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Aim. To assess the prognostic value of the integral assessment using various modern methods for diagnosing congestion in patients hospitalized with acute decompensated heart failure (ADHF).Material and methods. This single-center prospective study included 165 patients with ADHF. All patients underwent a standard clinical and paraclinical examination, including assessing NT-proBNP levels, lung ultrasound B-lines, liver transient elastography, bioelectrical impedance vector analysis (BIVA) at admission and discharge. To assess clinical congestion, the Heart Failure Association consensus document scale was used. Long-term clinical outcomes were assessed by telephone survey 1, 3, 6, 12 months after discharge. As an end point, the allcause mortality and readmissions were estimated.Results. In patients hospitalized with ADHF, at discharge, differences were found in the incidence of residual congestion according to certain paraclinical methods — from 22 to 38%, subclinical — from 14,5 to 27%. When using the integral assessment of stagnation, the incidence of residual and subclinical congestion was 53,6% and 35%, respectively. Patients with residual congestion had more severe symptoms of congestion, compared with those with subclinical congestion. Patients in whom congestion was detected by 4 methods, in contrast to those by 1, 2, and 3 methods, had worse clinical and paraclinical parameters. There was a significant increase in the risk of all-cause mortality and readmission in the presence of congestion, identified by 3 (hazard ratio, 9,4 (2,2-40,6); p

The meat industry has received great attention in Mongolia, having over 70 million livestock, and is important to the nation's economy. Systematic microbiological testing of carcasses has not been mandatorily regulated in all abattoir premises, and the efficacy of the introduction of the Good Hygiene Practice and Hazard Analysis Critical Control Points (HACCP) to some plants has not yet been tested microbiologically in Mongolia. Therefore, samples were collected from two establishments: plant A with an HACCP certificate from a third party and plant B without an HACCP certificate. The rates and levels of the total bacterial count (TBC) as overall hygiene indicators, the Enterobacteriaceae count (EBC) as fecal contamination indicators, and the Staphylococcus spp. count (SC) as personal hygiene indicators were determined on different parts of beef carcasses. The contamination rates in most parts were lower in plant A than in plant B (e.g., TBC in the rump and flank: 10 3 -10 5 and 10 5 -10 7 , in plant A vs. 10 4 -10 6 and 10 5 -10 8 in plant B, respectively). Plant A also had a lower EBC and SC ( p < 0.001). Furthermore, 2 out of 100 beef carcasses (2%) were positive for enterohemorrhagic Escherichia coli as a foodborne pathogen indicator in plant A.

Objective: The significance of liver stiffness (LS) in the setting of cardiovascular congestion during the course of acute decompensated heart failure (ADHF) is under investigation. The aim of this study was to assess LS with the use of transient elastography (TE) and its associations with volume overload as determined by means of bioimpedance vector analysis (BIVA) in ADHF., Methods and Results: TE (Fibroscan 502; Echosens) and BIVA (ABC-01, Medass) were performed in the first 48 hours of admission and on the day of discharge in 149 ADHF patients without known primary chronic liver disease or acute hepatitis. During hospitalization the median value of LS decreased from 12.2 kPa (interquartile range 6.3-23.6) to 8.7 (5.9-14.4) kPa (P < .001). Changes in LS correlated (P < .001) with changes in weight and BIVA parameters. LS was compared with histologic features of livers of ADHF patients who died (n = 7). Liver fibrosis 2B-4 was observed but was not associated with LS. LS at discharge was associated with increased risk of 12-month all-cause death, HF readmission, and the combined end point., Conclusions: There was a moderate association between LS with clinical congestion and volume overload according to BIVA and no correlation with degree of histologic liver fibrosis. LS may be a marker of negative HF outcomes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: There is growing evidence that liver stiffness (LS) in decompensated heart failure (DHF) is related to congestion, however data about its impact on outcomes are limited. The aim of the study was to evaluate associations and long-term prognostic significance of LS measured by transient elastography (TE) in DHF., Methods: Single-center prospective observational study of 194 patients hospitalized with DHF, of whom 71 % were male, 68 ± 11 years (mean ± SD), had a left ventricular ejection fraction of 39±14%. LS by TE (FibroScan 502, Echosens, France) was measured on admission (n=176) and/or discharge (n=165). Outcomes of interest were all-cause death or heart transplantation, heart failure (HF) rehospitalisation, heart valve repair surgery. Outcome analysis was performed with Kaplan-Meier survival curves compared by log-rank test and with Cox proportional hazards regression., Results: Median LS on admission and discharge were 11.1 (interquartile range 6.3;22.9) and 8.2 (5.8;14.0) kPa, respectively. Higher LS was associated with more clinical congestion on admission and discharge. Patients with LS on admission ≥11.1 kPa and at discharge ≥8.2 kPa were characterised by more pronounced clinical and echocardiographic signs of right-sided HF. Total of 5 (2.6%) patients died in hospital. Further, 31 (17.3%) deaths, 1 (0.6%) heart transplantation, 3 (1.7%) valve repair surgeries and 54 (30.2%) HF rehospitalizations occurred during follow-up (median 183 days). LS ≥ median was associated with higher probability of HF rehospitalizations and composite end point (all-cause death, heart transplantation, HF rehospitalisation and valve replacement therapy) both on admission (logrank p=0.004 and p=0.006) and at discharge (log-rank p=0.001 and p=0.004). Multivariable Cox regression analysis revealed that on a continuous scale LS increase per 1 kPa on admission was related to higher risk of HF hospitalization (hazard ratio [HR] 1.024, 95% confidential interval [CI] 1.002-1.046, p=0.03). LS at discharge was independently associated with increased all-cause mortality (HR per 1 kPa increase 1.098, 95% CI 1.025-1.176, p=0.008), higher risk of HF hospitalization (HR 1.075, 95% CI 1.035-1.117, p.

Background: Mutations in the type 1 ryanodine receptor gene (RYR1) result in malignant hyperthermia, a pharmacogenetic disorder typically triggered by administration of anesthetics. However, cases of sudden death during exertion, heat challenge, and febrile illness in the absence of triggering drugs have been reported. The underlying causes of such drug-free fatal "awake" episodes are unknown., Methods: De novo R3983C variant in RYR1 was identified in two unrelated children who experienced fatal, nonanesthetic awake episodes associated with febrile illness and heat stress. One of the children also had a second novel, maternally inherited D4505H variant located on a separate haplotype. Effects of all possible heterotypic expression conditions on RYR1 sensitivity to caffeine-induced Ca release were determined in expressing RYR1-null myotubes., Results: Compared with wild-type RYR1 alone (EC50 = 2.85 ± 0.49 mM), average (± SEM) caffeine sensitivity of Ca release was modestly increased after coexpression with either R3983C (EC50 = 2.00 ± 0.39 mM) or D4505H (EC50 = 1.64 ± 0.24 mM). Remarkably, coexpression of wild-type RYR1 with the double mutant in cis (R3983C-D4505H) produced a significantly stronger sensitization of caffeine-induced Ca release (EC50 = 0.64 ± 0.17 mM) compared with that observed after coexpression of the two variants on separate subunits (EC50 = 1.53 ± 0.18 mM)., Conclusions: The R3983C mutation potentiates D4505H-mediated sensitization of caffeine-induced RYR1 Ca release when the mutations are in cis (on the same subunit) but not when present on separate subunits. Nevertheless, coexpression of the two variants on separate subunits still resulted in a ∼2-fold increase in caffeine sensitivity, consistent with the observed awake episodes and heat sensitivity.

We identified a member of the BTB/Kelch protein family that is mutated in nemaline myopathy type 6 (NEM6), an autosomal-dominant neuromuscular disorder characterized by the presence of nemaline rods and core lesions in the skeletal myofibers. Analysis of affected families allowed narrowing of the candidate region on chromosome 15q22.31, and mutation screening led to the identification of a previously uncharacterized gene, KBTBD13, coding for a hypothetical protein and containing missense mutations that perfectly cosegregate with nemaline myopathy in the studied families. KBTBD13 contains a BTB/POZ domain and five Kelch repeats and is expressed primarily in skeletal and cardiac muscle. The identified disease-associated mutations, C.742C>A (p.Arg248Ser), c.1170G>C (p.Lys390Asn), and c.1222C>T (p.Arg408Cys), located in conserved domains of Kelch repeats, are predicted to disrupt the molecule's beta-propeller blades. Previously identified BTB/POZ/Kelch-domain-containing proteins have been implicated in a broad variety of biological processes, including cytoskeleton modulation, regulation of gene transcription, ubiquitination, and myofibril assembly. The functional role of KBTBD13 in skeletal muscle and the pathogenesis of NEM6 are subjects for further studies., (Copyright © 2010 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: Malignant hyperthermia susceptibility (MHS) is diagnosed by an invasive in vitro caffeine-halothane contracture test (CHCT) carried out on biopsied skeletal muscle tissue. We are presenting a novel blood test approach for malignant hyperthermia testing in a swine model. Our main aim was to determine whether adenosine production from lymphocytes after 4-chloro-m-cresol (4CmC) stimulation distinguishes homozygous swine carrying the Arg615Cys mutation in the ryanodine receptor type 1 (RyR1) gene (MHS swine) from normal swine., Methods: Lymphocytes were isolated from arterial blood (40 ml) obtained from MHS (n = 7) and normal (n = 7) swine. Cells were suspended in Hank's balanced salt solution and treated with 4CmC (0-10 mm) at 37°C in the presence of adenosine deaminase inhibitor. After termination and purification of samples, aliquots (50 μl) were assayed for adenosine content using high performance liquid chromatography., Results: Baseline adenosine levels before stimulating lymphocytes with 4CmC were 0.025 ± 0.004 and 0.041 ± 0.006 μm (mean ± SEM) in lymphocytes from normal and MHS swine, respectively (P = 0.125). Maximum responses were achieved at 1 mm 4CmC for both cell-line groups. Adenosine levels after stimulation with 4CmC (1 mm) were 0.185 ± 0.009 and 0.397 ± 0.038 μm in lymphocytes from normal and MHS swine, respectively (P = 0.0035). There was no overlap between adenosine levels in stimulated lymphocytes from MHS and normal swine., Conclusion: 4CmC stimulation of porcine lymphocytes induces increased adenosine formation in MHS cells relative to those from normal swine; evaluation of adenosine formation in response to RyR1 agonists in human lymphocytes is needed.

It has been suggested that exertional rhabdomyolysis (ER) and malignant hyperthermia (MH) are related syndromes. We hypothesize that patients with unexplained ER harbor mutations in the ryanodine receptor gene type 1 (RYR1), a primary gene implicated in MH, and therefore ER patients are at increased risk for MH. Although there are reported cases of MH in individuals of African descent, there are no data available on molecular characterization of these patients. We analyzed RYR1 in six, unrelated African American men with unexplained ER, who were subsequently diagnosed as MH susceptible (MHS) by the Caffeine Halothane Contracture Test. Three novel and two variants, previously reported in Caucasian MHS subjects, were found in five studied patients. The novel variants were highly conserved amino acids and were absent among 230 control subjects of various ethnic backgrounds. These results emphasize the importance of performing muscle contracture testing and RYR1 mutation screening in patients with unexplained ER. The MHS-associated variant Ala1352Gly was identified as a polymorphism predominant in individuals of African descent. Our data underscore the need for investigating RYR1 across different ethnic groups and will contribute to interpretation of genetic screening results of individuals at risk for MH.

Myofibrillar myopathies (MFMs) are an expanding and increasingly recognized group of neuromuscular disorders caused by mutations in DES, CRYAB, MYOT, and ZASP. The latest gene to be associated with MFM was FLNC; a p.W2710X mutation in the 24th immunoglobulin-like repeat of filamin C was shown to be the cause of a distinct type of MFM in several German families. We studied an International cohort of 46 patients from 39 families with clinically and myopathologically confirmed MFM, in which DES, CRYAB, MYOT, and ZASP mutations have been excluded. In patients from an unrelated family a 12-nucleotide deletion (c.2997&#95;3008del) in FLNC resulting in a predicted in-frame four-residue deletion (p.Val930&#95;Thr933del) in the seventh repeat of filamin C was identified. Both affected family members, mother and daughter, but not unrelated control individuals, carried the p.Val930&#95;Thr933del mutation. The mutation is transcribed and, based on myopathological features and immunoblot analysis, it leads to an accumulation of dysfunctional filamin C in the myocytes. The study results suggest that the novel p.Val930&#95;Thr933del mutation in filamin C is the cause of MFM but also indicate that filamin C mutations are a comparatively rare cause of MFM.

We previously reported that the level of c-Jun NH2-terminal kinase (JNK)/stress-activated protein kinase-associated protein 1 (JSAP1), a scaffold protein for JNK signaling, increases dramatically during nerve growth factor (NGF)-induced differentiation of PC12h cells. In the present study, we investigated the function of JSAP1 during PC12h cell differentiation by knocking down the level of JSAP1. The depletion of JSAP1 caused NGF-treated PC12h cells to form aggregates and impaired their differentiation. The aggregation was not observed in JSAP1-depleted cells that were untreated or treated with epidermal growth factor. Immunocytochemical studies indicated that N-cadherin, but not E-cadherin, was localized to sites of cell-cell contact in the aggregated cells. Furthermore, an inhibitory anti-N-cadherin antibody completely blocked the aggregation. Taken together, these results suggest that JSAP1 regulates cell-cell interactions in PC12h cells specifically in the NGF-induced signaling pathway, and does so by modulating N-cadherin.

Scaffold proteins of mitogen-activated protein kinase (MAPK) intracellular signal transduction pathways mediate the efficient and specific activation of the relevant MAPK signaling modules. Previously, our group and others have identified c-Jun NH2-terminal kinase (JNK)/stress-activated protein kinase-associated protein 1 (JSAP1, also known as JNK-interacting protein 3) as a scaffold protein for JNK MAPK pathways. Although JSAP1 is expressed in the testis in adults, its expression during development has not been investigated. In addition, it is unknown which types of cells in the testis express the scaffold protein. Here, we examined the expression of JSAP1 in the testis of mice aged 14 days, 20 days, 6 weeks, and 12 weeks by immunohistochemistry and Western blotting. The specificity of the anti-JSAP1 antibody was evaluated from its reactivity to exogenously expressed JSAP1 and a structurally related protein, and by antigen-absorption experiments. The immunohistochemical analyses with the specific antibody showed that the JSAP1 protein was selectively expressed in the spermatogonia and spermatocytes, but not in other cell types, including spermatids and somatic cells, during development. However, not all spermatogonia and spermatocytes were immunopositive either, especially in the 12-week-old mouse testis. Furthermore, we found by Western blotting that the expression levels of JSAP1 protein vary during development; there is high expression until 6 weeks after birth, which approximately corresponds to the end of the first wave of spermatogenesis. Collectively, these results suggest that JSAP1 function may be important in spermatogenic cells during early postnatal development.