Effect of left ventricular remodeling after cardiac resynchronization therapy on frequency of ventricular arrhythmias

We evaluated whether cardiac resynchronization therapy affects the prevalence of ventricular tachycardia in relation to reverse remodeling in patients with end-stage heart failure. Clinical, echocardiographic, and implantable cardioverter-defibrillator (ICD) data of 17 patients with ICDs were obtained before and after they had received an upgrade to an ICD-cardiac resynchronization therapy device.     

A missense mutation in the 3-ketodihydrosphingosine reductase FVT1 as candidate causal mutation for bovine spinal muscular atrophy

The bovine form of the autosomal recessive neurodegenerative disease spinal muscular atrophy (SMA) shows striking similarity to the human form of the disease. It has, however, been mapped to a genomic region not harboring the bovine orthologue of the SMN gene, mutation of which causes human SMA. After refinement of the mapping results we analyzed positional and functional candidate genes. One of three candidate genes, FVT1, encoding 3-ketodihydrosphingosine reductase, which catalyzes a crucial step in the glycosphingolipid metabolism, showed a G-to-A missense mutation that changes Ala-175 to Thr. The identified mutation is limited to SMA-affected animals and carriers and always appears in context of the founder haplotype. The Ala variant found in healthy animals showed the expected 3-ketodihydrosphingosine reductase activity in an in vitro enzyme assay. Importantly, the Thr variant found in SMA animals showed no detectable activity. Surprisingly, in an in vivo assay the mutated gene complements the growth defect of a homologous yeast knockout strain as well as the healthy variant. This finding explains the viability of affected newborn calves and the later neuron-specific onset of the disease, which might be due to the high sensitivity of these neurons to changes in housekeeping functions. Taken together, the described mutation in FVT1 is a strong candidate for causality of SMA in cattle. This result provides an animal model for understanding the underlying mechanisms of the development of SMA and will allow efficient selection against the disease in cattle.     

Apocynin but not L-arginine prevents and reverses dexamethasone-induced hypertension in the rat

BACKGROUND: Dexamethasone (Dex)-hypertension in rats is associated with increased oxidative stress. We investigated effects of the NAD(P)H oxidase inhibitor apocynin and the nitric oxide (NO) precursor L-arginine on Dex-hypertension to determine the relative roles of NAD(P)H oxidase and uncoupling in the reactive oxygen species (ROS) generation and hypertension. METHODS: Male Sprague-Dawley rats (n = 10/group) received Dex (20 microg/kg/day subcutaneously) or saline (vehicle) for 14 days. In a prevention study, rats received 4 days of apocynin treatement (1.5 mmol/L in drinking water) followed by Dex/saline for 12 days. In reversal studies, apocynin or L-arginine was given from day 8 to 14. Systolic blood pressure (SBP) was measured by tail cuff, and thymus weight was used as a marker of glucocorticoid activity. RESULTS: Administration of Dex increased SBP (104 +/- 3 to 122 +/- 3 mm Hg, P < .01, mean +/- SEM) and decreased thymus and body weight (P' < .05). Apocynin alone had no effect on SBP, BW, or thymus weight. Apocynin prevented (122 +/- 4 Dex, 111 +/- 3 mm Hg Apocynin+Dex, P' < .05) and reversed Dex-hypertension (130 +/- 4 to 116 +/- 4 mm Hg, P < .01). L-arginine did not reverse Dex-hypertension. CONCLUSIONS: In male SD rats, apocynin but not l-arginine prevented and reversed Dex-hypertension, suggesting that NAD(P)H oxidase-mediated superoxide production but not endothelial nitric oxide synthase uncoupling is important in Dex-hypertension.     

Genomic diversity of human papillomavirus genotype 53 in an ethnogeographically closed cohort of white European women

Human papillomavirus (HPV) genotype 53 is classified taxonomically in alpha HPV genus-species 6, together with HPV-30, HPV-56, and HPV-66 and is considered to be one of three "probable high-risk" HPV genotypes. Recent worldwide comparison of 44 isolates of HPV-53 showed the existence of nine long control region (LCR) genomic variants, which formed a phylogenetic tree with two deep dichotomic branches. In order to investigate further the genomic diversity of HPV-53, a total of 94 isolates of HPV-53 obtained from an ethnogeographically closed cohort of 70 white European women was analyzed. The identification and characterization of HPV-53 genomic variants was based on analysis of three different HPV genomic regions: LCR, E6 and E7. A higher genomic diversity of HPV-53 was identified in the ethnogeographically closed cohort of white European women than has been reported previously on isolates collected worldwide. Altogether, 19 HPV-53 genomic variants, composed of 13 LCR, 13 E6, and 5 E7 genomic variants, were identified. Eleven out of 13 LCR, all E6, and four out of five E7 genomic variants were described for the first time. The present study confirmed dichotomic phylogeny of HPV-53 described previously and, in addition, showed for the first time that after a dichotomic split, both groups of HPV-53 genomic variants formed star-like phylogenetic clusters. In women with persistent HPV-53 infection, HPV-53 genomic variants remained unchanged for up to 51 months. In rare cases, infection with multiple HPV-53 genomic variants is possible. Taking into account the results of this and previous studies, at least 26 different HPV-53 genomic variants exist today.     

A sertoli cell-specific knockout of connexin43 prevents initiation of spermatogenesis

The predominant testicular gap junctional protein connexin43 (cx43) is located between neighboring Sertoli cells (SCs) and between SCs and germ cells. It is assumed to be involved in testicular development, cell differentiation, initiation, and maintenance of spermatogenesis with alterations of its expression being correlated with various testicular disorders. Because total disruption of the cx43 gene leads to perinatal death, we generated a conditional cx43 knockout (KO) mouse using the Cre/loxP recombination system, which lacks the cx43 gene solely in SCs (SCCx43KO), to evaluate the SC-specific functions of cx43 on spermatogenesis in vivo. Adult SCCx43KO(-/-) mice showed normal testis descent and development of the urogenital tract, but testis size and weight were drastically lower compared with heterozygous and wild-type littermates. Histological analysis and quantitation of mRNA expression of germ cell-specific marker genes revealed a significant reduction in the number of spermatogonia but increased SC numbers/tubule with only a few tubules left showing normal spermatogenesis. Thus, SC-specific deletion of cx43 mostly resulted in an arrest of spermatogenesis at the level of spermatogonia or SC-only syndrome and in intratubular SC clusters. Our data demonstrate for the first time that cx43 expression in SCs is an absolute requirement for normal testicular development and spermatogenesis.