Missense variants in ANO4 cause sporadic encephalopathic or familial epilepsy with evidence for a dominant-negative effect

Anoctamins are a family of Ca$^{2+}$-activated proteins that may act as ion channels and/or phospholipid scramblases with limited understanding of function and disease association. Here, we identified five de novo and two inherited missense variants in ANO4 (alias TMEM16D) as a cause of fever-sensitive developmental and epileptic or epileptic encephalopathy (DEE/EE) and generalized epilepsy with febrile seizures plus (GEFS+) or temporal lobe epilepsy. In silico modeling of the ANO4 structure predicted that all identified variants lead to destabilization of the ANO4 structure. Four variants are localized close to the Ca$^{2+}$ binding sites of ANO4, suggesting impaired protein function. Variant mapping to the protein topology suggests a preliminary genotype-phenotype correlation. Moreover, the observation of a heterozygous ANO4 deletion in a healthy individual suggests a dysfunctional protein as disease mechanism rather than haploinsufficiency. To test this hypothesis, we examined mutant ANO4 functional properties in a heterologous expression system by patchclamp recordings, immunocytochemistry, and surface expression of annexin A5 as a measure of phosphatidylserine scramblase activity. All ANO4 variants showed severe loss of ion channel function and DEE/EE associated variants presented mild loss of surface expression due to impaired plasma membrane trafficking. Increased levels of Ca$^{2+}$-independent annexin A5 at the cell surface suggested an increased apoptosis rate in DEE-mutant expressing cells, but no changes in Ca$^{2+}$-dependent scramblase activity were observed. Co-transfection with ANO4 wild-type suggested a dominant-negative effect. In summary, we expand the genetic base for both encephalopathic sporadic and inherited fever-sensitive epilepsies and link germline variants in ANO4 to a hereditary disease

Innate Immune Responses of Pulmonary Epithelial Cells to Burkholderia pseudomallei Infection

10.1371/journal.pone.0007308PLoS ONE410

Frailty syndrome in ambulatory patients with COPD

Panita Limpawattana,1 Siraphong Putraveephong,2 Pratchaya Inthasuwan,2 Watchara Boonsawat,3 Daris Theerakulpisut,4 Jarin Chindaprasirt5 1Division of Geriatric Medicine, 2Department of Internal Medicine, 3Division of Respiratory System, Department of Internal Medicine, 4Division of Nuclear Medicine, Department of Radiology, 5Division of Oncology Medicine, Department of Internal Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand Abstract: Frailty is a state of increased risk of unfavorable outcomes when exposed to stressors, and COPD is one of the several chronic illnesses associated with the condition. However, few studies have been conducted regarding the prevalence of COPD and its related factors in Southeast Asia. The objectives of this study were to determine the prevalence of frailty in COPD patients and to identify the associated factors in these populations. A cross-sectional study of COPD patients who attended a COPD clinic was conducted from May 2015 to December 2016. Baseline characteristics were collected, and the diagnosis of frailty was based on the FRAIL (fatigue, resistance, ambulation, illnesses, and loss of weight) scale. Descriptive statistics were used to analyze baseline data. Factors associated with frailty were analyzed using univariate and multivariate regression analyses. The results showed that the prevalence rates of frailty and pre-frailty were 6.6% (eight out of 121 cases) and 41.3% (50 out of 121 cases), respectively, among COPD patients. Fatigue was the most common component of the FRAIL scale that was found more frequently in frail patients than in non-frail patients (odds ratio [OR] 91.9). Factors associated with frailty according to multivariate analyses were comorbid cancer (adjusted OR [AOR] 45.8), at least two instances of nonelective admission over the past 12 months (AOR 112.5), high waist circumference (WC) (AOR 1.3), and presence of sarcopenia (AOR 29.5). In conclusion, frailty affected 6.6% of stable COPD patients. Cancer, two or more instances of nonelective hospitalization over the past 12 months, high WC, and presence of sarcopenia were associated with frailty. Early identification and intervention in high-risk patients is recommended to prevent or delay the adverse outcomes of frailty. Keywords: frailty syndrome, FRAIL scale, chronic lung disease, sarcopeni

Which Shiftwork Pattern Is the Strongest Predictor for Poor Sleep Quality in Nurses?

10.3390/ijerph192113986International Journal of Environmental Research and Public Health192113986

Perceptions of Asthma Control by patients in Asia-Pacific Countries: results of the Asia-Pacific Asthma Insight and Management (AP-AIM) Survey

link_to_OA_fulltex

The burden of asthma in Asia-Pacific (AP) Countries: results of the AP Asthma Insight and Management (AIM) Survey of patients

link_to_OA_fulltex

The Asia-Pacific Asthma Insight and Management Survey (AP-AIM): a multinational survey of asthma patients from 8 Asia-Pacific Countries and Hong Kong

link_to_OA_fulltex

Insights, attitudes,and perceptions about asthma and its treatment: Findings from a multinational survey of patients from 8 Asia-Pacific countries and Hong Kong

link_to_OA_fulltex