Biomedical subjects

Motoji Sawabe

Publications and source records attributed to Motoji Sawabe.

At least 19 recordsLinked to original sources

PubMed2007

Polymorphisms in pro- and anti-inflammatory cytokine genes and susceptibility to atherosclerosis: a pathological study of 1503 consecutive autopsy cases.

Atherosclerosis is a chronic inflammatory disease in the intima of the arterial wall, where cytokines play a crucial role in the pathogenesis of this disease. However, the question of whether or not genetic variations in the cytokine genes could influence the development of atherosclerosis has been poorly investigated. We investigated the relationship of nine common single-nucleotide polymorphisms (SNPs) in tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, IL-10, IL-4 and transforming growth factor (TGF)-beta1 with the atherosclerotic severity in 10 different arteries based on 1503 consecutive autopsies of elderly Japanese subjects registered in the Japanese SNPs for geriatric research (JG-SNP) study. The -1031C allele of TNF-alpha was a significant protective factor for atherogenesis in the carotid, femoral and intracranial arteries [odds ratio (OR): 0.72, 0.73 and 0.70, respectively]. The -511T of IL-1beta and the +29T of TGF-beta1 were significant risk factors for atherogenesis in the subclavian and intracranial arteries (OR: 1.35 and 1.48, respectively). In contrast, conventional risk factors for atherogenesis, such as hypertension and diabetes mellitus, conferred independent risks for almost all arteries. Functional SNPs in TNF-alpha, IL-1beta and TGF-beta1 genes play a role in atherogenesis, although their influences are less pronounced than those of conventional risk factors and appear to be limited to specific arteries in the Japanese elderly.

Aged↗

PubMed2006

Telomere shortening with aging in the human pancreas.

We have conducted systematic studies to measure telomere length in human tissues of all types. Progressive telomere shortening with aging was studied in specimens of normal pancreas obtained at autopsy from 69 subjects aged 0 to 100 yr, and age-related shortening of telomere length at a rate of 36 base pairs (bp) per year was detected. Mean telomere length (+/-SD) was 13.9+/-1.4 kilobase pairs (kbp) in 16 neonates, as opposed to 8.4 kbp in 2 centenarians. Mean telomere length (+/-SD) in four age groups, 0-24, 25-49, 50-74, and 75-100 yr, was 13.5+/-1.5, 12.3+/-0.7, 11.3+/-2.5, and 10.7+/-1.8, respectively.

Adolescent↗

PubMed2006

Multiple candidate gene analysis identifies alpha-synuclein as a susceptibility gene for sporadic Parkinson's disease.

Parkinson's disease (PD), one of the most common human neurodegenerative diseases, is characterized by the loss of dopaminergic neurons in the substantia nigra of the midbrain. PD is a complex disorder with multiple genetic and environmental factors influencing disease risk. To identify susceptible genes for sporadic PD, we performed case-control association studies of 268 single nucleotide polymorphisms (SNPs) in 121 candidate genes. In two independent case-control populations, we found that a SNP in alpha-synuclein (SNCA), rs7684318, showed the strongest association with PD (P=5.0 x 10(-10)). Linkage disequilibrium (LD) analysis using 29 SNPs in a region around rs7684318 revealed that the entire SNCA gene lies within a single LD block (D'>0.9) spanning approximately 120 kb. A tight LD group (r2>0.85) of six SNPs, including rs7684318, associated most strongly with PD (P=2.0 x 10(-9)-1.7 x 10(-11)). Haplotype association analysis did not show lower P-values than any single SNP within this group. SNCA is a major component of Lewy bodies, the pathological hallmark of PD. Aggregation of SNCA is thought to play a crucial role in PD. SNCA expression levels tended to be positively correlated with the number of the associated allele in autopsied frontal cortices. These findings establish SNCA as a definite susceptibility gene for sporadic PD.

Adult↗

PubMed2006

Standard organ weights among elderly Japanese who died in hospital, including 50 centenarians.

The present study was conducted to determine standard organ weights among the elderly, because little has been reported on this subject. To analyze the human aging process in terms of organ weights, age-associated changes and correlations among organ weights and the contributions of age and nutrition to organ weights were also examined. The subjects included 1615 consecutive autopsy cases of patients aged 60-99 years who died between 1995 and 2003, and cases of 50 centenarians who died between 1973 and 2005. The weights of nine organs were measured before formalin fixation. If affected by serious diseases, such as cancer, the organs were excluded from the study. Values beyond 99% of the bilateral measurement limits were also excluded. In this manner the standard organ weights were obtained. The organ weights decreased significantly according to age in all organs except for the heart in men and the lungs in both genders. Undernutrition strongly contributed to organ weight except for the hypophysis, and was especially apparent in the heart and liver. In conclusion, the standard organ weights of elderly patients who died while hospitalized were determined. Undernutrition contributed significantly to a reduction in organ weights.

Aged↗

PubMed2006

Age-related alteration in the association of microsatellite instability with absent hMLH1 expression and histological types of colorectal carcinoma.

Microsatellite instability (MSI) is present in approximately 15-20% of sporadic colorectal cancers. However, despite the increased prevalence of absent hMLH1 expression and MSI in colorectal cancer in the elderly, few attempts have been made to define it in detail. The aim of the present paper was to correlate age-related alterations in absent hMLH1 expression and MSI with various histological types of colorectal carcinoma. hMLH1 expression and microsatellite status were studied in 184 colorectal carcinomas (49 well-differentiated, 49 moderately differentiated, 49 poorly differentiated adenocarcinomas, and 37 mucinous carcinomas). The prevalence of absent hMLH1 expression was higher in poorly differentiated adenocarcinoma (63%) and mucinous carcinoma (43%) than in well- (8%) and moderately (12%) differentiated adenocarcinomas. MSI was found more frequently in poorly differentiated adenocarcinoma (69%) and mucinous carcinoma (41%) than in well- and moderately differentiated adenocarcinomas (8% and 6%, respectively). Age-related differences in absent hMLH1 expression and MSI were found only in poorly differentiated adenocarcinoma, in which the prevalence of medullary-type carcinoma increased with advancing age. These results indicate that an age-related increase of medullary-type tumors in poorly differentiated adenocarcinoma may play an important role in the increase of absent hMLH1 expression and MSI in colorectal carcinoma.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Value of CK14 and CD56 immunostaining in distinguishing small cell carcinoma from squamous cell carcinoma of the esophagus.

Primary small cell carcinoma of esophagus (SCC) is a rare disease but has more aggressive behavior than esophageal squamous cell carcinoma (SQC). The distinction of SCC from SQC is very important therapeutically. Few systematic studies of immunohistochemical analysis to differentiate primary esophageal SCC with concomitant SQC, and adjacent normal esophageal epithelium have been reported. The objective of this study is to know the immunohistochemical markers in distinguishing SCC from SQC of esophagus. We studied 6 cases of primary esophageal SCC histologically and immunohistochemically using 15 different antibodies including a cytokeratin (CK) panel and neuroendocrine markers. Pure SCCs were identified in 2 of the 6 cases (33.3%), and the remaining 4 cases (66.7%) were found to exhibit combined SCC with an SQC component. Among the combined types, in situ SQC was observed in all 4 cases (100.0%) and invasive SQC was observed in 3 cases (75.0%). Among the normal esophageal epithelia specimens (n=7), CK14 expression was seen 6 out of 7 (85.7%) specimens and CKAE1/3 in 5 out of 7 (71.4%) specimens. CD56 was more frequently expressed among the SCC specimens (4/6; 66.7%) than among the SQC specimens (0/4; 0%; p = 0.07). The expression of p53 protein in SCC (4/6; 66.7%) and SQC (3/4; 75.0%) specimens was significantly more frequent than in normal esophageal epithelium (0/7; 0%; p = 0.02 each). Neurone-specific enolase (NSE), synaptophysin, and CKAE1/3 were expressed in 83.3%, 66.7%, and 66.7% of the SCC cases (n=6), respectively. NSE expression was significantly more frequent in SCC specimens (5/6; 83.3%) (p = 0.02) than in normal esophageal epithelium (0/7; 0%; p = 0.02). However, the frequencies of NSE expression in SCC (5/6; 83.3%) and SQC (2/4; 50%) were not significantly different. All of the SQC specimens (n=4) expressed CK14 and CKAE1/3. The CK14 expression was significantly more frequent in SQC specimens (4/4; 100.0%) than in (p = 0.04) SCC specimens (1/6; 16.6%; p = 0.04). These findings suggest that the CK14 and CD56 may be useful markers for differentiating SQC from SCC and vice versa. The p53 may also be useful to differentiate normal esophageal epithelium from SCC or SQC tissue.

CD56 Antigen↗

PubMed2005

Estrogen-metabolizing enzymes in breast cancers from women over the age of 80 years.

CONTEXT: Aromatase, steroid sulfatase, and 17beta-hydroxysteroid dehydrogenase type 1 (HSD-1) peripherally up-regulate, whereas estrogen sulfotransferase (EST) and HSD-2 down-regulate, the synthesis of active and more potent estrogens. These estrogen-metabolizing enzymes (EMEs) are important in postmenopausal breast cancers, but have never been systematically examined in breast cancers of the elderly. OBJECTIVE AND DESIGN: mRNA levels of EMEs in cancerous and normal breast tissues from 39 elderly patients (age, 80-99 yr) were compared with those from 39 controls (age, 37-70 yr) or compared according to estrogen (ER)/progesterone (PR) receptor status. RESULTS: Aromatase levels were higher in cancers of the elderly (EldCa) than in normal tissue of the elderly (P = 0.0008) or cancers of controls (P = 0.0033). In contrast, levels of steroid sulfatase and EST were higher in cancers of controls than normal tissue of controls (P = 0.0046 and P < 0.0001, respectively) or EldCa (P = 0.0001 and P < 0.0001, respectively). Levels of HSD-1 and HSD-2 did not differ significantly between any two of the categories. Among EldCa, HSD-1 levels were higher in ER/PR-positive than in ER/PR-negative carcinomas, whereas EST and HSD-2 exhibited opposite results. CONCLUSIONS: The importance of aromatase is relatively increased in EldCa. ER/PR-positive EldCa exhibited a pattern of EMEs more beneficial to the production of estrogen than did ER/PR-negative EldCa. The specific pattern exhibited in EldCa may elucidate the role of EMEs in the absence of ovarian estrogens in the pathogenesis of breast cancer.

Adenocarcinoma, Mucinous↗

PubMed2005

Chronological trend of calorie intake and the incidence of epithelial neoplasms of the large intestine during the past 30 years in Japan.

OBJECTIVES: The authors tried to elucidate the effects of food intake on the incidences of colorectal cancer and adenoma. MATERIALS AND METHODS: Large intestines obtained from a series of consecutive autopsies performed at the Tokyo Metropolitan Geriatric Hospital were scrutinized to detect colorectal neoplasms. Chronological trends and age-dependent incidences of adenoma and overt lethal cancer were checked, while cancer in adenoma were included in the category of adenoma. Data on food consumption were obtained from the 'The National Nutrition Survey in Japan' (Ministry of Health, Labor and Welfare of Japan). RESULTS: There were 405 cancers and 12,883 adenomas in the 7,091 large intestines examined. The incidences of cancer and adenoma increased with age; overt lethal cancer was found in 5.79% and adenoma in 56.79% of the general population > or =60 years in Tokyo. Calorie intake steeply increased since 1964, the year of the Olympic Games in Tokyo, until the early 1970s. Subsequently, it has continuously declined down to the level of the late 1940s, although the ingredients have changed tremendously. Chronological trends of the incidences of colorectal cancer and adenoma showed similar patterns as calorie intake, but, the influence of calorie intake on the incidences of cancer or adenoma was manifested 18 and 24 years later, respectively. CONCLUSIONS: (1) During the last 30 years, the incidences of colorectal cancer and adenoma were 5.79 and 56.79%, respectively, in individuals aged > or =60 years in Japan. (2) The chronological trends of both lesions showed a pattern similar to that of calorie intake, but, as the trend of cancer incidence preceded the course of adenoma by 6 years, adenoma is not the sole precursor lesion of overt lethal cancer.

Adenoma↗

PubMed2005

Sustained progression and loss of the gender-related difference in atherosclerosis in the very old: a pathological study of 1074 consecutive autopsy cases.

INTRODUCTION: Epidemiological surveys show decrease or reversal of male predominance in cardiovascular mortality in the very old, but the actual condition of atherosclerosis in the very old is largely unknown. The objective of this paper is to reveal whether the atherosclerosis continues to progress, or the gender-related difference exists in the very old. METHODS: The subjects were 1074 consecutive autopsy cases of in-hospital death. The male:female ratio was 1.1:1 and the average age was 80 years. Macroscopic evaluation was performed on the degree of atherosclerosis in 10 arteries including the intracranial arteries, carotid artery, aorta, coronary artery, and femoral artery. RESULTS: The severity of atherosclerosis differed greatly among arteries. The age-related increase of the atherosclerotic degree was evident, even after 80 years of age. The atherosclerosis was more severe in males than in females in their 60s, but this male predominance decreased with ageing and finally disappeared in their 90s. CONCLUSION: The sustained progression of atherosclerosis and loss of the gender-related difference probably account for the increase of cardiovascular mortality in very old females. They also suggest that the prevention of the atherosclerotic progression is still important in the seventh and eighth decade of life.

Aged↗

PubMed2005

The Val158Met polymorphism of the catechol-O-methyltransferase gene is associated with the PSA-progression-free survival in prostate cancer patients treated with estramustine phosphate.

OBJECTIVE: The aim of our study is to find out the good responders for estramustine phosphate (EMP) therapy in patients with prostate cancer. We have focused on the metabolism of EMP and studied the association between a functional single-nucleotide polymorphism in the catechol-O-methyltransferase gene (Val158Met of COMT) and PSA-progression-free survival in Japanese patients with prostate cancer treated by EMP. METHODS: Seventy-two Japanese patients with previously untreated prostate cancer who were found to be eligible for low-dose EMP therapy were enrolled in the study. Genotyping of the Val158Met polymorphism of COMT was conducted by both the polymerase chain reaction-based restriction fragment length polymorphism method and TaqMan assay. RESULTS: Patients with the Val/Val genotype of COMT had a significantly higher PSA-progression-free rate as compared to those with the Val/Met or Met/Met genotype (p=0.027). The adjusted hazard ratio of biochemical PSA failure for the Val158Met genotype of COMT was 2.164 (95% CI, 1.111 to 5.525). CONCLUSIONS: The Val158Met polymorphism of COMT is associated with the PSA-progression-free rate of EMP-treated patients in prostate cancer.

Aged↗

PubMed2005

Detection of human papillomavirus infection of the cervix in very elderly women using PCR.

PURPOSE: To determine the incidence of human papillomavirus (HPV) infection and the morphologic lesions induced by HPV infection of the uterine cervix in elderly Japanese women (including very elderly women) and to clarify the natural history and outcome of HPV infection. EXPERIMENTAL DESIGN: We detected squamous intraepithelial lesions (SIL) by cytology and the presence of HPV infection by PCR on cervical smears obtained at autopsy from 335 women ages 60 to 105 years (mean, 82.7 years). Two primers were used for PCR, one for low-risk HPV subtypes and one for high-risk HPV subtypes. RESULTS: SILs were observed in 20 (6.0%) of the women autopsied; 18 (5.4%) had low-grade SIL and 2 (0.6%) had high-grade SIL. HPV-DNA was not detected in any of the women with normal cervical cytology but was found in 9 (45.0%) of the 20 with SIL (2.7% of all subjects). Of these 9 women, 2 (22%) were positive for low-risk types of HPV and 7 (78%) were positive for high-risk types. All 9 had spent their last days in hospitals or nursing homes, the duration of institutional care ranging from 17 days to 10 years 2 months. CONCLUSIONS: Our results suggest that HPV infection of the cervix may occasionally persist for long periods of time (the maximum duration noted in this study being 10 years 2 months). It is also possible that HPV infection in young women with normal cervical cytology will not persist into advanced age.

Aged↗

PubMed2005

Islands of squamous epithelium and their surrounding mucosa in columnar-lined esophagus: a pathognomonic feature of Barrett's esophagus?

We examined 23 patients with columnar-lined esophagus (2 with long segment and 21 with short segment) endoscopically. After staining with Lugol's iodine solution, squamous islands were identified in the columnar mucosa in 18 (78%) of the 23 patients. When biopsy specimens were obtained from these islands, esophageal glands proper or their ducts were seen in 12 (67%) of the 18 cases. Because the identification of esophageal glands proper is a definite indicator that a piece of biopsy tissue is of esophageal origin, a diagnosis of columnar-lined esophagus could be made purely on the basis of the histological findings in these biopsy specimens of squamous islands. This was the case in 12 (52%) of the 23 patients examined in this study. Staining with Lugol's iodine solution, with subsequent biopsy of stained squamous islands, may assist in the diagnosis of short-segment columnar-lined esophagus. We also conclude, on the basis of our study, that columnar metaplasia of the esophagus cannot develop by direct outgrowth of epithelium from the ducts of esophageal glands proper. In addition, intestinal metaplasia was not always observed in the columnar mucosa around the duct orifices. From a practical point of view, biopsy specimens from columnar-lined mucosa of the esophagus do not always show intestinal metaplasia (specialized intestinal metaplasia).

Barrett Esophagus↗

PubMed2005

Ciliated surface in the esophagogastric junction zone: a precursor of Barrett's mucosa or ciliated pseudostratified metaplasia?

We have previously reported squamous metaplasia-like change at the esophagogastric junction (EGJ). In the present study, we examined these lesions histologically and by immunohistochemistry and electron microscopy. Samples of EGJ mucosa, 3 cm long and comprising 1.5-cm long portions of both columnar and squamous mucosa, were obtained from 43 esophagectomy resection specimens. Squamous metaplasia-like change was observed in 21 (49%) of the 43 cases. The squamous metaplasia-like change was generally positive with immunohistochemical stains for tubulin and cytokeratins (CKs) 4, 7, 8, 13, and 18, and was generally negative with stains for CKs 10, 14, and 20. This pattern of immunoreactivity is very similar to that of bronchial mucosa. Also, many cilia were detected at the apices of the cells by electron microscopy in 5 (31%) of the 16 cases that were able to be examined. Therefore, squamous metaplasia-like change at the EGJ has both a similar appearance and a similar immunohistochemical profile to respiratory bronchial epithelium. These findings may suggest that squamous metaplasia-like change at the EGJ is not a precursor of Barrett's mucosa but rather is a form of pseudostratified metaplasia.

Aged↗

PubMed2005

Adenomatoid tumor of the adrenal gland: case report with immunohistochemical study.

Adrenal adenomatoid tumor (AT) is a recently recognized disease with marked male predominance. Herein is presented a case of adrenal AT incidentally found in a 30-year-old man and results of immunohistochemical examination of the tumor. The left adrenal gland, weighing 17 g, contained a mass measuring 3 x 2.5 x 2.5 cm in the cortical tissue. Cut surface showed a relatively well-circumscribed firm tumor with a white solid appearance. Histologically, the tumor had the typical appearance of AT described in the genital tract. Immunohistochemically, the tumor cells were positive for calretinin, D2-40, WT1, mesothelial cell antigen, CA125, thrombomodulin, vimentin and cytokeratins (stained by AE1 + AE3, OV-TL 12/30, CAM5.2 and MNF116), and negative for endothelial markers (CD31, CD34 and factor VIII-related antigen) and CD56. CD56-positive adrenocortical cells were diffusely scattered in the tumor, especially in its periphery. Immunohistochemistry of estrogen, progesterone and androgen receptors was negative. These findings confirm mesothelial origin of the tumor and suggest that this tumor has little relation to sex hormone despite male predominance.

Adrenal Gland Neoplasms↗

PubMed2005

Diabetes mellitus complicated with rapidly progressive glomerulonephritis in an elderly patient.

An 88-year-old man with a 30-year history of type 2 diabetes and a 3-year history of chronic renal failure was admitted for evaluation of anasarca. On admission, findings of nephrotic syndrome and microscopic hematuria were observed. During the course of therapy, rapid deterioration of renal function occurred with the appearance of pneumonia. Irrespective of the therapy with hemodialysis and antibiotics, he died of respiratory failure. The autopsy showed a rare case of rapidly progressive glomerulonephritis (crescentic glomerulonephritis) superimposed on membranous nephropathy. This experience highlighted the importance of the differential diagnosis of non-diabetic glomerulopathy even in elderly patients with diabetes mellitus.

Aged↗

PubMed2005

[Establishment of brain bank for aging research].

We have established a brain bank for the prevention and treatment of aging-related movement and cognitive disturbances, as a joint project between a rural care hospital and a research institute. The resources of the bank are to be used for collaborative studies approved by the bank's committee. The collaborative investigators should also be qualified by the institute to conduct the research jointly. The collaborative studies require authorization by the institutional review board (IRB) of the institute, the hospital and each facility involved in collaborative studies. The bank continues to have the responsibility for the resources, after the transfer of the resources to the facilities of collaborative investigators, pursuant to Article 18 of the Cadaver Autopsy and Preservation Act Thus, the status of resource utilization and outcomes from their use in studies will be monitored periodically (every 6 months). We shared the philosophy with the brain banks in the United States that the resources of the bank, donated on the basis of a charitable spirit, belong to the public domain and are regarded as public resources to be used to contribute to promoting public welfare.

Aging↗

PubMed2005

Is there a set of histologic changes that are invariably reflux associated?

Many histologic changes have been described in the esophageal squamous mucosa in patients with gastroesophageal reflux disease (GERD), including dilated intercellular spaces, balloon cells, intrapapillary vessel dilation, elongated papillae, basal cell hyperplasia, acanthosis, intraepithelial eosinophils, Langerhans cells, and p53 protein overexpression. To define a set of histologic changes that are invariably reflux associated, we examined the histologic changes in esophageal specimens from normal controls, patients with GERD, patients without GERD but with a suspicion of other pathology, and patients with esophageal carcinoma. We also examined biopsy specimens from sites with differing endoscopic features, including cloudy white and reddened mucosa. A definitive set of reflux-associated histologic changes could not be defined from the small number of biopsy specimens examined in the present study. Histologic changes indicative of GERD are likely to be found somewhere in the esophagus in all patients with GERD, but these changes are nonspecific. A set of histologic changes that are invariably reflux associated may exist, but these changes are nonspecific. To develop a set of characteristic reflux-associated features, endoscopists may perform targeted biopsies from several sites with various endoscopic features and at different stages of disease.

Aged↗

PubMed2005

[Biopsy methods and pathology of Barrett's esophagus].

We reviewed the definition of the esophagogastric junction and the biopsy sites and histologic findings of biopsy specimens from Barrett's esophagus. The borderline between the esophagus and stomach has been defined as the distal limit of the longitudinal vessels by the Japan Esophageal Society, because the longitudinal vessels are always located within the esophagus. As squamous islands in Barrett's mucosa are usually the orifices of esophageal glands proper, biopsy specimens from the squamous islands show esophageal glands proper or their ducts. The identification of esophageal glands proper is a definite histological indicator that a piece of biopsy tissue is of esophageal origin. Therefore, a diagnosis of Barrett's esophagus can be made purely on the basis of the histologic findings in these biopsy specimens of squamous islands. Since columnar mucosa is usually recognizable at endoscopy, a diagnosis of Barrett's esophagus can be made solely on the basis of endoscopic examination, without any need for histologic confirmation, if squamous islands are recognized in columnar-lined mucosa.

Barrett Esophagus↗