Facilitation of I Kr current by some hERG channel blockers suppresses early afterdepolarizations.

Drug-induced block of the cardiac rapid delayed rectifying potassium current (I Kr), carried by the human ether-a-go-go-related gene (hERG) channel, is the most common cause of acquired long QT syndrome. Indeed, some, but not all, drugs that block hERG channels cause fatal cardiac arrhythmias. However, there is no clear method to distinguish between drugs that cause deadly arrhythmias and those that are clinically safe. Here we propose a mechanism that could explain why certain clinically used hERG blockers are less proarrhythmic than others. We demonstrate that several drugs that block hERG channels, but have favorable cardiac safety profiles, also evoke another effect; they facilitate the hERG current amplitude in response to low-voltage depolarization. To investigate how hERG facilitation impacts cardiac safety, we develop computational models of I Kr block with and without this facilitation. We constrain the models using data from voltage clamp recordings of hERG block and facilitation by nifekalant, a safe class III antiarrhythmic agent. Human ventricular action potential simulations demonstrate the ability of nifekalant to suppress ectopic excitations, with or without facilitation. Without facilitation, excessive I Kr block evokes early afterdepolarizations, which cause lethal arrhythmias. When facilitation is introduced, early afterdepolarizations are prevented at the same degree of block. Facilitation appears to prevent early afterdepolarizations by increasing I Kr during the repolarization phase of action potentials. We empirically test this prediction in isolated rabbit ventricular myocytes and find that action potential prolongation with nifekalant is less likely to induce early afterdepolarization than action potential prolongation with dofetilide, a hERG channel blocker that does not induce facilitation. Our data suggest that hERG channel blockers that induce facilitation increase the repolarization reserve of cardiac myocytes, rendering them less likely to trigger lethal ventricular arrhythmias

Highly Metastatic Ovarian Yolk Sac Carcinoma in a Rat

We investigated a highly metastatic ovarian yolk sac carcinoma in a 52-week-old female Crl:CD(SD) rat. Macroscopically, the present case had severe ascites, bilateral ovarian masses and numerous nodules in the abdominal and thoracic cavities. Histopathologically, these masses and nodules were generally composed of two types of cells mimicking a parietal and visceral yolk sac. The parietal cells were round to polygonal, contained eosinophilic droplets and were arranged in nests and cords in the eosinophilic matrix. Both the intracytoplasmic droplets and the matrix were stained positively with PAS. The visceral cells were cylindriform, and proliferated in papillary and tubular patterns and occasionally formed Shiller-Duval body-like structures. In the dissemination sites, the neoplastic cells proliferated on the surface of the various tissues and often infiltrated into deeper parts of the tissues. Immunohistochemically, both neoplastic cells were positive for α-fetoprotein and keratin, and the eosinophilic matrix was positive for laminin. Ultrastructurally, the parietal cells had dilated rough endoplasmic reticulums, which were filled with electron-lucent laminated structures. The visceral cells had poorly to moderately developed intracytoplasmic organelles and were interconnected with desmosomes. Taken together, the present tumor was diagnosed as yolk sac carcinoma arising from the ovary and was characterized by not only high metastasis but also invasive infiltration with biphasic proliferation of the parietal and visceral cells

L-BSE prions after propagation in a non-human primate model

Classical- (C-) and atypical L-type bovine spongiform encephalopathy (BSE) prions cause different pathological phenotypes in cattle brains, and the disease-associated forms of each prion protein (PrPSc) has a dissimilar biochemical signature. Bovine C-BSE prions are the causative agent of variant Creutzfeldt-Jakob disease. To date, human infection with L-BSE prions has not been reported, but they can be transmitted experimentally from cows to cynomolgus monkeys (Macaca fascicularis), a non-human primate model. When transmitted to monkeys, C- and L-BSE prions induce different pathological phenotypes in the brain. However, when isolated from infected brains, the two prion proteins (PrPSc) have similar biochemical signatures (i.e., electrophoretic mobility, glycoforms, and resistance to proteinase K). Such similarities suggest the possibility that L-BSE prions alter their virulence to that of C-BSE prions during propagation in monkeys. To clarify this possibility, we conducted bioassays using inbred mice. C-BSE prions with or without propagation in monkeys were pathogenic to mice, and exhibited comparable incubation periods in secondary passage in mice. By contrast, L-BSE prions, either with or without propagation in monkeys, did not cause the disease in mice, indicating that the pathogenicity of L-BSE prions does not converge towards a C-BSE prion type in this primate model. These results suggest that, although C- and L-BSE prions propagated in cynomolgus monkeys exhibit similar biochemical PrPSc signatures and consist of the monkey amino acid sequence, the two prions maintain strain-specific conformations of PrPSc in which they encipher and retain unique pathogenic traits

The Double Polymerase Chain Reaction with Consensus Primers Permits Rapid and Sensitive Detection of Genital Human Papillomavirus Oncogenes

We have developed a sensitive procedure for the detection of relatively low copy numbers of multiple genital human papillomaviruses (HPVs) using the polymerase chain reaction (PCR). HPV DNAs were detected by agarose gel electrophoresis and ethidium bromide staining after 2 rounds of PCR amplification (double PCR) with outer and inner consensus primer pairs for HPV-6, 11, 16, 18, 31, 33, 52, and 58. The detection limit of this method (i. e., 10?? copy of HPV DNA per cell in 1 μg cell DNA) was sufficient for analysis of cervical intraepithelial neoplasia (CIN) specimens. Overall prevalence rate of HPV was 100% in 20 cases of CIN specimens. HPV typing by restriction enzyme analysis revealed that HPV-16 sequence was present in 11 cases, HPV-18 in 1 case, HPV-31 in 4 cases, HPV-33 in 1 case, HPV-52 in 2 cases, HPV-58 in 3 cases, and an unidentified type(s) in 3 cases. There were 4 cases of mixed infections. This procedure obviates the use of hybridization- based for-mat for identification of at least 8 types of HPV sequences present in a small fraction of cells within a heterogeneous population

Interaction Rating Scale (IRS) as an Evidence-Based Practical Index of Children’s Social Skills and Parenting

Background: The purpose of this paper is to describe the features of the Interaction Rating Scale (IRS) as an evidence-based practical index of children’s social skills and parenting.Methods: The participants in our study, which was conducted as part of a Japan Science and Technology Agency (JST) project, were 370 dyads of children (aged 18, 30, and 42 month) and 81 dyads of 7-year-old children with their caregivers. The participants completed the five minute interaction session and were observed using the IRS.Results: The results indicated that the IRS can measure children’s social skill development and parenting with high validity. Along with the discriminate validity for pervasive development disorder (PDD), attention-deficit/hyperactivity disorder (ADHD), abuse and maltreatment, a high correlation with the SDQ (Strength and Difficulties Questionnaire), and high reliability, the IRS is effective in describing features of social skill development.Conclusions: The IRS provides further evidence of the fact that in order to study children’s social skill development, it is important to evaluate various features of the caregiver-child interaction as a predictor of social skills

The relationship between the development of social competence and sleep in infants: a longitudinal study

BackgroundMany reports argue that sleep is important for children’s health, learning, and academic performance. The purpose of this longitudinal study was to examine the association between sleep and the development of social competence in infants.MethodsThis study was conducted as part of a Japan Science and Technology Agency (JST) project. Caregivers responded to the Japan Children’s Study Sleep Questionnaire when children were 18 months old. The interactions of caregivers and children were observed when children were 18, 30, and 42 months old, and rated with the Interaction Rating Scale, which is a measure of social competence.ResultsNocturnal sleep duration of more than 10 h and an earlier bed time than 22:00 were significantly correlated with two trajectory groups (low point and high point transition groups) of children’s social competence at 18, 30, and 42 months. Further, total sleep duration of more than 12.25 h and an earlier bed time than 22:00 were significantly correlated with the trajectory of children’s social competence at 18, 30, and 42 months.ConclusionsSleep duration and sleep onset time are important factors in children’s development of social competence

Impurity-induced in-gap state and Tc in sign-reversing s-wave superconductors: analysis of iron oxypnictide superconductors

The sign-reversing fully gapped superconducting state, which is expected to be realized in oxypnictide superconductors, can be prominently affected by nonmagnetic impurities due to the interband scattering of Cooper pairs. We study this problem based on the isotropic two-band BCS model: In oxypnictide superconductors, the interband impurity scattering $I'$ is not equal to the intraband one $I$. In the Born scattering regime, the reduction in Tc is sizable and the impurity-induced density of states (DOS) is prominent if $I\sim I'$, due to the interband scattering. Although impurity-induced DOS can yield a power-law temperature dependence in $1/T_1$, a sizable suppression in Tc is inevitably accompanied. In the unitary scattering regime, in contrast, impurity effect is very small for both Tc and DOS except at $I=I'$. By comparing theory and experiments, we expect that the degree of anisotropy in the $s_\pm$-wave gap function strongly depends on compounds.Comment: 16 pages, 5 figures, to be published in New. J. Phy