Kaiyo Takubo

Age-related mitochondrial DNA deletion in human heart: Its relationship with cardiovascular diseases

Background and aims: Accumulation of damage to mitochondrial DNA (mtDNA) occurs in myocardial tissue with advancing age. However, despite higher incidence of cardiac diseases in the elderly, little attempt has been made to detect deletions of mtDNA in the myocardial tissue of aged individuals. The aim of the present study was to clarify the relationship between aging, mtDNA deletion and cardiovascular (CV) diseases. Methods: We examined 163 autopsy cases, aged 60 years or older, using two different kinds of polymerase chain reaction (PCR): highly sensitive PCR to detect a common 4977- bp deletion and long- PCR for multiple deletions, which could be detected in case that deleted mtDNA accounted for more than several percents in total mtDNA. Results: The common 4977- bp deletion was detected in 156 cases (95.7%), showing no significant difference among these age groups and no relation to CV diseases. By long- PCR, multiple deletions in cardiac mtDNA were found in 33 (20.2%) of 163 cases. The proportion of the mtDNA deletion in the nineties (46.2%) was significantly higher than those in the younger (15.3%, p<0.05). Female predominance was significantly found in the group with the mtDNA deletion (p<0.05). Multiple deletions of mtDNA were not significantly related to ischemic change, valvular diseases, left ventricular hypertrophy, congestive heart failure, coronary sclerosis, or heart weight except for right ventricular hypertrophy. Conclusions: These findings suggest that there is a close relationship between aging and deletion of mtDNA, and that the ratio of deleted mtDNA to total mtDNA increases with advancing age. Age-related deletion of mtDNA may have little influence on CV diseases except for right ventricular hypertrophy.

Double muscularis mucosae in Barrett's esophagus

To clarify the histology and morphogenesis of the double muscularis mucosae in Barretts esophagus, eight specimens resected from patients with Barretts esophagus were compared histopathologically with 352 specimens resected from patients without Barretts esophagus. A double muscularis mucosae was observed in seven (87.5%) of the eight cases with Barretts esophagus, but in none of the 352 cases without Barretts esophagus. The mucosa in the segment of Barretts esophagus consisted of columnar epithelium, a superficial lamina propria, a superficial muscularis mucosae, a deep lamina propria, and a deep muscularis mucosae. The distal end of the superficial muscularis mucosae was connected to the deep muscularis mucosae at the esophagogastric junction, and its proximal end was located in fibrous tissue below the squamocolumnar junction of the mucosal epithelium or the distal edge of the erosive lesion. The deep muscularis mucosae in the portion with Barretts esophagus was continuous with the original muscularis mucosae of the proximal esophagus and muscularis mucosae of the stomach. Barretts esophagus is considered to be not merely a metaplastic lesion within the epithelium, but a newly developed lesion containing columnar epithelium, lamina propria, and a superficial muscularis mucosae on the lamina propria of the esophageal mucosa.

Pathologic characteristics of gastric cancer in the elderly: a retrospective study of 994 surgical patients

BackgroundThe clinicopathologic features of gastric carcinoma in elderly people have been reported previously. The present study examined the patterns and distribution of gastric carcinomas in the elderly, especially in patients aged 85 and older.MethodsA retrospective study of 994 consecutive Japanese patients aged 65 years or older was performed. In this group, a total of 1147 lesions were analyzed. Pathological findings in the very old group (older than 85 years; n = 126) were compared with those in younger groups (65–74 years [young-old group]; n = 356) and (75–84 years [middle-old group]; n = 512).ResultsWhile the male-to-female ratio significantly decreased with advancing age, the relative odds of gastric cancer in men were higher than those in women in all age groups. In the very old group, cancer of the lower third of the stomach tended to increase with advancing age, and accounted for 43.7% of cases. In the population overall, differentiated-type adenocarcinoma accounted for 89.6% in the early cancers and 50.3% in the advanced cancers. The proportion of cases involving differentiated-type carcinoma significantly increased with advancing age in early cancer and female advanced cancer cases, whereas no significant change was found in male advanced-cancer patients. In the very old group, lymph node metastasis was found in 5.4% of early cancers and 72.7% in advanced cancers. Multiple cancers significantly increased with advancing age (P < 0.05; 10.7% in the younger-old group, 12.7% in the middle-old group, and 19.0% in the very old group).ConclusionThese results indicate that, in the very old group, gastric cancers showed a distal shift with predominantly differentiated-type carcinoma in the early stages and increased undifferentiated-type carcinomas in advanced stages. These results suggest increased histologic diversity with tumor growth. These findings have important implications for the screening and diagnosis of gastric cancer in the elderly.

Breast carcinoma in women over the age of 85: distinct histological pattern and androgen, oestrogen, and progesterone receptor status

Aims:u2002 The pathogenesis of breast carcinoma in very elderly women is of interest, because oestrogen levels are likely to be extremely low during the development of the disease. In an effort to understand the pathogenesis of breast carcinoma in these women, this study was undertaken to compare the histological patterns and hormone receptor status of breast carcinomas arising in very elderly and younger women.

Hypermethylation of the hMLH1 promoter with absent hMLH1 expression in medullary-type poorly differentiated colorectal adenocarcinoma in the elderly

To clarify the significance of hMLH1 promoter hypermethylation in the development of medullary-type poorly differentiated colorectal adenocarcinoma, we studied the status of promoter methylation and hMLH1 expression in 23 medullary-type and 12 pleomorphic-type carcinomas, as well as the pathology and microsatellite status. In medullary-type carcinomas, the percentages of cases with promoter methylation (83%) and an absence of hMLH1 expression (91%) were significantly higher than in pleomorphic-type carcinomas (14 and 17%), respectively. The rate of microsatellite instability in the medullary type was significantly higher than that of the pleomorphic type (87 vs 40%, P<0.01). Compared with pleomorphic-type carcinomas, medullary-type carcinomas were significantly associated with hMLH1 promoter methylation, absent expression of hMLH1 protein, microsatellite instability, as well as a proximal location, a Crohns-like lymphoid reaction, a low incidence of lymph node metastasis, and a favorable outcome. Medullary-type carcinomas accumulated with advancing age, especially in the female. These results indicated that hMLH1 hypermethylation, concurrent with a lack of its protein expression, may play an important role in the development of medullary-type poorly differentiated colorectal adenocarcinomas in the elderly.

Developments of geriatric autopsy database and Internet-based database of Japanese single nucleotide polymorphisms for geriatric research (JG-SNP)

To facilitate geriatric research on the roles of genetic polymorphisms of candidate genes, two databases were developed based on data obtained from autopsy examinations of elderly subjects: the geriatric autopsy database (GEAD) and the Japanese single nucleotide polymorphisms (SNP) database for geriatric research (JG-SNP) which is accessible on the Internet (http://www.tmgh.metro.tokyo.jp/jg-snp/english/E_top.html). The data for the GEAD were derived from 1074 consecutive autopsy cases (565 male and 509 female cases) with an average age of 80 years. The GEAD was installed on a stand-alone Windows 2000 server using Oracle 8i as the database application. The GEAD contains clinical diagnoses of 26 geriatric diseases, histories of smoking and alcohol consumption, pathological findings (720 items), severity of atherosclerosis, genetic polymorphism data, etc. On the JG-SNP website, case distribution corresponding to a specified SNP or disease can be searched or downloaded. Although there are several Internet-based SNP databases such as dbSNP, no databases are available at present on the web that contain both SNP data and phenotypic data. As autopsy studies can provide large amounts of accurate medical information, including the presence of undiagnosed diseases such as latent cancers, the GEAD is a unique and excellent database for research on genetic polymorphisms.

Morphological Heterogeneity of Esophageal Carcinoma

To clarify the morphological heterogeneity of esophageal carcinoma, the adenocarcinomatous, basaloid, and sarcoma‐like components of 178 esophageal carcinomas were studied with regard to histopathology, much histochemistry, immunohistochemistry, and ultrastructure. Adenocarcinomatous components with mucicarminophilic cells and/or glandular structures, basaloid components, and sarcoma‐like components were found in 55 lesions (30.9%), 17 lesions (9.3%), and five lesions (2.8%) respectively. Carcinoembryonic antigen staining was positive in 52 lesions (29.2%), secretory component staining was positive in 15 (8.4%), and lactoferrin staining was positive in 12 (6.7%). Eight intraepithelial carcinomas were found to have no adenocarcinomatous components, and two intramucosal carcinomas had adenocarcinomatous components in the invasive portions. These findings strongly suggest that the adenocarcinomatous components do not arise from the ductal epithelium, but occur during the process of invasion. There were no significant clinicopathological differences between the carcinomas with adenocarcinomatous components and those without. Ultrastructurally, the adenocarcinomatous components were seen to possess intracellular microcysts, intercellular lumina, and bundles of tonofilaments, having features of both glandular and squamous epithelia. On the basis of the concept that the basaloid components are histological variants of squamous cell carcinoma and that sarcoma‐like components arise from mesenchymal metaplasia of squamous cell carcinoma, it is possible that the three components may originate from the squamous component. The present study thus demonstrated a high incidence of histological variation among esophageal carcinomas.

Demonstration of human telomerase reverse transcriptase (hTERT) in human parathyroid tumours by in situ hybridization with a new oligonucleotide probe

background and objective Telomerase activity is present in most malignant tumours and might provide a mechanism for unlimited replication of neoplastic cells. Expression of the gene encoding human telomerase reverse transcriptase (hTERT), the telomerase catalytic subunit gene, is associated with telomerase activity, and it is overexpressed in most parathyroid carcinomas. We have therefore studied hTERT expression in parathyroid tumours.

The mitochondrial DNA A3243G mutation in Werner's syndrome

OBJECTIVEnThe contribution of the A3243G mutation in mitochondria DNA (mtDNA) to diabetes mellitus (DM) in Werners syndrome (WS) was studied.nnnPATIENTS AND METHODnDNA samples from peripheral white blood cells (WBCs) originating from 24 Japanese WS patients aged 30-56 were used. For control, 239 subjects aged 15-95 were also used. The mtDNA was amplified using specific primers. After HaeIII digestion, the ratio of the A3243G mutation was compared.nnnRESULTSnThe ratio of the A3243G mutation is 0.45+/-0.13% in WS, which is statistically insignificant from those in the control groups at various age. The mutation types of WRN in genomic DNA did not affect the ratio of the A3243G mtDNA mutation. No significant difference was observed concerning to the ratios among the WS patients with and without DM, and also controls. Furthermore, no significant difference was observed in the ratios of A3243G mutation among controls from various age groups.nnnCONCLUSIONnThe A3243G mutation in mtDNA does not accumulated in WBCs from WS. Mitochondria A3243G mutation may not contribute to the pathogenesis of DM observed in WS.

Large Cell Carcinoma of the Lung with Metastasis to the Gastric Submucosa.

A 66-year-old man was admitted with dyspnea on exertion and an abnormal shadow on chest roentgenogram. Transbronchial biopsy yielded a diagnosis of large cell carcinoma of the lung. His dyspnea improved following irradiation and corticosteroid treatment and one month later, he was admitted again for chemotherapy. Because occult blood in stool was detected, upper gastrointestinal endoscopy was performed. Gastric submucosal large cell carcinoma was diagnosed, and this was considered to be metastatic from the lung. Such cases diagnosed prior to death are rare.