Impact of CYP3A5 polymorphism on platelet reactivity at percutaneous coronary intervention and after 9 months of aspirin and clopidogrel therapy in Japanese patients with coronary artery disease

Background

High residual platelet reactivity in patients receiving clopidogrel is associated with an increased risk of a cardiovascular event after coronary stenting. The aim of our study was to evaluate the impact of the cytochrome P450 (CYP) 3A5 and CYP2C19 polymorphisms on platelet reactivity during dual antiplatelet therapy.

Methods

We determined the CYP2C19 and CYP3A5 genotypes of 101 angina patients (65 male patients, mean age 64 years) receiving dual antiplatelet therapy with aspirin and clopidogrel and evaluated the effect of these polymorphism on platelet reactivity at the early and late phases of treatment using a conventional light transmission aggregometry. Early and late phases were defined as 24 h after the loading dose and after 9 months on a maintenance dose of 75 mg daily, respectively.

Results

The distribution of the CYP2C19 genotype was 30 % in extensive metabolizers (EM; CYP2C19*1/*1), 46 % in intermediate metabolizers (IM; *1/*2, *1/*3), and 25 % in poor metabolizers (PM; *2/*2, *2/*3, *3/*3). Platelet reactivity levels in during the early and late phases were 3,793?±?1,476 and 2,960?±?1,410, respectively, in EM, 4,706?±?1,417 and 3,239?±?1,479, respectively, in IM, and 5,402?±?776 and 4,736?±?1,356 aggregation units (AU)?min, respectively in EM. The distribution of the CYP3A5 genotype was 33 % in patients carrying the wild-type or one loss-of-function allele (Expressor phenotype; *1/*1 and *1/*3, respectively) and 67 % in those carrying two loss-of-function alleles (Non-expressor; *3/*3). In total, eight patients were EM+Expressor, 22 were EM+Non-expressor, 18 were IM+Expressor, 28 were IM+Non-expressor, eight were PM+Expressor, and 17 were PM+Non-expressor. In the late phase of PM with the CYP2C19 polymorphism, the levels of platelet reactivity according to CYP3A5 genotype were 3,963?±?1,436 and 5,100?±?1,190 AU?min in Expressor and Non-expressor, respectively (P?<?0.05), however, there was no difference in platelet reactivity between Expressor and Non-expressor in EM and IM.

Conclusions

Our results suggest that antiplatelet response to clopidogrel in the late phase depends on the CYP3A5 polymorphism in PM with CYP2C19.     

A proxy for brain-to-endocranial cavity index in non-neornithean dinosaurs and other extinct archosaurs

Although the brain fills nearly the entire cranial cavity in birds, it can occupy a small portion of it in crocodilians. The lack of data regarding the volumetric correspondence between the brain and the cranial cavity hampers thorough assessments of the degree of encephalization in non-neornithean dinosaurs and other extinct archosaurs and, consequently, informed inferences regarding their cognitive capacities. Existing data suggest that, across extant archosaurs, the degree of endocranial doming and the volume of intracranial nonneural components are inversely related. We build upon this information to develop an equation relating these two anatomical features in non-neornithean dinosaurs and other extinct archosaurs. We rely on measurements of the endocast doming and brain-to-endocranial cavity (BEC) index in extant relatives of non-neornithean dinosaurs, namely, the crurotarsans Caiman crocodilus, Crocodylus niloticus, and Crocodylus porosus; the paleognaths Struthio camelus and Apteryx mantelli; and the fowl Macrocephalon maleo, Gallus gallus, Meleagris gallopavo, Phasianus colchicus, and Anas platyrhynchos. Applying the equation to representative endocasts from major clades of dinosaurs, we found that BEC varies from about 0.6 in ceratopsians and thyreophorans to around 0.7 in ornithopods, pachycephalosaurians, sauropods, and theropods. We, therefore, warn against the use of a catch-all value, like 0.5, and instead encourage refinement in the adoption of BEC across archosaurs.     

Aberrant expression of the maspin gene associated with epigenetic modification in melanoma cells

Maspin, a mammary serine protease inhibitor, was originally reported to be a tumor suppressor gene in breast and prostate cancers. The expression pattern of the maspin gene differs among cancer types and normal tissue however, and its significance as a tumor suppressor has been questioned. In this study, maspin expression and/or allele-specific methylation status were investigated in five melanoma cell lines and a normal human epidermal melanocyte (NHEM) cell line, and 80 surgically resected tumors (40 melanomas and 40 melanocytic nevi). One (HMV-I) of five melanoma cell lines overexpressed maspin protein whereas the remaining four melanoma cell lines and NHEM did not. The 19 CpG sites of the maspin promoter region were extensively hypomethylated in HMV-I, a maspin-positive cell line, and those of the remaining four melanoma and NHEM cell lines were hypermethylated. Furthermore, maspin-negative cell lines exhibited activation after treatment with 5-aza-2'-deoxycytidine, a DNA demethylating agent. Immunoreactivity for maspin was negative in normal skin melanocytes and 40 melanocytic nevi, but five (12.5%) of 40 melanomas were positive. The methylation status judged by the methylation-specific PCR method was inversely correlated with maspin protein expression in vitro and in vivo. These results suggest that maspin expression in normal skin melanocytes and melanocytic nevi may be repressed in a cell-type-specific manner, whereas maspin is expressed aberrantly in a subset of melanoma cells by epigenetic modification. Further investigations are required to determine the significance of aberrant maspin expression.     

A case of primary cutaneous CD30+ T-cell lymphoproliferative disorder with features of granulomatous slack skin disease

We present a patient with primary CD30+ cutaneous T-cell lymphoma whose histological and clinical features overlapped with those of granulomatous slack skin disease (GSSD). A 26-year-old woman had infiltrative erythema on the abdominal wall and an incurable ulcerative lesion on the left knee. Her skin progressively became atrophic and pendulous, showing a hyperpigmented appearance over almost the whole body. Histopathologically, a dense lymphoid cell infiltrate accompanying numerous macrophages and multinucleated giant cells (MGC) extended into the subcutaneous tissue. Most lymphoid cells were small and positive for T-cell markers. Some relatively large atypical cells were scattered in the lesion, most of which (60%) were positive for CD30. T-cell receptor-beta gene rearrangement was confirmed in the abdominal lesion. MGC infiltrated more dominantly into a deeeper layer of the skin with the elastic fibres there almost completely disappearing. Immunoreactivity for CD30 of MGC was negative and overexpression of elastolytic metalloproteinases was observed. The association between primary cutaneous CD30+ lym- phoproliferative disorders and GSSD has not previously been reported. Overexpression of elastolytic metalloproteinases in MGC contributes to the disappearance of the elastic fibres and enhances the severity of the clinical course.     

Treatment with a Direct Oral Anticoagulant for Nonbacterial Thrombotic Endocarditis

We herein report a case of nonbacterial thrombotic endocarditis (NBTE) in a patient with previously undiagnosed lung cancer. A 62-year-old woman presented to our hospital with multiple cerebral infarctions. There was no evidence of valvular heart disease or vegetations. Whole-leg ultrasonography revealed deep vein thrombosis of the left peroneal vein. We administered direct oral anticoagulants (DOACs) for a presumed diagnosis of paradoxical embolisms caused by patent foramen ovale. Unfortunately, she experienced further embolization and died. At a postmortem examination, she was diagnosed with NBTE and metastatic adenocarcinoma of the lung. Our experience with this patient suggests that DOACs may be an insufficient treatment for NBTE.     

Design of the Nationwide Nursery School Survey on Child Health Throughout the Great East Japan Earthquake

Background

The Great East Japan Earthquake inflicted severe damage on the Pacific coastal areas of northeast Japan. Although possible health impacts on aged or handicapped populations have been highlighted, little is known about how the serious disaster affected preschool children’s health. We conducted a nationwide nursery school survey to investigate preschool children’s physical development and health status throughout the disaster.

Methods

The survey was conducted from September to December 2012. We mailed three kinds of questionnaires to nursery schools in all 47 prefectures in Japan. Questionnaire “A” addressed nursery school information, and questionnaires “B1” and “B2” addressed individuals’ data. Our targets were children who were born from April 2, 2004, to April 1, 2005 (those who did not experience the disaster during their preschool days) and children who were born from April 2, 2006, to April 1, 2007 (those who experienced the disaster during their preschool days). The questionnaire inquired about disaster experiences, anthropometric measurements, and presence of diseases.

Results

In total, 3624 nursery schools from all 47 prefectures participated in the survey. We established two nationwide retrospective cohorts of preschool children; 53 747 children who were born from April 2, 2004, to April 1, 2005, and 69 004 children who were born from April 2, 2006, to April 1, 2007. Among the latter cohort, 1003 were reported to have specific personal experiences with the disaster.

Conclusions

With the large dataset, we expect to yield comprehensive study results about preschool children’s physical development and health status throughout the disaster.Key words: natural disaster, preschool children, physical development, children’s health, retrospective cohort     

Serum Immunoglobulin A Concentration Is an Independent Predictor of Liver Fibrosis in Nonalcoholic Steatohepatitis Before the Cirrhotic Stage

Background and Aims  

The similarity of alcoholic liver disease and nonalcoholic steatohepatitis (NASH) in terms of pathogenic mechanisms suggests that immunoglobulin A (IgA) may play an important role in the pathogenesis of NASH. We aimed to determine whether serum IgA concentrations allow a diagnosis of liver fibrosis in NASH.     

Severe headache complicated by vertical atlantoaxial subluxation in diffuse systemic sclerosis with crowned dens pattern calcification

We report a 34-year-old female case of diffuse systemic sclerosis (SSc) with generalized ectopic calcification, who developed severe headache with vertical atlantoaxial subluxation (AAS) complicated by calcification around the odontoid process (crowned dens pattern calcification). Although a rare complication, AAS should be considered as a differential diagnosis of severe headache in SSc patients with extensive calcification.