Structural mapping of GABRB3 variants reveals genotype–phenotype correlations

PurposePathogenic variants in GABRB3 have been associated with a spectrum of phenotypes from severe developmental disorders and epileptic encephalopathies to milder epilepsy syndromes and mild intellectual disability (ID). In this study, we analyzed a large cohort of individuals with GABRB3 variants to deepen the phenotypic understanding and investigate genotype–phenotype correlations.MethodsThrough an international collaboration, we analyzed electro-clinical data of unpublished individuals with variants in GABRB3, and we reviewed previously published cases. All missense variants were mapped onto the 3-dimensional structure of the GABRB3 subunit, and clinical phenotypes associated with the different key structural domains were investigated.ResultsWe characterized 71 individuals with GABRB3 variants, including 22 novel subjects, expressing a wide spectrum of phenotypes. Interestingly, phenotypes correlated with structural locations of the variants. Generalized epilepsy, with a median age at onset of 12 months, and mild-to-moderate ID were associated with variants in the extracellular domain. Focal epilepsy with earlier onset (median: age 4 months) and severe ID were associated with variants in both the pore-lining helical transmembrane domain and the extracellular domain.ConclusionThese genotype–phenotype correlations will aid the genetic counseling and treatment of individuals affected by GABRB3-related disorders. Future studies may reveal whether functional differences underlie the phenotypic differences.     

Patients’ experiences of niacin-induced flushing in clinical practice: A structured telephone interview

Background: Niacin is highly effective at raising high-density lipoprotein cholesterol but remains underused because of the adverse event of flushing.Objective: The objective of this study was to determine the incidence and severity of niacin-induced flushing and their relationship to niacin discontinuation and skipping or delaying niacin doses in clinical practice. The use of aspirin to avoid niacin-induced flushing was also assessed.Methods: Structured telephone interviews were performed with patients identified from administrative claims data as having newly initiated niacin. The main outcome measures were rate and severity of flushing, association between flushing and niacin discontinuation, and rate of prophylactic aspirin use to avoid flushing. Flushing was evaluated on a scale of none, mild, moderate, severe, and extreme.Results: Telephone interviews were conducted with 500 patients who had newly initiated niacin. The patients interviewed were predominantly white men with at least some college education and a mean (SD) age of 55.0 (10.9) years. The mean (SD) time between therapy initiation and interview was 9.3 (3.3) months. At the time of the interview, 27.2% of respondents reported having discontinued niacin (“discontinuers”; n = 136), with a mean duration of niacin use of 4.3 months, and 72.8% continued taking niacin (“continuers”; n = 364). Approximately 91.2% (124/136) of niacin discontinuers and 82.1% (299/364) of continues reported experiencing flushing symptoms (P = 0.013), and 54.4% of discontinuers versus 20.9% of continuers experienced severe or extreme flushing (P < 0.001). Significantly more discontinuers (79.4%) than continuers (58.0%) reported that the greatest degree of flushing they could tolerate was “mild” or “moderate” (P < 0.001). Multivariate logistic regression indicated that flushing symptom severity was a strong predictor of discontinuation as compared with no flushing symptoms (severe: odds ratio [OR], 3.19; 95% CI, 1.43–7.15; extreme: OR, 11.29; 95% CI, 4.20–30.39). Similar percentages of discontinuers and continuers reported both receiving a physician's advice to take prophylactic aspirin (42.0% vs 49.5%, respectively; P = NS) and actually taking aspirin regardless of what their physicians advised (36.0% vs 43.7%; P = NS).Conclusions: Severe or extreme symptoms of flushing, which occurred in about one third of patients newly treated with niacin, were associated with discontinuation of this otherwise highly effective therapy. Less than half of patients reported being advised by their physician to take prophylactic aspirin or took aspirin regardless of their physician's recommendation to avoid niacin-induced flushing symptoms.     

Upper-body muscular endurance in female university-level modern dancers: a pilot study

Physical demands vary among dance styles, and injury patterns differ accordingly. Modern dance tends to be high in upper-body demands, and university-level female modern dancers are suggested to be at high risk for upper-body injury. Low muscular endurance is a known injury risk factor. Whether modern dancers have different upper-body muscular endurance than non-dancers is unclear. Thus, the purpose of this study was to compare upper-body endurance in female university-level modern dancers (n = 17) and physically active non-dancers (n = 15), using the modified push-up test. Pearson-correlations examined relationships between anthropometrics and push-ups. Multiple regression analyses were used to determine whether anthropometrics and physical activity could predict push-up scores. One-way ANOVAs compared upper-body endurance (number of push-ups) and physical activity between groups (p < 0.05). Except for height (r = -.37), no variables were related to push-ups. Neither anthropometrics nor physical activity were able to predict push-up scores (p = 0.25). Despite dancers being more active/day (3.6 ± 1.9 vs. 0.9 ± 0.4 hrs/day, p < 0.001), more times per week (5.4 ± 1.2 vs. 4.0 ± 1.8, p = 0.02), and having greater overall physical activity volumes (20.4 ± 11.4 vs. 3.3 ± 2.5 hrs/week, p < 0.001) than non-dancers, both groups had similar upper-body endurance (22.2 ± 8.6 vs. 19.9 ± 8.2, p = 0.44). A probable explanation for this similarity exists in the lack of physical activity beyond dance itself performed by the dancers; our preliminary work suggests that modern dance alone may not produce upper-body muscle endurance gains. Hence, it is suggested that modern dancers should engage in strength and conditioning training programs to enhance upper-body endurance.     

Nonweight-bearing anterior knee laxity is related to anterior tibial translation during transition from nonweight bearing to weight bearing.

We examined the relationship between anterior knee laxity (AKL), evaluated while the knee was nonweight bearing, and anterior translation of the tibia relative to the femur (ATT), evaluated when the knee transitioned from nonweight-bearing to weight-bearing conditions in response to an applied compressive load at the foot. Twenty subjects with normal knees (10 M, 10 F; 25.2 +/- 4.1 years, 169.8 +/- 11.5 cm, 71.6 +/- 16.9 kg) underwent measurements of AKL and ATT of the right knee on 2 days. AKL was measured at 133N with the KT-2000. ATT was measured with the Vermont Knee Laxity Device and electromagnetic position sensors attached to the patella and the anteromedial aspect of the proximal tibia. Three trials for each measure were averaged and analyzed. Measurement consistency was high for both AKL (ICC = 0.97; SEM = 0.44 mm) and ATT (ICC = 0.88; SEM = 0.84 mm). Linear regression revealed that AKL predicted 35.5% of the variance in ATT (p = 0.006), with a prediction equation of Y(ATT) = 3.20 + 0.543(X(AKL)). Our findings suggest that increased AKL is associated with increased ATT as the knee transitions from nonweight-bearing to weight-bearing conditions. The potential for increased knee joint laxity to disrupt normal knee biomechanics during activities such as landing from a jump, or the foot strike phase of gait deserves further study.     

Retained capsule endoscope leading to the identification of small bowel adenocarcinoma in a patient with undiagnosed Crohn disease

Small intestinal neoplasia is a rare condition that frequently presents a diagnostic challenge. We describe the case of a 70-year-old patient who presented with several years of chronic, intermittent abdominal pain, previously diagnosed as irritable bowel syndrome. Radiographic evaluation, including upper gastrointestinal series with small bowel follow-through and computed tomography, demonstrated dilated small bowel with possible strictures. Colonoscopy and upper endoscopy were unrevealing. Attempted capsule endoscopy resulted in capsule retention. Subsequent laparoscopy led to the identification of severe, active Crohn disease with strictures, ulcers, crypt abscesses, pyloric metaplasia, and transmural inflammation. Extensive flat and polypoid high- and low-grade dysplasia were present, as well as an area of well-differentiated adenocarcinoma invading into the muscularis propria. We discuss the epidemiology, pathogenesis, and diagnosis of small bowel malignancy.     

Association of Medication Adherence with Workplace Productivity and Health-Related Quality of Life in Patients with Asthma

Objective. Examine the association of medication adherence with workplace productivity and health-related quality of life (HRQL) in asthma patients. Methods. Adult patients with asthma in a state health insurance program identified from medical claims (July 2001–June 2003) were mailed a three-part survey to measure HRQL (St. George's Respiratory Questionnaire), workplace productivity (Workplace Productivity Short Inventory), and self-reported medication adherence (Morisky Scale). Results. The symptoms domain had the worst HRQL scores, followed by the activity and impacts domains; 39% of the participants reported themselves as “high” adherent, whereas 19% were “medium,” and 42% were “low” adherent. Asthma resulted in productivity losses of $597 ± $1,024 (absenteeism) and $658 ± $1,808 (presenteeism) per enrollee per year. Conclusions. Asthma was associated with HRQL detriments and workplace productivity losses.     

Differentiated NSC-34 cells as an in vitro cell model for VX

The US military has placed major emphasis on developing therapeutics against nerve agents (NA). Current efforts are hindered by the lack of effective in vitro cellular models to aid in the preliminary screening of potential candidate drugs/antidotes. The development of an in vitro cellular model to aid in discovering new NA therapeutics would be highly beneficial. In this regard, we have examined the response of a differentiated hybrid neuronal cell line, NSC-34, to the NA VX. VX-induced apoptosis of differentiated NSC-34 cells was measured by monitoring the changes in caspase-3 and caspase-9 activity post-exposure. Differentiated NSC-34 cells showed an increase in caspase-3 activity in a manner dependent on both time (17–23?h post-exposure) and dose (10–100?nM). The maximal increase in caspase-3 activity was found to be at 20-h post-exposure. Caspase-9 activity was also measured in response to VX and was found to be elevated at all concentrations (10–100?nM) tested. VX-induced cell death was also observed by utilizing annexin V/propidium iodide flow cytometry. Finally, VX-induced caspase-3 or -9 activities were reduced with the addition of pralidoxime (2-PAM), one of the current therapeutics used against NA toxicity, and dizocilpine (MK-801). Overall the data presented here show that differentiated NSC-34 cells are sensitive to VX-induced cell death and could be a viable in vitro cell model for screening NA candidate therapeutics.     

Mosaicism for a pathogenic <Emphasis Type="Italic">MFN2</Emphasis> mutation causes minimal clinical features of CMT2A in the parent of a severely affected child

Charcot-Marie-Tooth disease (CMT) refers to a genetically heterogeneous group of disorders which cause a peripheral motor and sensory neuropathy. The overall prevalence is 1 in 2500 individuals. Mutations in the MFN2 gene are the commonest cause for the axonal (CMT2) type. We describe a Caucasian 5-year old girl affected by CMT2A since the age of 2 years. She presented with unsteady gait, in-turning of the feet and progressive foot deformities. Nerve conduction studies suggested an axonal neuropathy and molecular testing identified a previously reported pathogenic variant c.1090C > T, p.(Arg364Trp) in the MFN2 gene. This variant was also detected in a mosaic state in blood and saliva by Sanger sequencing in her subjectively healthy father. Next generation sequencing showed that the level of mosaicism was 21% in blood and 24% in saliva. A high recurrence risk was given because the father had proven somatic mosaicism and an affected child implying gonadal mosaicism. The parents were referred for pre-implantation genetic diagnosis. To the best of our knowledge, this is the first reported case of somatic mosaicism for MFN2. This study has important implications for genetic counselling in families with CMT2A.