Myotonic dystrophy (DM) is a multi-systemic disease that impacts cardiac and skeletal muscle as well as the central nervous system (CNS). DM is unusual because it is an RNA-mediated disorder due to the expression of toxic microsatellite expansion RNAs that alter the activities of RNA processing factors, including the muscleblind-like (MBNL) proteins. While these mutant RNAs inhibit MBNL1 splicing activity in heart and skeletal muscles, Mbnl1 knockout mice fail to recapitulate the full-range of DM symptoms in these tissues. Here, we generate mouse Mbnl compound knockouts to test the hypothesis that Mbnl2 functionally compensates for Mbnl1 loss. Although Mbnl1−/−; Mbnl2−/− double knockouts (DKOs) are embryonic lethal, Mbnl1−/−; Mbnl2+/− mice are viable but develop cardinal features of DM muscle disease including reduced lifespan, heart conduction block, severe myotonia and progressive skeletal muscle weakness. Mbnl2 protein levels are elevated in Mbnl1−/− knockouts where Mbnl2 targets Mbnl1-regulated exons. These findings support the hypothesis that compound loss of MBNL function is a critical event in DM pathogenesis and provide novel mouse models to investigate additional pathways disrupted in this RNA-mediated disease.

Our results, using a new mouse model mimicking an acute reduction of cMLCK, suggest that cMLCK plays a pivotal role in the transition from compensated to decompensated hypertrophy via sarcomeric disorganization.

Background Heterozygous human mutations of NKX2-5 are highly penetrant and associated with varied congenital heart defects. The heterozygous knockout of murine Nkx2-5, in contrast, manifests less profound cardiac malformations, with low disease penetrance. We sought to study this apparent discrepancy between human and mouse genetics. Since missense mutations in the NKX2-5 homeodomain (DNA binding domain) are the most frequently reported type of human mutation, we replicated this genetic defect in a murine knock-in model. Methods and Results We generated a murine model in a 129/Sv genetic background by knocking-in an Nkx2-5 homeodomain missense mutation previously identified in humans. The mutation was located at homeodomain position 52Arg→Gly (R52G). All the heterozygous neonatal Nkx2-5+/R52G mice demonstrated a prominent trabecular layer in the ventricular wall, so called noncompaction, along with diverse cardiac anomalies, including atrioventricular septal defects, Ebstein’s malformation of the tricuspid valve, and perimembranous and/or muscular ventricular septal defects. In addition, P10 Nkx2-5+/R52G mice demonstrated atrial septal anomalies, with significant increase in the size of the inter-atrial communication and fossa ovalis, and decrease in the length of the flap valve compared to control Nkx2-5+/+ or Nkx2-5+/− mice. Conclusion The results of our study demonstrate that heterozygous missense mutation in the murine Nkx2-5 homeodomain (R52G) are highly penetrant, and result in pleiotropic cardiac effects. Thus, in contrast to heterozygous Nkx2-5 knockout mice, the effects of the heterozygous knock-in mimic findings in humans with heterozygous missense mutation in NKX2-5 homeodomain.

Cardiac rehabilitation is a class 1 recommendation for acute coronary syndrome (ACS) patients according to the American College of Cardiology/American Heart Association. However, only 1 in 5 ACS patients are referred for cardiac rehabilitation nationally, and even fewer at our institution. We sought to improve the number of referrals to cardiac rehabilitation for post-ACS patients admitted to our inpatient cardiology service, and ultimately their participation in the program. We designed a quality improvement initiative that included education of patients and house staff, automated referral order, and participation of cardiac rehabilitation staff members on multidisciplinary rounds. We compared the number of patients who received a referral to cardiac rehabilitation, had the first appointment scheduled before hospital discharge, and attended the program before and after our intervention. Six months after initiation of the project, the proportion of ACS patients referred to cardiac rehabilitation before hospital discharge increased from 10% to 43% (P < 0.001). The mean number of patients with a cardiac rehabilitation appointment scheduled before discharge was 2 before and 5 after the intervention (P < 0.001), and the mean number of patients who attended their scheduled appointment was 1 before and 3 after the intervention (P = 0.001). Run charts demonstrated that the number of referrals and the number of scheduled appointments remained above the median following the intervention. In conclusion, an initiative that included education, automated referrals, and direct one-on-one contact with cardiac rehabilitation staff before discharge increased the number of cardiac rehabilitation referrals, and appointments scheduled and attended in post-ACS patients.

Background Heterozygous human NKX2-5 homeodomain (DNA binding domain) missense mutations are highly penetrant for varied congenital heart defects, including progressive atrioventricular block (AVB) requiring pacemaker implantation. We recently replicated this genetic defect in a murine knock-in model, in which we demonstrated highly penetrant, pleiotropic cardiac anomalies. In this study, we examined postnatal AV conduction in the knock-in mice. Methods and Results A murine knock-in model (Arg52Gly, Nkx2-5+/R52G) in a 129/Sv background was analyzed by histopathology, surface and telemetry ECG, and in vivo electrophysiology studies (EPS), comparing with control Nkx2-5+/+ mice at diverse postnatal stages, ranging from postnatal day 1 (P1) to 17 months. PR-prolongation (1st degree AVB) was present at 4 weeks, 7 months, and 17 months of age but not at P1 in the mutant mice. Advanced AVB was also occasionally demonstrated in the mutant mice. EPS showed that AV nodal function, and right ventricular effective refractory period, were impaired in the mutant mice, while sinus nodal function was not affected. AV nodal size was significantly smaller in the mutant mice compared to their controls at 4 weeks of age, corresponding to the presence of PR-prolongation, but not P1, suggesting, at least in part, that the conduction abnormalities are the result of a morphologically atrophic AV node. Conclusions The highly penetrant and progressive AVB phenotype seen in human heterozygous missense mutations in NKX2-5 homeodomain was replicated in mice by knocking-in a comparable missense mutation.

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To date there have been few reports on the impact of dietary intervention on the clinical course of acute shigellosis. Current management of acute shigellosis is primarily focused on antibiotic therapy with less emphasis on nutritional management. In a randomised clinical trial, we examined the role of an energy-dense diet on the clinical outcome in malnourished children with acute dysentery due to shigellosis. Seventy-five children aged 12–48 months with acute dysentery randomly received either a milk–cereal formula with an energy density of 4960 kJ/l (test group) or a milk–cereal formula with energy of 2480 kJ/l (control group) for 10 d in hospital. In both milk–cereal formulas, protein provided 11 % energy. In addition, the standard hospital diet was offered to all children and all children received an appropriate antibiotic for 5 d. The mean food intakes (g/kg per d) in the test and control groups were: 112 (SE 2·28) AND 116 (se 3·48) (P=0·16) on day 1; 118 (se 2·72) and 107 (se 3·13) (P=0·04) on day 5; 120 (se 2·25) and 100 (se 3·83) (P=0·04) on day 10. The mean energy intakes (kJ/kg per d) in the test and control groups respectively were: 622 (se 13·2) and 315 (se 11·3) (P<0·05) on day 1; 655 (se 15·1) and 311 (se 7·98) (P<0·05) on day 5; 672 (se 14·7) and 294 (se 11·1) (P<0·05) on day 10. The food and energy intakes were mostly from the milk–cereal diet. There was no difference between two groups in resolution of fever, dysenteric (bloody and or mucoid) stools, stool frequency and tenesmus. However, vomiting was more frequently observed among the test-group children during the first 5 d of intervention (67 % v. 41 %, P=0·04). There was an increase in the mean weight-for-age (%) in the test group compared with the control group after the 10 d of dietary intervention (6·2 (se 0·6) v. 2·7 (se 0·4), P<0·01). In addition, resolution of rectal prolapse was better (26 % v. 8 %, P=0·04) in the test group v. control group after 5 d, and 13 % v. 6 %, (P=0·08) after 10 d of dietary intervention. Supplementation with a high-energy diet does not have any adverse effect on clinical course of acute shigellosis and reduces the incidence of rectal prolapse in malnourished children.

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