Alcohol and Aldehyde Dehydrogenase Genotypes and Drinking Behavior in Japanese

The effects of the genotype of alcohol dehydrogenase-2 (ADH2) and mitochondrial aldehyde dehydrogenase (ALDH2) on drinking behavior were investigated in a population of 451 Japanese. Although the ALDH2*2 allele had a significant inhibitory effect on alcohol consumption, hence on drinking problems, the apparent association was not confirmed between ADH2 genotype and overall drinking patterns for either males or females. However, the frequency of the ADH2*2 allele was significantly lower in male Japanese classified as alcoholic on the basis of the Kurihama Alcoholism Screening Test than in nonalcoholic males. These results corroborate a previous study that revealed a significantly lower ADH2*2 allele frequency in hospitalized Japanese alcoholics than in the general population. Together, these studies suggest that the ALDH2*2 allele has an inhibitory effect on drinking behavior, irrespective of the level of alcohol consumption, whereas the effect of the ADH2 polymorphism only becomes apparent in individuals with higher alcohol consumption, such as alcoholics.     

The effect of beta-blocker on intractable ascites in cirrhotic patients undergoing hepatectomy for hepatocellular carcinoma

BACKGROUND/AIMS: Intractable ascites is one of the serious complications after hepatectomy. Only little is known about their effect on postoperative ascites in patients with liver cirrhosis although beta-blockers have been used for cirrhotic complications including ascites. METHODOLOGY: Here, we report five cases of intractable ascites after hepatectomy, which were treated by propranolol (1 mg/kg/body). RESULTS: In three patients, plasma renin activity and aldosterone concentrations were markedly increased before propranolol administration, but fell to normal levels thereafter. Ascites subsided in all subjects except one, who developed cardiac dysfunction. CONCLUSIONS: Beta-blockers might be a promising drug for intractable ascites in cirrhotic patients undergoing hepatectomy.     

The genetic and molecular basis of muscular dystrophy: roles of cell–matrix linkage in the pathogenesis

Muscular dystrophies are a heterogeneous group of genetic disorders. In addition to genetic information, a combination of various approaches such as the use of genetic animal models, muscle cell biology, and biochemistry has contributed to improving the understanding of the molecular basis of muscular dystrophy's etiology. Several lines of evidence confirm that the structural linkage between the muscle extracellular matrix and the cytoskeleton is crucial to prevent the progression of muscular dystrophy. The dystrophin–glycoprotein complex links the extracellular matrix to the cytoskeleton, and mutations in the component of this complex cause Duchenne-type or limb-girdle-type muscular dystrophy. Mutations in laminin or collagen VI, muscle matrix proteins, are known to cause a congenital type of muscular dystrophy. Moreover, it is not only the primary genetic defects in the structural or matrix proteins, but also the primary mutations of enzymes involved in the protein glycosylation pathway that are now recognized to disrupt the matrix–cell interaction in a certain group of muscular dystrophies. This group of diseases is caused by the secondary functional defects of dystroglycan, a transmembrane matrix receptor. This review considers recent advances in understanding the molecular pathogenesis of muscular dystrophies that can be caused by the disruption of the cell–matrix linkage.     

Potential tumor suppressive pathway involving DUSP6/MKP-3 in pancreatic cancer

We previously found frequent loss of heterozygosity at 12q21 and 12q22-q23.1 in primary pancreatic cancers, and the DUSP6/MKP-3 gene residing in this region at 12q22 lost its expression in the great majority of pancreatic cancer cell lines. The DUSP6/MKP-3 protein is a dual-specificity phosphatase that dephosphorylates the active form of ERK, making a feedback loop to control ERK activity. Gain-of-function mutations of KRAS2 occur in the great majority of pancreatic cancer cells, and loss of expression of DUSP6/MKP-3 may synergistically promote constitutive activation of ERK and uncontrolled cell growth. To study loss of the feedback pathway and its impact on pancreatic cancer cell growth, we first investigated the expression of DUSP6/MKP-3 in primary pancreatic cancer tissues immunohistochemically; we found up-regulation in mildly as well as severely dysplastic/in situ carcinoma cells and down-regulation in invasive carcinoma, especially in the poorly differentiated type. Adenovirus-mediated reintroduction of DUSP6/MKP-3 into cultured pancreatic cancer cells induced strong expression of recombinant DUSP6/MKP-3 and reduction of phosphorylated ERK in a dose-dependent manner based on the multiplicity of infection and resulted in suppression of cell growth. Moreover, analyses by flow cytometry and immunocytochemistry revealed that the exogenous expression of DUSP6/MKP-3 induced apoptosis. These results show that DUSP6 exerts apparent tumor-suppressive effects in vitro and suggest that DUSP6 is a strong candidate tumor suppressor gene at 12q22 locus.     

Immunohistochemical analysis of steroidogenic enzymes in ovarian‐type stroma of pancreatic mucinous cystic neoplasms: Comparative study of subepithelial stromal cells in intraductal papillary mucinous neoplasms of the pancreas

Mucinous cystic neoplasms (MCNs) are generally defined as cyst‐forming epithelial neoplasms that arise in the pancreas and harbor characteristic ovarian‐type stroma beneath the epithelium. In this study, we compared the immunoreactivity of steroid‐related factors in these subepithelial stromal cells in MCNs to those in intraductal papillary mucinous neoplasms (IPMNs) to further characterize this unique MCN ovarian‐type stroma through evaluation of sex steroid biosynthesis. Twenty MCNs and twenty IPMNs were examined. Immunoreactivity of steroid hormone receptors, including estrogen receptor (ERα and ERβ), progesterone receptor (PR, PR‐A, and PR‐B), and androgen receptor (AR), was more frequently detected in MCN ovarian‐type stromal cells than in IPMN stromal cells (P < 0.01). The H‐scores (mean ± SD) of steroidogenic factor (SF)‐1 were also significantly higher in MCNs (112.3 ± 33.1) than in IPMNs (0.9 ± 1.2) (P < 0.01). The steroidogenic enzymes cytochrome P450 cholesterol side‐chain cleavage enzyme (P450scc), cytochrome P450 17 alpha‐hydroxylase (P450c17) and 3β‐hydroxysteroid dehydrogenase (3β‐HSD) showed immunoreactivity in 9/20 (45.0 %), 15/20 (75.0 %) and 13/20 (65.0 %), respectively, of ovarian‐type stroma from MCN cases. These results demonstrate that the ovarian‐type stroma of MCNs can express steroidogenic enzymes. Thus, the ovarian‐type stroma of MCNs can produce sex steroids that may also act on these cells.     

Dedifferentiated chondrosarcoma of the rib with a malignant mesenchymomatous component: An autopsy case report

A rare variant of dedifferentiated chondrosarcoma wlth malignant mesenchymomatous component in a 57-year-old male is reported. The patient presented with a posterior mediastinal mass arising from the left eighth and ninth ribs showing well differentiated, low-grade chondrosarcoma. Five years later, local recurrence occurred and an excised specimen also showed the same histological features as the primary tumor. Another 6 years later, the tumor recurred and metastasized to the multiple organs, the patient dying 4 months later. Autopsy revealed that the recurrent and metastatic tumors showed malignant mesenchymomatous 'dedifferentiation' of chondrosarcoma composed of rhab domyosarcoma, angiosarcoma, chondrosarcoma, osteosarcoma, and leiomyosarcoma, in addition to fibrosarcomatous areas. Although the less differentiated component of dedifferentiated chondrosarcoma usually shows the histological features of malignant fibrous histiocytoma and fibrosarcoma, multilineage differentiation can occur in that component. The phenomenon of 'dedifferentiation' in chondrosarcoma and the relationship to and distinction from malignant mesenchymoma of soft tissue and bone are discussed.     

Multicolor Flow Cytometry for the Diagnosis of Primary Immunodeficiency Diseases

Purpose

Primary immunodeficiency diseases (PIDDs) are rare inherited diseases that impair the human immune system. We established a multicolor flow cytometric assay to comprehensively evaluate the immune status and immunological characteristics of patients with PIDDs.

Methods

Fifty-nine normal controls and 75 patients with PIDDs, including X-linked severe combined immunodeficiency (X-SCID), X-linked agammaglobulinemia (XLA), X-linked hyper IgM syndrome (X-HIGM), ataxia telangiectasia (AT), Wiskott-Aldrich syndrome (WAS), hyper IgE syndrome (HIES), and chronic mucocutaneous candidiasis disease (CMCD), were enrolled in this study. Immunophenotyes were evaluated by multicolor flow cytometry using seven different panels that allowed the detection of major leukocyte populations in peripheral blood.

Results

Multicolor flow cytometry revealed distinct leukocyte populations and immunological features of patients with X-SCID, XLA, X-HIGM, AT, WAS, HIES, and CMCD.

Conclusions

Immunophenotyping by multicolor flow cytometry is useful to evaluate immune status and contributes to the diagnosis and management of patients with PIDDs.