Identification of a Novel ACVRL1 Gene Mutation (c.100T>A, p.Cys34Ser) in a Japanese Patient with Possible Hereditary Hemorrhagic Telangiectasia (Osler-Weber-Rendu Disease)

Hereditary hemorrhagic telangiectasia (HHT; also known as Osler-Weber-Rendu disease) is an autosomal dominant genetic disorder that causes frequent epistaxis, mucocutaneous telangiectasia, and visceral arteriovenous malformations. Four genes (ENG, ACVRL1, SMAD4, and GDF2) have been identified as pathogenic in HHT. We describe the case of a 50-year-old Japanese man highly suspected of having HHT due to recurrent epistaxis, mucocutaneous telangiectasia, and a family history. Genomic analysis revealed a novel missense mutation of c.100T>A, p.Cys34Ser in the patient’s ACVRL1 gene. We used 6 freeware programs to perform an in silico analysis of this mutation. The results demonstrated the mutation’s high pathogenicity

The Audiovisual Tau Effect in Infancy

Perceived spatial intervals between successive flashes can be distorted by varying the temporal intervals between them (the “tau effect”). A previous study showed that a tau effect for visual flashes could be induced when they were accompanied by auditory beeps with varied temporal intervals (an audiovisual tau effect).We conducted two experiments to investigate whether the audiovisual tau effect occurs in infancy. Forty-eight infants aged 5–8 months took part in this study. In Experiment 1, infants were familiarized with audiovisual stimuli consisting of three pairs of two flashes and three beeps. The onsets of the first and third pairs of flashes were respectively matched to those of the first and third beeps. The onset of the second pair of flashes was separated from that of the second beep by 150 ms. Following the familiarization phase, infants were exposed to a test stimulus composed of two vertical arrays of three static flashes with different spatial intervals. We hypothesized that if the audiovisual tau effect occurred in infancy then infants would preferentially look at the flash array with spatial intervals that would be expected to be different from the perceived spatial intervals between flashes they were exposed to in the familiarization phase. The results of Experiment 1 supported this hypothesis. In Experiment 2, the first and third beeps were removed from the familiarization stimuli, resulting in the disappearance of the audiovisual tau effect. This indicates that the modulation of temporal intervals among flashes by beeps was essential for the audiovisual tau effect to occur (Experiment 2).These results suggest that the cross-modal processing that underlies the audiovisual tau effect occurs even in early infancy. In particular, the results indicate that audiovisual modulation of temporal intervals emerges by 5–8 months of age

Circuit Simulation Models for Coming MOSFET Generations

Abstract-The urgent tasks of MOSFET modeling for circuit simulation are easy adaptation to new physical phenomena arising for advancing technologies, and, of course, sufficient simulation accuracy. Approaches currently being pursued for developing such MOSFET models are summarized. Their capabilities for accomplishing these tasks as well as the important remaining problems are discussed

Novel Treatment Criteria for Persistent Ductus Arteriosus in Neonates

BackgroundThe indications for ductus arteriosus ligation in very-low-birth-weight infants (VLBWIs) with persistent ductus arteriosus (PDA) are unclear. Increased left ventricular end-diastolic dimension (LVDd) is commonly found in patients with PDA. Here, the enlargement of LVDd in term and preterm neonates without congenital heart disease was estimated by two-dimensional echocardiography.MethodsThe value of the measured LVDd was divided by the normal LVDd as an index (LVDd ratio) to compare 30 patients who underwent PDA ligation with 30 patients treated with indomethacin and 30 patients who did not undergo radical therapy.ResultsAn LVDd ratio between 122% and 197% (mean, 142%) was considered to be an indication for the ligation procedure. The proportion of patients exceeding 130% in the LVDd ratio was 87% (26/30) in those patients who underwent ligation. Catecholamines and/or vasodilators were required in 83% patients for the treatment of low ejection fraction or hypertension after operations, suggesting that patients had been in preload and/or afterload remodeling failure during the operation. The percentage of patients with less than 115% in the LVDd ratio was 90% in the non-radical-therapy patients. The LVDd ratios of 130% and 115% were regarded as cut-off values for surgical ligation and indomethacin treatment.ConclusionThe LVDd ratio is a useful measure to determine the treatment of VLBWIs with PDA

Cetylpyridinium chloride at sublethal levels increases the susceptibility of rat thymic lymphocytes to oxidative stress

Cetylpyridinium chloride (CPC) is an antimicrobial agent used in many personal care products, with subsequent release into the environment. Since CPC is found at low concentrations in river and municipal wastewater, its influence on wildlife is of concern. Therefore, in this study, we used flow cytometry to examine the effects of sublethal concentrations of CPC on rat thymic lymphocytes in order to characterize the cellular actions of CPC at low concentrations in the presence and absence of H2O2-induced oxidative stress. CPC treatment increased the population of living cells with phosphatidylserine exposed on the outer surface of their plasma membranes (a marker of early stage apoptosis), elevated intracellular Zn2+ levels, and decreased the cellular content of nonprotein thiols. CPC also potentiated the cytotoxicity of H2O2. Our results suggest that, even at environmentally relevant sublethal concentrations, CPC exerts cytotoxic effects under oxidative stress conditions by increasing intracellular Zn2+ concentration and decreasing the cellular content of nonprotein thiols. These findings indicate that, under some in vitro conditions, CPC is bioactive at environmentally relevant concentrations. Therefore, CPC release from personal care products into the environment may need to be regulated to avoid its adverse effects on wildlife

Multiple myeloma with t(11;14)-associated immature phenotype has lower CD38 expression and higher BCL2 dependence

CD38 expression on myeloma cells is a critical factor affecting the early response to the anti-CD38 antibody daratumumab. However, factors affecting CD38 expression in untreated multiple myeloma are not fully elucidated. In this study, we found that CD38 expression was significantly lower in myeloma patients with the translocation t(11;14)-associated immature plasma cell phenotype, and particularly in those expressing B-cell-associated genes such as PAX5 and CD79A. CD138, a representative marker of plasmacytic differentiation, was also significantly lower in these patients, suggesting that CD38 expression may be associated with the differentiation and maturation stages of myeloma cells. Furthermore, the BCL2/BCL2L1 ratio, a response marker of the BCL2 inhibitor venetoclax, was significantly higher in patients with the immature phenotype expressing B-cell-associated genes. The BCL2/BCL2L1 ratio and CD38 expression were significantly negatively correlated. We also confirmed that patients with translocation t(11;14) expressing B-cell-associated genes were indeed less sensitive to daratumumab-mediated direct cytotoxicity but highly sensitive to venetoclax treatment in ex vivo assays. Moreover, all-trans-retinoic acid, which enhances CD38 expression and induces cell differentiation in myeloma cells, reduced B-cell marker expression and the BCL2/BCL2L1 ratio in myeloma cell lines, leading to reduced efficacy of venetoclax. Venetoclax specifically induces cell death in myeloma with t(11;14), although why patients with translocation t(11;14) show BCL2 dependence is unclear. These results suggest that BCL2 dependence, as well as CD38 expression, are deeply associated with the differentiation and maturation stages of myeloma cells. This study highlights the importance of examining t(11;14) and considering cell maturity in myeloma treatment strategies