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BACKGROUND AND PURPOSE Chronic heart failure (CHF) is associated with action potential prolongation and Ca2+ overload, increasing risk of ventricular tachyarrhythmias (VT). We therefore investigated whether ICa blockade was anti-arrhythmic in an intact perfused heart model of CHF. EXPERIMENTAL APPROACH CHF was induced in rabbits after 4 weeks of rapid ventricular pacing. Hearts from CHF and sham-operated rabbits were isolated and perfused (Langendorff preparation), with ablation of the AV node. VT was induced by erythromycin and low [K+] (1.5mM). Electrophysiology of cardiac myocytes, with block of cation currents, was simulated by a mathematical model. KEY RESULTS Repolarization was prolonged in CHF hearts compared with sham-operated hearts. Action potential duration (APD) and overall dispersion of repolarization were further increased by erythromycin (300 µM) to block IKr in CHF hearts. After lowering [K+] to 1.5mM, CHF and sham hearts showed spontaneous episodes of polymorphic non-sustained VT. Additional infusion of verapamil (0.75 µM) suppressed early afterdepolarizations (EAD) and VT in 75% of sham and CHF hearts. Verapamil shortened APD and dispersion of repolarization, mainly by reducing transmural dispersion of repolarization via shortening of endocardial action potentials. Mathematical simulations showed that EADs were more effectively reduced by verapamil assuming a state-dependent block than a simple block of ICa. CONCLUSIONS AND IMPLICATIONS Blockade of ICa was highly effective in suppressing VT via reduction of transmural dispersion of repolarization and suppression of EAD. Such blockade might represent a novel therapeutic option to reduce risk of VT in structurally normal hearts and also in heart failure. LINKED ARTICLE This article is commented on by Stams et al., pp. 554-556 of this issue. To view this commentary visit [ABSTRACT FROM AUTHOR]

Background: Molecular remodeling in heart failure includes slowing of repolarization, leading to proarrhythmia.Objective: To evaluate the effects of Na(+)/Ca(2+) exchanger (NCX) inhibition on repolarization as a novel antiarrhythmic concept in chronic heart failure (CHF).Methods and Results: CHF was induced by rapid ventricular pacing in rabbits. Left ventricular function was assessed by echocardiography. Monophasic action potentials (MAPs) showed a prolongation of repolarization in CHF after atrioventricular block and stimulation at different cycle lengths. Sotalol (100 μM, n = 13) or veratridine (0.5 μM; n = 15) resulted in a further significant increase in the MAP duration. CHF was associated with an increased dispersion of repolarization, as compared with sotalol-treated (+22 ± 7 ms; P < .05) and veratridine-treated (+20 ± 6 ms; P < .05) sham hearts. In the presence of a low potassium concentration, sotalol and veratridine reproducibly induced early afterdepolarizations (EADs) and polymorphic ventricular tachyarrhythmias (VTs). SEA0400 (1 μM), a pharmacological inhibitor of NCX, significantly shortened the MAP duration (P < .01) and reduced dispersion (P < .05). It suppressed EAD in 6 of 13 sotalol-treated failing hearts and in 9 of 10 veratridine-treated failing hearts, leading to a reduction in VT (60% in sotalol-treated failing hearts and 83% in veratridine-treated failing hearts). Simulations using a mathematical model showed a reduction in the action potential duration and the number of EADs by the NCX block in all subgroups.Conclusions: In an experimental model of CHF, the acute inhibition of NCX (1) reduces the MAP duration, (2) decreases dispersion of repolarization, and (3) suppresses EAD and VT. Our observations indicate for the first time that pharmacological NCX inhibition increases repolarization reserve and protects against VTs in heart failure. [ABSTRACT FROM AUTHOR]

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Purpose: To retrospectively evaluate the long-term outcome of the bell-bottom technique for the endovascular repair of common iliac artery (CIA) aneurysms. Methods: Between September 2003 and September 2008, 89 patients (84 men; mean age 73.7+/-8.4 years) with aortic and CIA aneurysms were treated at 2 European centers with aortic extension cuffs or large iliac limbs that gave a bell-bottom configuration to the iliac portion of an aortoiliac stent-graft. The mean maximum aortic diameter was 65.7+/-12.3 mm (range 42-98), and the mean diameter of the treated CIA aneurysms was 22.1+/-3.0 mm (range 20-30). Results: Technical success was achieved in 97.8% (87/89). There was no early (<30-day) mortality, but 8 (8.9%) patients died (none aneurysm-related) during follow-up. Cumulative survival by Kaplan-Meier analysis was 96.3% at 1 year, 85.5% at 3 years, and 83.1% at 5 years. After a mean follow-up of 56.5 months, computed tomography documented 3 (3.4%) type I endoleaks: one proximal leak was treated by conversion to open repair, and the other 2 distal type I endoleaks were treated by implantation of an iliac extension. Two (2.2%) type II endoleaks were accompanied by an increase in the aneurysm diameter; one was treated by coil embolization of the inferior mesenteric artery and the other by conversion to open repair after repeated coil embolization. One patient underwent thrombectomy for iliac limb occlusion. The freedom from secondary intervention was 91.6% at 5 years. The mean maximum diameter of the CIA aneurysms showed no significant change over time (24.1+/-3 mm at 30 days and 23.4+/-4 mm at latest follow-up). Conclusion: Moderate-size CIA aneurysms (<30 mm) can be safely and effectively treated using the bell-bottom technique. The risk of distal type I endoleak is low. Iliac-related complications can be successfully treated by endovascular techniques. [ABSTRACT FROM AUTHOR]

Background: Long QT syndrome (LQTS) is associated with sudden cardiac death resulting from torsades de pointes (TdP), which are triggered by early afterdepolarizations (EADs). The cardiac Na(+)/Ca(2+) exchanger (NCX) has been suggested to work as a trigger for EADs.Objective: The purpose of this study was to test the hypothesis that inhibition of NCX with a newly developed selective NCX inhibitor (SEA0400) reduces TdP.Methods and Results: In 34 Langendorff-perfused rabbit hearts, the I(Kr)-blocker sotalol (100 microM; n = 18) as well as veratridine (0.5 microM; n = 16), an inhibitor of sodium channel inactivation, led to a significant increase in monophasic action potential (MAP) duration thereby mimicking LQTS2 and LQTS3. In bradycardic hearts, recordings of eight MAPs demonstrated an increased dispersion of repolarization (sotalol: 67%; veratridine: 89%; P <.05). After lowering of potassium concentration, sotalol (56%) and veratridine (63%) induced TdP. Perfusion with SEA0400 (1 microM) suppressed EADs in 15 of 16 sotalol hearts and in seven of 13 veratridine hearts. SEA0400 significantly shortened MAP duration and reduced dispersion of repolarization in both groups (P <.05). This reduced TdP incidence in the sotalol group (100%) and in the veratridine group (77%). To investigate the effects of NCX inhibition on the cellular level, we used a computer model of the rabbit ventricular myocyte. I(Na) and I(Kr) were modified to mimic the effects of veratridine and sotalol, respectively. Consistent with our in vitro experiments, reduction of NCX activity accelerated repolarization of the cellular action potential and prevented EADs.Conclusion: In an intact rabbit heart model of LQT2 and LQT3 as well as in a computer model of the rabbit cardiac myocyte, inhibition of NCX is effective in preventing TdP due to a suppression of EADs, a reversion of action potential prolongation, and a reduction of dispersion of repolarization. Our observations suggest a therapeutic benefit of selective NCX inhibition in LQTS. [ABSTRACT FROM AUTHOR]

Coxsackievirus and adenovirus receptor (CAR) is a member of the immunoglobulin (Ig) superfamily and a component of epithelial tight junction. CAR also functions as a primary receptor for coxsackievirus B and adenovirus (Ad) infection. In this study, we report the identification of a novel protein, CAR-like soluble protein (CLSP), which is closely related to CAR. Mouse CLSP (mCLSP) was composed of 390 amino acids, including three Ig domains, and showed strong homology to the IgV domain of CAR. Interestingly, mCLSP lacks a transmembrane domain, indicating that this is a soluble protein. mCLSP mRNA was detected primarily in the brain and ovary. When mCLSP cDNA was introduced into SK HEP-1 cells, which were known to be CAR positive and easily infected with Ad vector, the infection with Ad vector was severely inhibited. On the other hand, mCLSP promoted the infection with Ad vector in CAR-negative NIH3T3 cells. Furthermore, recombinant CLSP directly bound to Ad and inhibited the Ad vector-mediated transduction in SK HEP-1 cells. Computational analysis for a genome database showed that the CLSP gene is rodent-specific, and that human and bovine lack this gene. These results suggest that CLSP may play a role in the antiviral defense of the host in rodent animals.Gene Therapy (2007) 14, 1199–1207; doi:10.1038/sj.gt.3302975; published online 31 May 2007 [ABSTRACT FROM AUTHOR]

The aim of this study was to examine the effect of a 20° Trendelenburg position on the blockade of nerves that exit the brachial plexus proximally in patients undergoing single-injection axillary brachial plexus block. After a pilot study of eight cadavers suggested that a head-down and lateral position would encourage the proximal spread of local anaesthetic, 72 patients undergoing elective surgery were divided into two equal groups: a Supine group and a Modified Position group (lateral position, 20° head-down tilt). Patients were left in the allocated position for 30 min after an axillary block had been performed with alkalinised mepivacaine 1% 49.5 ml. Sensory and motor blockade evaluation showed that there was a significantly higher proportion of axillary nerve (76% vs. 0%, p < 0.001), thoracodorsal nerve (86% vs. 0%, p < 0.001) and subscapular nerve (89% vs. 0%, p < 0.001) blockade in the Modified Position group. Sensory block of the radial nerve was also improved by the modified position (100% vs. 86%, p < 0.05). [ABSTRACT FROM AUTHOR]

Supratentorial primitive neuroectodermal tumors (sPNET) and atypical teratoid/rhabdoid tumors (AT/RT) of the CNS represent a biological and clinical enigma, despite advances in both molecular techniques and clinical management for these two rare embryonal brain tumors of childhood. Epigenetic changes hold great potential as possible disease mechanisms and may be manipulated therapeutically. We thus studied aberrant methylation of the genes RASSF1A and CASP8 and its consequence on expression in cell lines and primary tumors using a combination of semiquantitative methylation specific PCR (MSP), bisulfite sequencing and RT–PCR. In all, 17 samples of autopsy-derived normal appearing brain served as controls. Opposed to control tissues 19/24 sPNET and 4/6 AT/RT demonstrated aberrant methylation for the RASSF1A promoter region. Treatment of cell lines using 5-Aza-2′-deoxycytidine (5AZA) alone or in combination with trichostatin A (TSA) succeeded in re-establishing expression of RASSF1A in cell lines derived from a renal rhabdoid, an AT/RT and a medulloblastoma. A 5′ CpG-rich region of CASP8 was methylated in normal tissues and in tumors. However, CASP8 showed inconsistent expression patterns in normal and tumor tissues. Our results indicate that aberrant methylation of the RASSF1A promoter region may be of importance in the origin and progression of sPNET and AT/RT while the analysed 5′-CpG rich region of the CASP8 gene does not seem to play an important role in these tumors. Further studies of epigenetic changes in these rare tumors are warranted as their biology remains obscure and treatment efforts have been rather unsuccessfull.Oncogene (2006) 25, 1111–1117. doi:10.1038/sj.onc.1209137; published online 26 September 2005 [ABSTRACT FROM AUTHOR]

The article presents information on capsaicin 8% cutaneous patch which is a promising treatment for brachioradial pruritus. A successful treatment of brachioradial pruritus (BRP) with a single application of a high-dose capsaicin patch is reported. The intraepidermal nerve fibre density (IENF) in itchy skin was lessened in comparison with their intraindividual nonlesional IENF.

Highlights: [•] There are radioactively contaminated soils having a radioactive cesium transfer of 0.01. [•] Micro-PIXE analysis has revealed an existence of phosphorus in a contaminated soil. [•] Radioactive cesium captured by phosphorus compound would be due to radioactive transfer. [ABSTRACT FROM AUTHOR]

Not available.

The genus Macaca is widely distributed, occupies a variety of habitats, shows diverse phenotypic characteristics, and is one of the best-studied genera of nonhuman primates. Here, we reported five re-sequencing Macaca genomes, including one M. cyclopis, one M. fuscata, one M. thibetana, one M. silenus, and one M. sylvanus. Together with published genomes of other macaque species, we combined 20 genome sequences of 10 macaque species to investigate the gene introgression and genetic differences among the species. The network analysis of the SNV-fragment trees indicates a reticular phylogeny of macaque species. Combining the results from various analytical methods, we identified extensive ancient introgression events among macaque species. The multiple introgression signals between different species groups were also observed, such as between fascicularis group species and silenus group species. However, gene flow signals between fascicularis and sinica group were not as strong as those between fascicularis group and silenus group. On the other hand, the unidirect gene flow in M. arctoides probably occurred between the progenitor of M. arctoides and the common ancestor of fascicularis group. Our study also shows that the genetic backgrounds and genetic diversity of different macaques vary dramatically among species, even among populations of the same species. In conclusion, using whole genome sequences and multiple methods, we have studied the evolutionary history of the genus Macaca and provided evidence for extensive introgression among the species., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The house mouse ( Mus musculus ), which is commensal to humans, has spread globally via human activities, leading to secondary contact between genetically divergent subspecies. This pattern of genetic admixture can provide insights into the selective forces at play in this well-studied model organism. Our analysis of 163 house mouse genomes, with a particular focus on East Asia, revealed substantial admixture between the subspecies castaneus and musculus , particularly in Japan and southern China. We revealed, despite the different level of autosomal admixture among regions, that all Y Chromosomes in the East Asian samples belonged to the musculus -type haplogroup, potentially explained by genomic conflict under sex-ratio distortion owing to varying copy numbers of ampliconic genes on sex chromosomes, Slx and Sly Our computer simulations, designed to replicate the observed scenario, show that the preferential fixation of musculus -type Y Chromosomes can be achieved with a slight increase in the male-to-female birth ratio. We also investigated the influence of selection on the posthybridization of the subspecies castaneus and musculus in Japan. Even though the genetic background of most Japanese samples closely resembles the subspecies musculus , certain genomic regions overrepresented the castaneus -like genetic components, particularly in immune-related genes. Furthermore, a large genomic block (∼2 Mbp) containing a vomeronasal/olfactory receptor gene cluster predominantly harbored castaneus -type haplotypes in the Japanese samples, highlighting the crucial role of olfaction-based recognition in shaping hybrid genomes., (© 2024 Fujiwara et al.; Published by Cold Spring Harbor Laboratory Press.)

The house shrew ( Suncus murinus-S . montanus species complex) colonized regions across southern Asia and the Indian Ocean following human activity. The house shrew is distributed on islands of the Ryukyu Archipelago, the southernmost part of Japan, but the evolutionary history of the shrew on those islands and possible associations between these populations and humans remain unknown. In this study, we conducted phylogenetic and population genetic analyses based on both nuclear and mitochondrial genome sequences of house shrews. Phylogenetic analyses based on mitochondrial cytochrome b ( cytb ) sequences revealed that shrews from the Ryukyu Archipelago showed strong genetic affinity to Vietnamese and southern Chinese shrews. Demographic analyses of cytb sequences indicated a rapid population expansion event affecting the haplotype group in Vietnam, southern China, and the Ryukyu Archipelago 3300-7900 years ago. Furthermore, gene flow between Ryukyu (Yonaguni Island) and Taiwan and between Ryukyu and Vietnam inferred from f 4 statistics of the nuclear genomes suggested repeated immigration to Ryukyu in recent years. The present study demonstrates that the Nagasaki population has a different origin from the Ryukyu population. These findings elucidate the complex pattern of genetic admixture in house shrews and provide insights into their evolutionary history.