after MTBI. The other was a randomized controlled trial of the effectiveness of 6 days of bed rest on posttraumatic complaints 6 months postinjury, compared with no bed rest, and found no effect. Conclusions Some evidence suggests that early, reassuring educational information is beneficial after MTBI. Well-designed intervention studies are required to develop effective treatments and improve outcomes for adults and children at risk for persistent symptoms after MTBI.
The synovium is a mesenchymal tissue composed mainly of fibroblasts, with a lining and sublining that surround the joints. In rheumatoid arthritis the synovial tissue undergoes marked hyperplasia, ...becomes inflamed and invasive, and destroys the joint
. It has recently been shown that a subset of fibroblasts in the sublining undergoes a major expansion in rheumatoid arthritis that is linked to disease activity
; however, the molecular mechanism by which these fibroblasts differentiate and expand is unknown. Here we identify a critical role for NOTCH3 signalling in the differentiation of perivascular and sublining fibroblasts that express CD90 (encoded by THY1). Using single-cell RNA sequencing and synovial tissue organoids, we found that NOTCH3 signalling drives both transcriptional and spatial gradients-emanating from vascular endothelial cells outwards-in fibroblasts. In active rheumatoid arthritis, NOTCH3 and Notch target genes are markedly upregulated in synovial fibroblasts. In mice, the genetic deletion of Notch3 or the blockade of NOTCH3 signalling attenuates inflammation and prevents joint damage in inflammatory arthritis. Our results indicate that synovial fibroblasts exhibit a positional identity that is regulated by endothelium-derived Notch signalling, and that this stromal crosstalk pathway underlies inflammation and pathology in inflammatory arthritis.
To determine short-term outcomes of infants with evidence of hypoxia-ischemia at birth and classified as mild neonatal encephalopathy (NE) at <6 h of age.
Prospective multicenter study. Mild NE was ...defined as ⩾1 abnormal category in modified Sarnat score. Primary outcome was any abnormality on early amplitude integrated electroencephalogram (aEEG) or seizures, abnormal brain magnetic resonance imaging (MRI) or neurological exam at discharge.
A total of 54/63 (86%) of enrolled infants had data on components of the primary outcome, which was abnormal in 28/54 (52%): discontinuous aEEG (n=4), MRI (n=9) and discharge exam (n=22). Abnormal tone and/or incomplete Moro were the most common findings. MRI abnormalities were confined to cerebral cortex but two infants had basal ganglia and/or thalamus involvement. The 18 to 24 months follow-up is ongoing.
A larger than expected proportion of mild NE infants with abnormal outcomes was observed. Future research should evaluate safety and efficacy of neuroprotection for mild NE.
This document outlines the important aspects of caring for patients who have been diagnosed with advanced pelvic cancer. It is primarily aimed at those who are establishing a service that adequately ...caters to this patient group. The relevant literature has been summarized and an attempt made to simplify the approach to management of these complex cases.
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