A Mutation in the Gene Encoding Mitochondrial Mg2+ Channel MRS2 Results in Demyelination in the Rat

The rat demyelination (dmy) mutation serves as a unique model system to investigate the maintenance of myelin, because it provokes severe myelin breakdown in the central nervous system (CNS) after normal postnatal completion of myelination. Here, we report the molecular characterization of this mutation and discuss the possible pathomechanisms underlying demyelination. By positional cloning, we found that a G-to-A transition, 177 bp downstream of exon 3 of the Mrs2 (MRS2 magnesium homeostasis factor (Saccharomyces cerevisiae)) gene, generated a novel splice acceptor site which resulted in functional inactivation of the mutant allele. Transgenic rescue with wild-type Mrs2-cDNA validated our findings. Mrs2 encodes an essential component of the major Mg2+ influx system in mitochondria of yeast as well as human cells. We showed that the dmy/dmy rats have major mitochondrial deficits with a markedly elevated lactic acid concentration in the cerebrospinal fluid, a 60% reduction in ATP, and increased numbers of mitochondria in the swollen cytoplasm of oligodendrocytes. MRS2-GFP recombinant BAC transgenic rats showed that MRS2 was dominantly expressed in neurons rather than oligodendrocytes and was ultrastructurally observed in the inner membrane of mitochondria. Our observations led to the conclusion that dmy/dmy rats suffer from a mitochondrial disease and that the maintenance of myelin has a different mechanism from its initial production. They also established that Mg2+ homeostasis in CNS mitochondria is essential for the maintenance of myelin

Transabdominal Ultrasound Real-time Tissue Elastography as a Screening Method for Early Chronic Pancreatitis

Background and Purpose: The concept of early chronic pancreatitis was proposed in Japan with the aim to improve the prognosis of patients with chronic pancreatitis. Endoscopic ultrasonography plays an important role in early diagnoses, but is limited by its invasiveness and poor objectivity. Hence, this study aimed to determine the usefulness of transabdominal ultrasound real-time tissue elastography as a screening method for early chronic pancreatitis. Methods: We retrospectively examined 73 patients who underwent simultaneous ultrasound real-time tissue elastography and endoscopic ultrasonography from 2011 to 2014. The correlation between feature values (MEAN, %AREA, COMP) calculated by real-time tissue elastography and the Rosemont classification of endoscopic ultrasonography diagnostic criteria for chronic pancreatitis, and the diagnostic ability of ultrasound real-time tissue elastography to recognize “indeterminate for chronic pancreatitis” findings, which correspond to early chronic pancreatitis, were evaluated. Main Results: Based on the Rosemont classification, 26 patients were “normal”, 16 were “indeterminate for chronic pancreatitis”, 13 were “suggestive of chronic pancreatitis”, and 18 were “consistent with chronic ancreatitis”. There were significant correlations between the feature values (MEAN, %AREA, COMP) and the Rosemont classification (p < 0.001; ρ = –0.788, 0.779, and 0.489, respectively). The area under the curve for the ability of MEAN to diagnose “indeterminate for chronic pancreatitis” was 0.889 (sensitivity, 93.8%; specificity, 76.9%). Conclusions: The feature values calculated by ultrasound real-time tissue elastography were correlated with the Rosemont classification. Ultrasound real-time tissue elastography may be a useful screening method for early chronic pancreatitis

SORL1 Is Genetically Associated with Late-Onset Alzheimer’s Disease in Japanese, Koreans and Caucasians

To discover susceptibility genes of late-onset Alzheimer’s disease (LOAD), we conducted a 3-stage genome-wide association study (GWAS) using three populations: Japanese from the Japanese Genetic Consortium for Alzheimer Disease (JGSCAD), Koreans, and Caucasians from the Alzheimer Disease Genetic Consortium (ADGC). In Stage 1, we evaluated data for 5,877,918 genotyped and imputed SNPs in Japanese cases (n = 1,008) and controls (n = 1,016). Genome-wide significance was observed with 12 SNPs in the APOE region. Seven SNPs from other distinct regions with p-values ,261025 were genotyped in a second Japanese sample (885 cases, 985 controls), and evidence of association was confirmed for one SORL1 SNP (rs3781834, P=7.3361027 in the combined sample). Subsequent analysis combining results for several SORL1 SNPs in the Japanese, Korean (339 cases, 1,129 controls) and Caucasians (11,840 AD cases, 10,931 controls) revealed genome wide significance with rs11218343 (P=1.7761029) and rs3781834 (P=1.0461028). SNPs in previously established AD loci in Caucasians showed strong evidence of association in Japanese including rs3851179 near PICALM (P=1.7161025) and rs744373 near BIN1 (P = 1.3961024). The associated allele for each of these SNPs was the same as in Caucasians. These data demonstrate for the first time genome-wide significance of LOAD with SORL1 and confirm the role of other known loci for LOAD in Japanese. Our study highlights the importance of examining associations in multiple ethnic populations

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure &lt; 100 mmHg (n = 1127), estimated glomerular filtration rate &lt; 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Nodular Calcification in Saphenous Vein Graft Successfully Treated by Percutaneous Coronary Intervention

Nodular calcification is sometimes detected in the native coronary artery. However, it is very rare to find in a saphenous vein graft (SVG). We herein report a rare case of stable angina pectoris (AP) due to nodular calcification. A 75-year-old man who had previously undergone coronary artery bypass grafting was admitted to our hospital due to stable AP. On angiography, significant stenosis was detected in the proximal SVG. Based on the findings of coronary angiography and optical coherence tomography, a red thrombus was suspected at the culprit lesion. However, nodular calcification was also suspected, as there were calcifications around the lesion. As intravascular ultrasound showed the protruding calcification, which we judged to be a nodular calcification, the calcified SVG lesion was successfully treated by percutaneous coronary intervention without any complications. Nodular calcification should be considered as a potential cause of AP, even when located in a SVG