Morphological, behavioral and cellular analyses revealed different phenotypes in Wolfram syndrome wfs1a and wfs1b zebrafish mutant lines

Wolfram syndrome (WS) is a rare genetic disease characterized by diabetes, optic atrophy and deafness. Patients die at 35 years of age, mainly from respiratory failure or dysphagia. Unfortunately, there is no treatment to block the progression of symptoms and there is an urgent need for adequate research models. Here, we report on the phenotypical characterization of two loss-of-function zebrafish mutant lines: wfs1aC825X and wfs1bW493X. We observed that wfs1a deficiency altered the size of the ear and the retina of the fish. We also documented a decrease in the expression level of unfolded protein response (UPR) genes in basal condition and in stress condition, i.e. after tunicamycin treatment. Interestingly, both mutants lead to a decrease in their visual function measured behaviorally. These deficits were associated with a decrease in the expression level of UPR genes in basal and stress conditions. Interestingly, basal, ATP-linked and maximal mitochondrial respirations were transiently decreased in the wfs1b mutant. Taken together, these zebrafish lines highlight the critical role of wfs1a and wfs1b in UPR, mitochondrial function and visual physiology. These models will be useful tools to better understand the cellular function of Wfs1 and to develop novel therapeutic approaches for WS

Clinical profile, management, and outcome in patients with out of hospital cardiac arrest: insights from a 20-year registry

Ashfaq Ahmad Patel, Abdul Rahman Arabi, Hakam Alzaeem, Jassim Al Suwaidi, Rajvir Singh, Hajar A Al BinaliDepartment of Cardiology, Heart Hospital, Hamad Medical Corporation, Doha, QatarBackground: There is limited information regarding the clinical characteristics and outcome of out of hospital cardiac arrest (OHCA) in Middle Eastern patients. The aim of this study was to evaluate clinical characteristics, treatment, and outcomes in patients admitted following OHCA at a single center in the Middle East over a 20-year period.Methods: The data used for this hospital-based study were collected for patients hospitalized with OHCA in Doha, Qatar, between 1991 and 2010. Baseline clinical characteristics, in-hospital treatment, and outcomes were studied in comparison with the rest of the admissions.Results: A total of 41,453 consecutive patients were admitted during the study period, of whom 987 (2.4%) had a diagnosis of OHCA. Their average age was 57±15 years, and 72.7% were males, 56.5% were Arabs, and 30.9% were South Asians. When compared with the rest of the admissions taken as a reference, patients with OHCA were more likely to have diabetes mellitus (42.8% versus 39.1%, respectively, P=0.02), prior myocardial infarction (21.8% versus 19.2%, P=0.04), and chronic renal failure (7.4% versus 3.9%, P=0.001), but were less likely to have dyslipidemia (16.9% versus 25.4%, P=0.001). Further, 52.6% of patients had preceding symptoms, the most common of which was chest pain (27.2%) followed by dyspnea (24.8%). An initially shockable rhythm (ventricular fibrillation or ventricular tachycardia) was present in 25.1% of OHCA patients, with ST segment elevation myocardial infarction documented in 30.0%. Severely reduced left ventricular systolic function (ejection fraction ≤35%) was present in 53.2% of OHCA patients; 42.9% had cardiogenic shock requiring use of inotropes at presentation. An intra-aortic balloon pump was inserted in 3.6% of cases. Antiarrhythmic medications were used in 27.4% and thrombolytic therapy in 13.9%, and 10.8% underwent a percutaneous coronary procedure (coronary angiography ± percutaneous coronary intervention). The in-hospital mortality rate was 59.8%.Conclusion: OHCA was associated with higher incidences of diabetes, prior myocardial infarction, and chronic kidney disease as compared with the remaining admissions. Approximately half of the patients had no preceding symptoms. In-hospital mortality was high (59.8%), but similar to the internationally published data.Keywords: out of hospital cardiac arrest, cardiogenic shock, in-hospital mortalit