Loss of Nexilin function leads to a recessive lethal fetal cardiomyopathy characterized by cardiomegaly and endocardial fibroelastosis.

The Nexilin F-Actin Binding Protein (Nexilin) encoded by NEXN is a cardiac Z-disc protein important for cardiac function and development in humans, zebrafish, and mice. Heterozygote variants in the human NEXN gene have been reported to cause dilated and hypertrophic cardiomyopathy. Homozygous variants in NEXN cause a lethal form of human fetal cardiomyopathy, only described in two patients before. In a Swedish, four-generation, non-consanguineous family comprising 42 individuals, one female had three consecutive pregnancies with intrauterine fetal deaths caused by a lethal form of dilated cardiomyopathy. Whole-exome sequencing and variant analysis revealed that the affected fetuses were homozygous for a NEXN variant (NM_144573:c.1302del;p.(Ile435Serfs*3)). Moreover, autopsy and histology staining declared that they presented with cardiomegaly and endocardial fibroelastosis. Immunohistochemistry staining for Nexilin in the affected fetuses revealed reduced antibody staining and loss of striation in the heart, supporting loss of Nexilin function. Clinical examination of seven heterozygote carriers confirmed dilated cardiomyopathy (two individuals), other cardiac findings (three individuals), or no cardiac deviations (two individuals), indicating incomplete penetrance or age-dependent expression of dilated cardiomyopathy. RNA sequencing spanning the variant in cDNA blood of heterozygote individuals revealed nonsense-mediated mRNA decay of the mutated transcripts. In the current study, we present the first natural course of the recessively inherited lethal form of human fetal cardiomyopathy caused by loss of Nexilin function. The affected family had uneventful pregnancies until week 23-24, followed by fetal death at week 24-30, characterized by cardiomegaly and endocardial fibroelastosis.

[Self-reported level of skills in practical procedures following internship in general practice]. / Selvrapportert ferdighetsnivå i praktiske prosedyrer etter turnustjeneste i distrikt.

BACKGROUND: Previous reports have demonstrated variable and partly insufficient skills in standard practical procedures among young doctors who have served their internship. The present study examines the development of interns' self-reported level of skills in practical procedures during internship in general practice in relation to quantity and quality of supervision, gender and the size of the community they served in. MATERIAL AND METHODS: Between 1996 and 1999, all doctors going through internships in Norway were asked to indicate their level of skills in 88 practical clinical procedures before and after internship in general practice. Of 575 interns asked, 439 replied (76 %). RESULTS: All interns reported a significant overall improvement in self-reported practical skills during internship in general practice. Supervision and feedback was also significantly better in general practice than in internships in hospital. INTERPRETATION: The quality of the general practice internship in Norway is superior to the quality of hospital training. Supervision and feedback is a standard part of the education of general practitioners and represents a valuable tradition. A combination of internship in hospitals and in general practice is necessary for acquiring adequate skills in practical procedures.

[Self-reported level of practical skills after the revision of a medical school curriculum in Trondheim]. / Selvrapportert ferdighetsnivå i praktiske prosedyrer etter ny og etter gammel studieordning i Trondheim.

BACKGROUND: The medical curriculum of the University of Trondheim was recently changed from a traditional (2.5 years preclinical studies followed by 3.5 years clinical studies) to an integrated, problem-based approach. This study examines self-reported levels of skills in practical procedures before and after internship among doctors educated under the old vs. the new curriculum. MATERIALS AND METHODS: Between 1996-99 (old curriculum) and 1999-2001 (new curriculum) all doctors who had graduated from the University of Trondheim were asked to indicate their level of skills in 88 practical clinical procedures before and after their hospital internships. RESULTS: Of the 174 interns included, 114 replied on both occasions (66%). Before internship, graduates with the new curriculum reported a significant better level of skills than those with the old curriculum. After internship, however, no difference according to curriculum could be observed. The gender difference in the self-reports from students under the old curriculum was absent. INTERPRETATION: The new problem-based curriculum seems to have improved the practical level of skills prior to internship. This difference does, however, disappear after hospital internship.

[Physicians' clinical skills after finishing internship]. / Laegers kliniske faerdigheder efter turnusuddannelsen.

INTRODUCTION: The aim of this study was to evaluate Danish interns' clinical skills after their internship in order to identify areas where systematic training is needed. This study was a follow-up of a previous study on a group of interns at the beginning of their internship. MATERIAL AND METHODS: A questionnaire listing 88 practical skills was posted to a group of trainees before and after internship. The interns were asked to rate their level of mastery in each skill on a scale 0-10, where 0 = not mastery/not competent and 10 = mastery/competent. RESULTS: In all, 74 out of 100 trainees returned the questionnaire. In 60 of the skills the trainees reported a higher level of mastery after internship and in 28 procedures the level of skill did not improve. Ten of these are procedures used in emergency settings. DISCUSSION: The reliability of self-reported clinical skills can be discussed, but it is a major concern that skills particularly in emergency procedures do not improve. There is a need to define clear objectives, implement structured training programmes, and assess skills in order to accomplish a reliable and sufficient level of competency.

Effects of cariporide and losartan on hypertrophy, calcium transients, contractility, and gene expression in congestive heart failure.

BACKGROUND: The purpose of this study was to compare long-term effects of cariporide with those of losartan in postinfarction heart failure. METHODS AND RESULTS: Female Sprague-Dawley rats with large myocardial infarctions and sham controls were randomized to losartan, cariporide, or placebo after 7 days and treated for 49 days. Cardiac function was assessed by echocardiography and measurement of left ventricular pressures, and gene expression was assessed by competitive reverse transcription-polymerase chain reaction. Cell dimensions, shortening, and relaxation were determined by videomicroscopy and calcium transients by fura 2. Losartan reduced postinfarction systolic and diastolic left ventricular dilation (by 24% and 31%, respectively), left and right ventricular weight (by 22% and 26%, respectively), and cardiomyocyte hypertrophy length and width (by 62% and 54%, respectively). Induction of myocardial atrial natriuretic peptide decreased 66%. Cariporide did not affect postinfarction hypertrophy or atrial natriuretic peptide. Losartan and cariporide respectively improved reduced cellular contractility (55% and 30%) and reduced elevated systolic (86% and 27%) and diastolic (49% and 43%) calcium. Losartan and cariporide respectively reduced prolonged time to 50% relaxation (66% and 25%) and time to 50% calcium reduction (55% and 53%). CONCLUSIONS: Losartan and cariporide improve cardiomyocyte contractility and calcium regulation in chronic heart failure. Losartan has salutary effects on postinfarction remodeling and gene expression, whereas cariporide is neutral.