Expression of ErbB4 in substantia nigra dopamine neurons of monkeys and humans

Abnormal neuregulin-1 signaling through its receptor (ErbB4) might be associated with schizophrenia, although their neuropathological contribution remains controversial. To assess the role of neuregulin-1 in the dopamine hypothesis of schizophrenia, we used in situ hybridization and immunoblotting to investigate the cellular distribution of ErbB4 mRNA in the substantia nigra of Japanese monkeys (Macaca fuscata) and human postmortem brains. In both monkeys and humans, significant signal for ErbB4 mRNA was detected in substantia nigra dopamine neurons, which were identified by melanin deposits. The expression of ErbB4 mRNA in nigral dopamine neurons was confirmed with an independent RNA probe, as well as with combined tyrosine hydroxylase immunostaining. Immunoblotting appeared to support the observation of in situ hybridization. Immunoreactivity for ErbB4 protein was much more enriched in substantia nigra pars compacta containing dopamine neurons than in neighboring substantia nigra pars reticulata. These observations suggest that ErbB4 is expressed in the dopaminergic neurons of primate substantia nigra and ErbB4 abnormality might contribute to the dopaminergic pathology associated with schizophrenia or other brain diseases.     

A chimeric CYP11B1/CYP11B2 gene in glucocorticoid-insuppressible familial hyperaldosteronism

Although a chimeric gene combining the 11beta-hydroxylase gene (CYP11B1) and the aldosterone synthase gene (CYP11B2) explains the pathophysiology of familial hyperaldosteronism (FH) type I, the contribution of this abnormality to FH type II has not been tested. We screened genomic DNA from a Japanese family with FH type II for the CYP11B1/CYP11B2 gene. The index patient was a 27-year-old woman with hypertension. Hypokalaemia, elevated plasma aldosterone and suppressed plasma renin activity suggested primary aldosteronism. Though computed tomography failed to reveal an adrenal tumour, left adrenalectomy was indicated due to a high aldosterone concentration in left adrenal venous blood. The resected adrenal gland contained an adenoma. As her mother had also been diagnosed with primary aldosteronism due to an adenoma, we administered oral dexamethasone to our patient before the operation and observed the response of the blood pressure and plasma aldosterone concentration for 2 weeks. Both parameters remained elevated during the treatment period, confirming the diagnosis of FH type II. Total DNA was isolated from blood cells of the index patient, her mother, and an unaffected brother. Samples were amplified by polymerase chain reaction using specific primers from CYP11B1 and CYP11B2. Unique DNA fragments of 1.4 kb were obtained from the index patient and her mother, but not from the healthy subject. The CYP11B1/CYP11B2 chimeric gene was found in a Japanese family with FH type II.     

The management of prenatally diagnosed sacrococcygeal teratoma

Two of our own and 18 other reported cases with prenatally diagnosed sacrococcygeal teratoma that were delivered by cesarean section are reviewed. Six infants delivered at a gestational age of from 25 to 32 weeks died perinatally. Causes of death were immaturity, intratumoral hemorrhage, and tumor rupture. It is concluded that an attempt should be made to continue pregnancy until 32 weeks' gestation and that after this age infants should be delivered by elective cesarean section as soon as possible. Offprint requests to: H. Ikeda     

Necrobiotic xanthogranuloma with paraproteinemia; an atypical case

Necrobiotic xanthogranuloma (NXG) is a rare marker for paraproteinemia. An 86-year-old woman had a one year history of large red-yellow to brown annular plaques involving all limbs. Biopsies showed a non-palisading granuloma with numerous multinucleated giant cells showing prominent elastophagocytosis and extensive areas of necrobiosis throughout the entire dermis. Complete loss of elastic fibers was observed in the central atrophic area of an annular plaque. Small vascular thromboses were also present. Laboratory findings revealed paraproteinemia of IgG-lambda type. Immunohistochemical staining detected the presence of roughly equal numbers of IgG-lambda-and IgG-kappa-staining plasma cells in the dermis. We diagnosed NXG with paraproteinemia with monoclonal gammopathy (IgG-lambda type) of unknown significance.     

Gastric resection in the aged (≥ 80 years) with gastric carcinoma: a multivariate analysis of prognostic factors

Background : The incidence of gastric neoplasm is increasing in the elderly population. Therefore, a rational method of treatment for gastric cancer in the elderly should be constituted to improve the survival. The purpose of the present study was to clarify whether the patient’s age is an independent prognostic factor and to determine clinicopathological characteristics in the elderly. Methods : Curative resection of gastric cancer was carried out on 601 patients who were 40 years or older. They were divided into the following two groups: younger patients (between 40 and 79 years old) and elderly patients (80 years or older). The clinicopathologic features of these patients were reviewed retrospectively and multivariate analysis was carried out. Results : The distinguishing features of gastric cancer in the elderly patients were intestinal and mixed types of cancer, distal third stomach dominancy in the tumour location, advanced stage of disease, and a low rate of extensive lymph node dissection (D3 or more). Regarding the recurrence site, the liver was the dominant site in the elderly group (25.3% in the younger group vs 54.5% in the elderly group). The 10‐year disease‐free survival rate of the elderly group was 53.2%, which was significantly worse than that (79.9%) of the younger patients (P = 0.0004). In multivariate analysis, an age of ≥ 80 years is an independent prognostic factor, as well as stage, depth of tumour invasion, lymph node metastasis, scirrhous carcinoma, and blood transfusion. Conclusions : Results indicate that gastric cancer in elderly patients has a poorer prognosis than that in younger patients.     

Elimination of metabolic cooperation by glycyrrhetinic acid, an anti-tumor promoter, in cultured Chinese hamster cells

The effect of glycyrrhetinic acid (GA) on the metabolic cooperationbetween 6-thioguanine-resistant (6TG^R) and sensitive (6TG^s)Chinese hamster V79 H3 cells, was investigated. Because GA hasbeen reported to inhibit strongly tumor formation in mouse skininduced by 7, 12-dimethylbenz(a)anthracene (DMBA) plus teleocidinor DMBA plus 12-O-tetradecanoylphorbol-13-acetate (TPA), weexpected that GA might restore the metabolic cooperation inhibitedby TPA. The results were contrary to our expectations. GA (20–50µM)acted cummulatively with TPA to inhibit metabolic cooperationeven more, and GA (20–75µM), by itself, was foundto be a strong inhibitor of metablic cooperation. GA was notmutagenic at the concentrations examined (0–100µM)     

Force-time integral does not improve predictability of cardiac O2 consumption from pressure-volume area (PVA) in dog left ventricle

Summary We have proposed the systolic pressure-volume area (PVA) as a measure of the total mechanical energy generated by ventricular contraction, and we found a closely linear correlation between PVA and cardiac oxygen consumption (V_{O 2}). Although the force-time integral (FTI) has long been considered to be the most reliable correlate of cardiac oxygen consumption (V_{O 2}), we have already shown that V_{O 2} remained constant although FTI was changed while PVA was kept constant in the excised, cross-circulated dog left ventricle. This means that PVA is superior to FTI as a predictor of V_{O 2}. In the present study, we studied whether a linear addition of FTI to PVA could improve the prediction of V_{O 2} from PVA in isovolumic and ejecting contractions with different afterload pressures in the same type of dog left ventricle preparation. Although left ventricular V_{O 2} was always closely correlated with either PVA (r=0.967, mean after z-transformation) or FTI (mean r=0.925), multiple regression analysis indicated that PVA alone accounted for as much as 94% (mean) of the variance of V_{O 2} and that FTI linearly added to PVA accounted for an additional few percent of the variance (statistically significant in less than half the cases). We conclude that the addition of FTI to PVA does not improve the predictability of V_{O 2} from PVA in ordinary contractions.     

Aberrant nuclear localization and gene mutation of beta-catenin in low-grade adenocarcinoma of fetal lung type: up-regulation of the Wnt signaling pathway may be a common denominator for the development of tumors that form morules.

The salient histopathologic features of low-grade adenocarcinoma of the fetal lung type (L-FLAC)/well-differentiated fetal adenocarcinoma (WDFA) include complex glandular structures and morules with biotin-rich optically clear nuclei. Interestingly, these characteristic features are shared by the cribriform-morular variant of papillary thyroid carcinoma, whose morphology is identical to that of familial adenomatous polyposis (FAP)-associated thyroid carcinoma. Furthermore, the single reported case of lung cancer associated with FAP was L-FLAC/WDFA. These observations lead us to hypothesize that up-regulation of the Wnt signaling pathway underlies the development of L-FLAC/WDFA. To verify this hypothesis, 11 cases of L-FLAC/WDFA, including the one FAP-associated case, eight cases of high-grade adenocarcinoma of the fetal lung type (H-FLAC), 24 cases of conventional pulmonary adenocarcinoma (CAC), and 13 fetal lungs were immunostained for beta-catenin. All cases of L-FLAC/WDFA showed predominantly aberrant nuclear/cytoplasmic expression, especially in budding glands and morules, whereas six of eight cases (75%) of H-FLAC and all but one case (96%) of CAC showed predominantly membranous expression. Fetal lungs showed nuclear/cytoplasmic expression restricted to the distal branching airway epithelium. Mutational analysis of exon 3 of the beta-catenin gene in five sporadic cases of L-FLAC/WDFA showed a point mutation at codon 34 and codon 37 in two cases, respectively. The present study indicates that up-regulating disturbances in the Wnt signaling pathway, including mutation of the beta-catenin gene, underlie tumorigenesis of L-FLAC/WDFA. The expression pattern of beta-catenin in L-FLAC/WDFA resembles that of the developing fetal lung airway. With the expression pattern of beta-catenin as a marker, most cases of H-FLAC as well as CAC appear to have different oncogenic pathways from cases of L-FLAC/WDFA. The present study together with other available data also suggests that abnormal up-regulation of the Wnt signaling pathway may be a common denominator for the development of tumors with morular formation from a variety of anatomic sites.     

An Occupational Hazard for Pathologists and Pathology Technicians in Japan

The incidence of pulmonary tuberculosis among pathology workers in Japan is elevated, presumably due to frequent exposure to tubercle bacilli in the work place. To demonstrate the etiological significance of the association between this disease and occupation epidemiologically, a questionnaire survey was performed to assess the incidence of pulmonary tuberculosis among 1,201 pathologists and 1,187 pathology technicians throughout Japan. Pathology department workers other than pathologists and technicians, such as secretaries (n = 207), and workers in university departments of preventive medicine and public health (n = 732) served as control groups. While non-occupation-related tuberculosis was found in both departmental groups with nearly equal incidence, the incidence of pulmonary tuberculosis among pathologists and pathology technicians after engagement in their current specialist work was significantly higher than that in the control groups (odds ratio = 6.08–10.98). The incidence of disease among pathology technicians who assisted in autopsies was markedly higher than among those not involved in autopsies (odds ratio = 6.65). This elevated incidence was significantly related to the duration of work in pathology activities, and showed little change over the last decade. These findings indicate that specific environmental conditions in pathology departments, particularly autopsy of cadavers harboring active tuberculosis, constitute a serious occupational hazard. Acta Pathol Jpn 40: 116–127, 1990.