Brugada syndrome (BrS) is a common heritable channelopathy. Mutations in the SCN5A-encoded sodium channel (BrS1) culminate in the most common genotype.
This study sought to perform a retrospective ...analysis of BrS databases from 9 centers that have each genotyped >100 unrelated cases of suspected BrS.
Mutational analysis of all 27 translated exons in SCN5A was performed. Mutation frequency, type, and localization were compared among cases and 1,300 ostensibly healthy volunteers including 649 white subjects and 651 nonwhite subjects (blacks, Asians, Hispanics, and others) that were genotyped previously.
A total of 2,111 unrelated patients (78% male, mean age 39 +/- 15 years) were referred for BrS genetic testing. Rare mutations/variants were more common among BrS cases than control subjects (438/2,111, 21% vs. 11/649, 1.7% white subjects and 31/651, 4.8% nonwhite subjects, respectively, P <10(-53)). The yield of BrS1 genetic testing ranged from 11% to 28% (P = .0017). Overall, 293 distinct mutations were identified in SCN5A: 193 missense, 32 nonsense, 38 frameshift, 21 splice-site, and 9 in-frame deletions/insertions. The 4 most frequent BrS1-associated mutations were E1784K (14x), F861WfsX90 (11x), D356N (8x), and G1408R (7x). Most mutations localized to the transmembrane-spanning regions.
This international consortium of BrS genetic testing centers has added 200 new BrS1-associated mutations to the public domain. Overall, 21% of BrS probands have mutations in SCN5A compared to the 2% to 5% background rate of rare variants reported in healthy control subjects. Additional studies drawing on the data presented here may help further distinguish pathogenic mutations from similarly rare but otherwise innocuous ones found in cases.
Purpose We examined symptom variability in men and women with urological chronic pelvic pain syndrome. We describe symptom fluctuations as related to early symptom regression and its effect on ...estimated 1-year symptom change. We also describe a method to quantify patient specific symptom variability. Materials and Methods Symptoms were assessed biweekly in 424 subjects with urological chronic pelvic pain syndrome during 1 year. To evaluate the impact of early symptom regression subjects were classified as improved, no change or worse according to the rate of change using 1) all data, 2) excluding week 0 and 3) excluding weeks 0 and 2. Patient specific, time varying variability was calculated at each interval using a sliding window approach. Patients were classified as high, medium or low variability at each time and ultimately as high or low variability overall based on the variability for the majority of contacts. Results Prior to excluding early weeks to adjust for early symptom regression 25% to 38% and 5% to 6% of patients were classified as improved and worse, respectively. After adjustment the percent of patients who were improved or worse ranged from 15% to 25% and 6% to 9%, respectively. High and low variability phenotypes were each identified in 25% to 30% of participants. Conclusions Patients with urological chronic pelvic pain syndrome show symptom variability. At study enrollment patients had worse symptoms on average, resulting in a regression effect that influenced the estimated proportion of those who were improved or worse. Prospective studies should include a run-in period to account for regression to the mean and other causes of early symptom regression. Further, symptom variability may be quantified and used to characterize longitudinal symptom profiles of urological chronic pelvic pain syndrome.
Background Eosinophilic airway inflammation is heterogeneous in asthmatic patients. We recently described a distinct subtype of asthma defined by the expression of genes inducible by TH 2 cytokines ...in bronchial epithelium. This gene signature, which includes periostin, is present in approximately half of asthmatic patients and correlates with eosinophilic airway inflammation. However, identification of this subtype depends on invasive airway sampling, and hence noninvasive biomarkers of this phenotype are desirable. Objective We sought to identify systemic biomarkers of eosinophilic airway inflammation in asthmatic patients. Methods We measured fraction of exhaled nitric oxide (F eno ), peripheral blood eosinophil, periostin, YKL-40, and IgE levels and compared these biomarkers with airway eosinophilia in asthmatic patients. Results We collected sputum, performed bronchoscopy, and matched peripheral blood samples from 67 asthmatic patients who remained symptomatic despite maximal inhaled corticosteroid treatment (mean FEV1 , 60% of predicted value; mean Asthma Control Questionnaire ACQ score, 2.7). Serum periostin levels are significantly increased in asthmatic patients with evidence of eosinophilic airway inflammation relative to those with minimal eosinophilic airway inflammation. A logistic regression model, including sex, age, body mass index, IgE levels, blood eosinophil numbers, F eno levels, and serum periostin levels, in 59 patients with severe asthma showed that, of these indices, the serum periostin level was the single best predictor of airway eosinophilia ( P = .007). Conclusion Periostin is a systemic biomarker of airway eosinophilia in asthmatic patients and has potential utility in patient selection for emerging asthma therapeutics targeting TH 2 inflammation.
Neurodegenerative diseases are challenging for systems biology because of the lack of reliable animal models or patient samples at early disease stages. Induced pluripotent stem cells (iPSCs) could ...address these challenges. We investigated DNA, RNA, epigenetics, and proteins in iPSC-derived motor neurons from patients with ALS carrying hexanucleotide expansions in C9ORF72. Using integrative computational methods combining all omics datasets, we identified novel and known dysregulated pathways. We used a C9ORF72 Drosophila model to distinguish pathways contributing to disease phenotypes from compensatory ones and confirmed alterations in some pathways in postmortem spinal cord tissue of patients with ALS. A different differentiation protocol was used to derive a separate set of C9ORF72 and control motor neurons. Many individual -omics differed by protocol, but some core dysregulated pathways were consistent. This strategy of analyzing patient-specific neurons provides disease-related outcomes with small numbers of heterogeneous lines and reduces variation from single-omics to elucidate network-based signatures.
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•Multi-omic analysis of differentiated C9ORF72 iPSC-derived motor neurons•Network-based integrative computational analysis•Pathogenic versus compensatory pathways elucidated using C9ORF72 Drosophila model•Pathways confirmed with alternative differentiation protocol and postmortem data
Biological sciences; Neuroscience; Systems neuroscience; Systems biology; Omics
Background Asthma is heterogeneous, and airway dysbiosis is associated with clinical features in patients with mild-to-moderate asthma. Whether similar relationships exist among patients with severe ...asthma is unknown. Objective We sought to evaluate relationships between the bronchial microbiome and features of severe asthma. Methods Bronchial brushings from 40 participants in the Bronchoscopic Exploratory Research Study of Biomarkers in Corticosteroid-refractory Asthma (BOBCAT) study were evaluated by using 16S ribosomal RNA–based methods. Relationships to clinical and inflammatory features were analyzed among microbiome-profiled subjects. Secondarily, bacterial compositional profiles were compared between patients with severe asthma and previously studied healthy control subjects (n = 7) and patients with mild-to-moderate asthma (n = 41). Results In patients with severe asthma, bronchial bacterial composition was associated with several disease-related features, including body mass index ( P < .05, Bray-Curtis distance-based permutational multivariate analysis of variance; PERMANOVA), changes in Asthma Control Questionnaire (ACQ) scores ( P < .01), sputum total leukocyte values ( P = .06), and bronchial biopsy eosinophil values (per square millimeter, P = .07). Bacterial communities associated with worsening ACQ scores and sputum total leukocyte values (predominantly Proteobacteria) differed markedly from those associated with body mass index (Bacteroidetes/Firmicutes). In contrast, improving/stable ACQ scores and bronchial epithelial gene expression of FK506 binding protein (FKBP5) , an indicator of steroid responsiveness, correlated with Actinobacteria. Mostly negative correlations were observed between biopsy eosinophil values and Proteobacteria. No taxa were associated with a TH 2-related epithelial gene expression signature, but expression of TH 17-related genes was associated with Proteobacteria. Patients with severe asthma compared with healthy control subjects or patients with mild-to-moderate asthma were significantly enriched in Actinobacteria, although the largest differences observed involved a Klebsiella genus member (7.8-fold increase in patients with severe asthma, adjusted P < .001). Conclusions Specific microbiota are associated with and may modulate inflammatory processes in patients with severe asthma and related phenotypes. Airway dysbiosis in patients with severe asthma appears to differ from that observed in those with milder asthma in the setting of inhaled corticosteroid use.
To the Editor: Chronic spontaneous urticaria (CSU) presents as recurrent itchy wheals, angioedema, or both for at least 6 weeks without a specific trigger.1 Roughly half of the patients with CSU ...achieve symptomatic control with H1-antihistamine therapy at approved doses, increased doses, or with additional therapies such as leukotriene receptor antagonists.1 CSU can be unpredictable and debilitating for patients because of a lack of clinical response.2 Recently, omalizumab, a neutralizing anti-IgE mAb, has gained approval for treatment of patients with CSU on the basis of evidence of substantial efficacy.3 However, the treatment benefit with omalizumab is usually lost when treatment is stopped. Specific IgE may target an endogenous antigen, a hypothesis supported by evidence that approximately 50% of patients with CSU have elevated levels of antithyroperoxidase IgE.5 Quilizumab, a humanized, afucosylated, monoclonal IgG1 antibody, binds membrane IgE at the M1-prime segment, which is absent in soluble IgE.6 In animal studies, quilizumab bound membrane IgE on IgE-switched B cells and plasmablasts and depleted them through apoptosis and antibody-dependent cell-mediated cytotoxicity.6 In clinical trials, quilizumab reduced serum total and specific IgE levels in healthy volunteers and in patients with allergic rhinitis or mild asthma.7,8 These reductions were sustained for at least 6 months after the last dose, suggesting that quilizumab affected long-term IgE memory.
Abstract In subjects with aortic regurgitation (AR) or mitral regurgitation (MR), transthoracic echocardiography (TTE) is recommended for surveillance. Few prospective studies have directly compared ...the ability of TTE and cardiac magnetic resonance (CMR) to predict clinical outcomes in AR and MR. We hypothesized that, given its higher reproducibility, CMR would predict the need for valve surgery or heart failure (HF) hospitalization better than TTE. Quantitative TTE and CMR were performed on the same day for 51 subjects: 29 with chronic AR and 22 with chronic, primary MR for quantification of valve regurgitation. Baseline measures of valve regurgitation were compared to the combined primary endpoint of new HF and valve surgery using receiver operating characteristics, simple logistic regression and Kaplan-Meier survival analyses. The primary endpoint occurred in 5 AR subjects (all surgery) and 8 MR subjects (7 surgery, 1 HF) after a mean follow-up of 4.4 ± 1.5 years. For AR, CMR-derived regurgitant volume >50mL identified those at high risk with 50% undergoing valve surgery versus 0% for those with regurgitant volume ≤50 ml, and was more strongly associated with outcomes than regurgitant volume by TTE (p<0.05). For MR, 6.8% of those with regurgitant volume by TTE ≤30 mL developed the primary endpoint versus 70% in those with regurgitant volume >30 mL. Regurgitant volume by CMR showed no significant separation of survival curves for MR. In conclusion, regurgitant volume by CMR was more predictive of outcomes than by TTE in subjects with AR. In MR, the two modalities performed similarly.
Abstract Objective Alcoholism is a risk factor for osteoporotic fractures and low bone density, but the effects of moderate alcohol consumption on bone are unknown. We performed a systematic review ...and meta-analysis to assess the associations between alcohol consumption and osteoporotic fractures, bone density and bone density loss over time, bone response to estrogen replacement, and bone remodeling. Methods MEDLINE, Current Contents, PsychINFO, and Cochrane Libraries were searched for studies published before May 14, 2007. We assessed quality using the internal validity criteria of the US Preventive Services Task Force. Results We pooled effect sizes for 2 specific outcomes (hip fracture and bone density) and synthesized data qualitatively for 4 outcomes (non-hip fracture, bone density loss over time, bone response to estrogen replacement, and bone remodeling). Compared with abstainers, persons consuming from more than 0.5 to 1.0 drinks per day had lower hip fracture risk (relative risk = 0.80 95% confidence interval, 0.71-0.91), and persons consuming more than 2 drinks per day had higher risk (relative risk = 1.39 95% confidence interval, 1.08-1.79). A linear relationship existed between femoral neck bone density and alcohol consumption. Because studies often combined moderate and heavier drinkers in a single category, we could not assess relative associations between alcohol consumption and bone density in moderate compared with heavy drinkers. Conclusion Compared with abstainers and heavier drinkers, persons who consume 0.5 to 1.0 drink per day have a lower risk of hip fracture. Although available evidence suggests a favorable effect of alcohol consumption on bone density, a precise range of beneficial alcohol consumption cannot be determined.
Current epidemiology of Meniere's syndrome Alexander, Thomas H; Harris, Jeffrey P
Otolaryngologic clinics of North America,
10/2010, Letnik:
43, Številka:
5
Journal Article
Recenzirano
The burden of Ménière syndrome (MS) is substantial, especially when considering the significant impact on the quality of life of those affected. Reported estimates of incidence and prevalence have ...varied widely due to methodological differences between studies, changes in criteria for diagnosis of MS, and differences in populations studied. Reported prevalence rates for MS range from 3.5 per 100,000 to 513 per 100,000. A recent study using health claims data for more than 60 million patients in the United States found prevalence of 190 per 100,000 with a female:male ratio of 1.89:1. The prevalence of MS increases with increasing age.
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