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Biomedical subjects

M Sakamoto

Publications and source records attributed to M Sakamoto.

At least 127 records · Page 7Linked to original sources

Genetic alteration of the DCX gene in Japanese patients with subcortical laminar heterotopia or isolated lissencephaly sequence.

We examined mutations of the doublecortin (DCX) gene, which is responsible for X-linked subcortical laminar heterotopia (SCLH) and lissencephaly, in eight unrelated Japanese patients, four with SCLH and four with isolated lissencephaly sequence (ILS). Polymerase chain reaction (PCR) disclosed a deletion of part of the DCX gene in one male ILS patient. Single-strand conformational polymorphism analysis and subsequent sequence analysis were carried out in the remaining seven patients. One male ILS patient had a nonsense mutation in exon V, which would result in premature termination of the gene product. One female SCLH patient had a missense mutation in exon IV. Our results indicate that in the Japanese, as has been seen elsewhere, abnormality of the DCX gene is the common cause of SCLH and ILS.

Brain↗

Extended high-frequency ototoxicity induced by the first administration of cisplatin.

The ototoxicity induced by cisplatin results in high-frequency hearing loss. The sound-pressure thresholds at extended high frequencies of 8 to 20 kHz were measured in 12 patients with head and neck cancer before and after the first administration of cisplatin. Ototoxicity was defined statistically by the newly introduced regression-line analysis. This analysis revealed that the threshold of 1 of the 12 patients increased evenly from 8 to 10 kHz, and the damage to the hearing system of this patient was permanent. The reasons for such a low rate of ototoxicity might be the long-term administration of low doses of cisplatin and the addition of fosfomycin.

Adult↗

Acute cerebellar ataxia of a patient with SLE.

We described a 28-year-old woman with systemic lupus erythematosus (SLE) presented with digestive tract, skin and renal symptoms and afterwards developed acute cerebellar ataxia, a paresis of the right inferior rectus muscle, left abducens paralysis and left facial palsy which seemed to be consistent with a brainstem lesion visible on magnetic resonance imaging (MRI). This lesion disappeared within 9 days of corticosteroid treatment. It is suggested that this lesion is focal edema induced by acute changes in the blood brain barrier secondary to a vasculopathy. Other causes, including local infarction, are unlikely.

Acute Disease↗

Loss of cell-cell contact is induced by integrin-mediated cell-substratum adhesion in highly-motile and highly-metastatic hepatocellular carcinoma cells.

The cadherin-mediated cell-cell adhesion system plays a critical role in normal development and morphogenesis. Inactivation of this system is thought to be responsible for cancer invasion and metastasis. A human hepatocellular carcinoma (HCC) cell line, KYN-2, was observed to have great potential for intrahepatic metastasis when orthotopically implanted into the liver of SCID mice. In vitro cultures of KYN-2 cells showed that they formed trabecular structures in suspension but lost tight cell-cell adhesion and became scattered when attached to a substratum such as collagen or fibronectin. In response to adhesion to the substratum, subcellular colocalization of E-cadherin and actin filaments were shown to be reduced, and a significant amount of alpha-catenin was dissociated from the E-cadherin-catenin complex in KYN-2 cells. These changes of cell-cell adhesion were blocked by inhibitory monoclonal antibodies against beta1 and beta5 integrins. We found that c-Src was coimmunoprecipitated with E-cadherin-catenin complex and was tyrosine-dephosphorylated and activated in the adherent cells. The tyrosine dephosphorylation of c-Src was induced by cell adhesion to the substratum and inhibited by addition of inhibitory monoclonal antibodies against beta1 and beta5 integrins. These findings indicate that integrin-mediated cell-substratum adhesion inhibits cadherin-mediated cell-cell adhesion, possibly through c-Src activation, and suggest that this cross-talk mediates transient inactivation of the cadherin system and plays an important role in intrahepatic metastasis of human HCC. Modulation of this interaction might provide a new approach to prevent metastasis and recurrence of HCC.

CSK Tyrosine-Protein Kinase↗

Altered expression of the ERM proteins in lung adenocarcinoma.

Radixin is a member of the ERM (ezrin/radixin/moesin) protein family that is proposed to function as a membrane-cytoskeletal linker. Using differential display analysis, we have identified radixin as a gene down-regulated in primary lung adenocarcinoma. Real-time quantitative reverse transcription polymerase chain reaction confirmed that radixin mRNA was decreased, both in 10 early-stage bronchioloalveolar carcinomas and in 16 invasive lung adenocarcinomas, by 69% (p = 0.0002) and 82% (p < 0.0001), respectively, compared with 9 nontumor lung tissues. Similarly, moesin and ezrin mRNA levels were reduced in lung adenocarcinoma. Immunohistochemistry confirmed that cancer cells expressed very little radixin and moesin, whereas non-neoplastic alveolar and bronchiolar epithelial cells, and endothelial cells, including those within the tumor stroma, were consistently positive for these two proteins. Ezrin was localized in the apical surface of non-neoplastic bronchiolar and alveolar epithelial cells and, in contrast to radixin and moesin, the majority of tumor cells retained expression of ezrin. Localization of ezrin was altered in a significant proportion of tumor cells: whereas tumor cells forming lumina displayed membranous staining on the apical side, tumor cells with disorganized structures were either negative or diffusely positive for ezrin in the cytoplasm. Furthermore, a fraction of tumor cells invading the stroma in a scattered manner were strongly positive for ezrin. In conclusion, expression of radixin and moesin is down-regulated in lung adenocarcinoma, including early-stage bronchioloalveolar carcinoma. An intriguing implication of this finding is that these two genes may function as tumor suppressors in lung adenocarcinoma oncogenesis. Although structurally related to radixin and moesin, ezrin may have a distinct function in tumor-cell invasion.

Adenocarcinoma↗

Genetic instability and aberrant DNA methylation in chronic hepatitis and cirrhosis--A comprehensive study of loss of heterozygosity and microsatellite instability at 39 loci and DNA hypermethylation on 8 CpG islands in microdissected specimens from patients with hepatocellular carcinoma.

A study was conducted to examine the significance of genetic instability and aberrant DNA methylation during hepatocarcinogenesis. Genomic DNA was extracted from 196 microdissected specimens of noncancerous liver tissue that showed no marked histologic findings or findings compatible with chronic hepatitis or cirrhosis, and 80 corresponding microdissected specimens of hepatocellular carcinoma (HCC) from 40 patients. Loss of heterozygosity (LOH) and microsatellite instability (MSI) were examined by polymerase chain reaction (PCR) using 39 microsatellite markers, and DNA methylation status on 8 CpG islands was examined by bisulfite-PCR. In noncancerous liver tissues, LOH, MSI, and DNA hypermethylation were found in 15 (38%), 6 (15%), and 33 (83%) of 40 cases, respectively. The incidence of DNA hypermethylation in histologically normal liver was similar to that in chronic hepatitis and cirrhosis, although neither LOH nor MSI was found in histologically normal liver. In cancerous tissues, LOH, MSI, and DNA hypermethylation were found in 39 (98%), 8 (20%), and 40 (100%) of 40 cases, respectively. CpG islands of the p16 gene and methylated in tumor 1, 2, 12, and 31 clones were frequently methylated in cancerous tissues, although neither the thrombospondin-1 nor the human Mut L homologue (hMLH1) gene was methylated. Absence of silencing of the hMLH1 gene by DNA hypermethylation is consistent with the low incidence of MSI in HCCs. The results of this study indicate that LOH and aberrant DNA methylation contribute to hepatocarcinogenesis; DNA hypermethylation in particular, which precedes or may even cause LOH, is as an early event during hepatocarcinogenesis.

Adult↗

Enhancement pattern of normal extraocular muscles in dynamic contrast-enhanced MR imaging with fat suppression.

PURPOSE: To evaluate the internal structure of normal extraocular muscles on fat-suppressed dynamic contrast-enhanced MR imaging. MATERIAL AND METHODS: Ten subjects were examined using fat-suppressed dynamic contrast-enhanced MR imaging. We evaluated the enhancement pattern (C-shaped or ring-like) of extraocular muscles and quantified the maximum ratios of enhancement (Rmax) and maximum ratios of signal increase (Vmax). We also quantified Rmax and Vmax in the central and peripheral portions of medial rectus muscles. RESULTS: In the early phase of dynamic contrast-enhanced MR imaging, a C-shaped or ring-like pattern was observed in 100% of inferior rectus, 95% of medial rectus, 55% of superior rectus, 20% of lateral rectus, and 15% of superior oblique muscles. Overall mean Rmax and Vmax values showed statistically significant differences to the temporal muscles. For the peripheral portion of medial rectus muscles, mean Rmax and Vmax values were greater than for the central portion. CONCLUSION: Using fat-suppressed dynamic contrast-enhanced MR imaging, the C-shape or ring-like internal structure of the extraocular muscles could be visualized, and were considered to reflect their structure of orbital and global layers. Potential usefulness of the fat-suppressed dynamic contrast-enhanced MR imaging for detecting pathological status is suggested.

Adipose Tissue↗

Effects of prenatal aflatoxin B1 exposure on behaviors of rat offspring.

The effects of prenatal aflatoxin B1 (AFB) exposure on eight behavioral parameters in Jcl:Wistar rat offspring were assessed. Pregnant rats were injected subcutaneously with 0.3 mg/kg/day of AFB dissolved in dimethylsulfoxide on days 11-14 (Group A) or 15-18 (Group B) of gestation. Controls received the vehicle similarly on days 11-18 of gestation. Before weaning, the offspring were examined using the cliff avoidance response (5 days of age), the negative geotaxis reflex (7 days), and swimming development (6, 8, and 10 days). After weaning, animals were examined using the rotarod test (5 weeks of age), the open field test (6 weeks), a conditioned avoidance learning test (14 weeks), an underwater T-maze test (15 weeks), and a reproduction test (16 weeks). The preweaning offspring in the AFB-A group showed significantly lower success rates than controls in cliff avoidance responses. In swimming development, the offspring in the AFB-A group had significantly lower scores than controls for swimming direction. In the rotarod test, the AFB-A group remained on the rod for a significantly shorter time than the controls at 15 rpm on both the first and second trial days. The avoidance performance of the rats in AFB-A and AFB -B groups was significantly poorer than that of controls. These results indicate that prenatal exposure to AFB produced a delay of early response development, impaired locomotor coordination, and impaired learning ability in the offspring of rats exposed to AFB during middle pregnancy, and the early gestational exposure appears to produce more effects than latter exposure.

Aflatoxin B1↗

Repeat intervention for in-stent restenosis: re-expansion of the initial stent is a predictor of recurrence of restenosis.

BACKGROUND: In-stent restenosis has become a significant clinical problem as use of stents has increased. The optimal strategy for dealing with in-stent restenosis needs to be evaluated. OBJECTIVE: To compare the acute and late results of interventions for in-stent restenosis according to the device used, and to analyze the clinical and procedural variables of the lesions treated and identify the determinants of recurrence of restenosis and target lesion revascularization (TLR). METHODS: Procedural and late outcomes for 58 lesions in 50 patients who underwent repeat intervention for in-stent restenosis were analyzed. The results of interventions according to the device employed were compared. The predictors of recurrence of restenosis and TLR within 6 months were analyzed. The ratio of balloon diameter in repeat intervention to minimal lumen diameter after initial stenting (MLD0) was used as an index of re-expansion of stents. Serial intravascular ultrasound imaging was performed before and after repeat intervention for 33 lesions, and re-expansion of the initial stent was evaluated. RESULTS: Repeat intervention was successful in treating all lesions. Angiographic follow-up was possible for 49 lesions (84%). The overall incidences of recurrence of restenosis and TLR were 40.1 and 27.6%, respectively. Despite the immediate results having been good, the late results of stenting for in-stent restenosis were not favorable. Diffuse-type in-stent restenosis, early in-stent restenosis, and balloon diameter:MLD0 ratio > 1.25 are independent predictors of poor late results. Intravascular ultrasound findings have shown that expansion of the initial stent leads to recurrence of restenosis and TLR. CONCLUSIONS: Re-expansion of the initial stent can cause further vascular injury and there is a risk of recurrence of restenosis. Alternative therapeutic strategies that work without dilating the initial stent may be necessary for treating lesions with high risk of recurrence of restenosis.

Aged↗

Comparison of the oral bacterial flora in saliva from a healthy subject and two periodontitis patients by sequence analysis of 16S rDNA libraries.

The oral bacterial flora in the saliva from two patients with periodontitis and from a periodontally healthy subject were compared using a sequence analysis of 16S rDNA libraries without cultivation. 16S rDNAs were amplified from salivary DNA by PCR and cloned. Randomly selected clones were partially sequenced. On the basis of sequence similarities, the clones were classified into several clusters corresponding to the major phylum of the domain Bacteria. The major phylum in the libraries was the low G+C Gram-positive bacteria. There was no clonal sequence affiliated with periodontopathic bacteria in the salivary sample from the healthy subject, while a number of periodontal pathogens such as Campylobacter rectus, Prevotella intermedia, Porphyromonas gingivalis and Treponema socranskii were detected in the salivary samples from the patients with periodontitis. In addition, a number of previously uncharacterized and uncultured microorganisms were recognized. These organisms may have some role in periodontal disease. This study reveals some potential for a molecular-biological technique to analyze the oral microflora associated with periodontal disease, including previously uncharacterized and uncultured microorganisms, without cultivation.

Adult↗

Glycyrrhizin inhibits the lytic pathway of complement--possible mechanism of its anti-inflammatory effect on liver cells in viral hepatitis.

Glycyrrhizin, an aqueous extract of licorice root, has anti-inflammatory activity and has been used for the treatment of chronic viral hepatitis. In the present study we describe the mechanism by which glycyrrhizin inhibits complement. Glycyrrhizin inhibited the cytolytic activity of complement via the activation of both the classical and alternative pathways, while it had no effect on immune adherence, suggesting that it blocks C5 or a later stage of the complement cascade. Further analysis revealed that glycyrrhizin inhibits the lytic pathway in which the membrane attack complex (MAC) is formed. This mechanism suggests that glycyrrhizin may prevent tissue injury caused by MAC not only in chronic hepatitis but in many autoimmune and inflammatory diseases.

Animals↗

Expression of tumor-rejection antigens in gynecologic cancers.

We recently reported the four tumor-rejection antigens (SART1(259), SART2, SART3, and ART4) that possess tumor epitopes capable of inducing HLA-A2402-restricted cytotoxic T lymphocytes (CTLs) in cancer patients. This study investigated the expression of these tumor antigens in gynecologic cancers, including 33 ovarian cancers, 38 cervical cancers, and 40 endometrial cancers. SART1(259) antigen was detected in 56%, 35%, and 30% of ovarian, cervical and endometrial cancers, while SART2 antigen was detected in 46%, 66%, and 30% of these cancers, respectively. Both SART3 and ART4 antigens were detectable in the majority of these gynecologic cancers tested. In contrast, none of these antigens was detectable in any of the normal ovarian and uterine tissues tested. Peripheral blood mononuclear cells (PBMCs) of HLA-A24(+) patients with gynecologic cancers were found to produce significant levels of interferon-gamma in response to HLA-A24(+) SART3(+) gynecologic cancer cells after having been stimulated three times in vitro with either SART3(109 - 118) or SART3(315 - 323) peptide. These PBMCs lysed HLA-A24(+) SART3(+) gynecologic cancer cells, but not HLA-A24(-) SART3(+) gynecologic cancer cells or HLA-A24(+) normal cells. Therefore, these four antigens and their peptides, including SART3 peptides, would be appropriate molecules for use in specific immunotherapy of HLA-A24(+) gynecologic cancer patients.

Antigens, Neoplasm↗

[HIV-1 (human immunodeficiency virus type 1) mutant strain associated with zidovudine resistance detected from a Japanese patient with primary HIV-1 infection].

Sequences of HIV-1 pol gene were determined by direct sequencing from a Japanese patient with primary HIV-1 infection. The patient did not receive antiretroviral therapies. However we observed a HIV-1 mutant strain associated with zidovudine (ZDV) resistance. The patient had both the codon 70 and the codon 215 amino acid substitutions in the RT region. Our data indicated that the patient was infected with a HIV-1 mutant strain associated with ZDV resistance and this is the first report in Japan.

Acquired Immunodeficiency Syndrome↗

[Gastrointestinal diseases associated with HIV infection].

A clinical studies were carried out on gastrointestinal diseases associated with HIV infection. During the 6 years between January 1993 and December 1998, 71 HIV infected cases visited to Yokohama Municipal Citizen's hospital, and 26 of them developed gastrointestinal complications during the course of their illness. They consisted of 24 males and 2 females, with the mean age of 44.7 years and the medial value of 42.5 years. Of the 26 patients, 21 were Japanese, and the remaining 5 were Southeast Asian. The mean CD4 count was 143/microliter and the medial value was 32/microliter at the time of development of complications. Gastrointestinal complications were esophageal candidiasis in 6 patients, cytomegalovirus (CMV) gastritis and gastric Kaposi's sarcoma in 1 patient each, amebiasis in 8 patients, infectious colitis in 11 patients, and asymptomatic pathogen carriers in 3 patients. Esophageal and gastric complications were common in patients with low count of CD4, and endoscopy was useful for diagnosis. Amebiasis developed even in patients with normal CD4 and was common in males with experience in homosexual contact. It seems that homosexual contact acquire not only HIV infection but also Entamoeba histolytica through sexual contact. Protozoan and acid-fast bacteria were detected at high rate in patients with infectious colitis and asymptomatic pathogen carriers. Besides food-born infections, imported infections were seen in foreign and Japanese patients who had traveled abroad. The gastrointestinal diseases associated with HIV infections for the most part were opportunistic infections or tumors but imported, food-born, and sexually transmitted infections were also observed. It seems necessary to take into consideration of varying background of patients in the treatment of gastrointestinal diseases associated with HIV infections.

AIDS-Related Opportunistic Infections↗

Evaluation of the therapeutic effect of transcatheter arterial embolization for hepatocellular carcinoma.

Transcatheter arterial embolization (TAE) has been widely performed for patients with hepatocellular carcinoma (HCC). However, the method of evaluating the therapeutic effect of TAE has not been established. We examined the rate of necrotic area to whole tumor (TN) by CT, the tumor regression rate (TR) and the reduction rate in serum alpha-fetoprotein (AFP) levels in patients with HCC who received hepatic resection within 3 months after TAE. In the evaluation of TN, the lipiodol accumulation in tumor was regarded as being necrotic. Rates of necrotic area, which were also examined pathologically (PN) in resected tumors, were compared with TN, TR and AFP reduction rates, respectively. Eighty-eight patients were enrolled in this study, and there was a significant positive correlation between TN and PN (r = 0.80, p < 0.001). Although TR significantly correlated to PN (p = 0.001), the correlation coefficient between them was low (r = 0.34). The correlation coefficients between AFP reduction rate and PN was 0.76 (p < 0.001) in 26 patients (30%) with an AFP level >/=200 ng/ml before TAE. The evaluation method using lipiodol accumulation in CT is the most useful for assessing the therapeutic effect of TAE, particularly when a sufficiently long interval exists between TAE and the evaluation, because of the highest correlation coefficient between TN and PN, and the availability of TN for all patients. The reduction rate in serum AFP levels was also useful in patients with AFP levels >200 ng/ml before treatment.

Adult↗

Genetic aberrations detected by comparative genomic hybridization in ovarian clear cell adenocarcinomas.

Genetic abnormalities were detected by comparative genomic hybridization (CGH) in 12 ovarian clear cell adenocarcinomas. DNA sequence copy number abnormalities (CNAs) occurring in more than 20% of the cancers included increased copy numbers of 8q11-q13, 8q21-q22, 8q23, 8q24-qter, 17q25-qter, 20q13-qter and 21q22-qter and reduced copy numbers of 19p. Increases in copy numbers of 8q11-q13, 8q21-q22, 8q23 and 8q24-qter occurred more frequently in disease-free patients than in recurrent/non-surviving patients (p < 0.05). However, increases in copy numbers of 17q25-qter and 20q13-qter occurred more frequently in recurrent/non-surviving patients than in disease-free patients (p < 0.05). Furthermore, increases in copy numbers of 17q25-qter and 20q13-qter occurred together (p < 0.05). Additionally, there were negative correlations between increases in copy numbers of 8q21-q22 and 17q25-qter, and between 8q21-q22 and 20q13-qter (p < 0.05). It appears that ovarian clear cell adenocarcinomas can be classified into two subtypes, one being cancer with an increase in copy numbers of 8q and the other being cancer with increases in copy numbers of 17q25-qter and 20q13-qter.

Adenocarcinoma, Clear Cell↗