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Biomedical subjects

K Hosokawa

Publications and source records attributed to K Hosokawa.

At least 73 records · Page 4Linked to original sources
PubMed1998

Breast reconstruction by means of innervated rectus abdominis myocutaneous flap.

We performed immediate breast reconstruction in 22 patients using rectus abdominis myocutaneous flap accompanied by neurorrhaphy in the past 2 years. In the neurorrhaphy, the 11th intercostal nerve, which controls the sensation of the myocutaneous flap, was anastomosed to the lateral cutaneous branch of the 4th intercostal nerve, which controls the sensation of the breast. Our study included 15 patients, and the postoperative follow-up period was 4 to 24 months, with an average of 14.0 months. For control subjects, there were 16 cases of rectus abdominis myocutaneous flap, whose sensory nerve had not been reconstructed (postoperative follow-up period 11 to 41 months, average 24.1 months). The sensory examination included tests of touch, pain, and temperature. The innervated myocutaneous flap sensation showed gradual recovery at about 6 months after surgery and reached the value of the normal side after about 1 year. In the control subjects, recovery of sensation was not observed at all in the first 10 postoperative months. Then, after more than 1 year, the recovery was gradual and reached the value of the normal side in only some control subjects. Therefore, we consider the present technique useful for recovery of sensation in immediate breast reconstruction.

Abdominal Muscles↗
PubMed1998

Induction of Ad4BP/SF-1, steroidogenic acute regulatory protein, and cytochrome P450scc enzyme system expression in newly established human granulosa cell lines.

We have established immortalized human granulosa cells by triple transfection of primary cells obtained from in vitro fertilization patients with SV40 DNA, Ha-ras oncogene, and a temperature sensitive (ts) mutant of the tumor suppressor gene p53 (p53val135). Forty-one clones were isolated, and their steroidogenic responses were analyzed. While all the cell lines proliferate rapidly and show only traces of progesterone production, upon stimulation with 50 microM of forskolin (FK), which elevates intracellular cAMP, they become steroidogenic as evidenced by progesterone production. The steroidogenic response of the cell lines was stable even after 20 generations and several cycles of freezing and thawing. A highly responsive cell line (HO-23) was further examined for characteristics of the steroidogenic response. Cells stimulated with FK and 8-Br-cAMP produced high levels of pregnenolone, progesterone, and 20alpha-hydroxy-4-pregnen-3-one (20alpha-OH-progesterone) comparable with amounts produced by highly differentiated primary human granulosa-luteal cells. Hydrocortisone and dexamethasone highly augment the cAMP-stimulated progesterone production, whereas testosterone and PRL enhanced cAMP-induced progesterone synthesis only moderately. Estradiol, insulin-like growth factor I, and insulin showed no significant effect on cAMP-induced steroidogenesis. The phorbol ester TPA, and basic fibroblast growth factor, dramatically suppress cAMP-induced production of progesterone, whereas bovine corneal endothelial cell ECM (BCE/ECM) enhanced cAMP-induced progesterone and antagonized basic fibroblast growth factor suppression of cAMP-induced steroidogenesis. Steroidogenic factor 1 (Ad4BP/SF-1) was expressed in control cells, and its expression was augmented by FK, whereas the steroidogenic acute regulatory protein showed low expression in the nonstimulated cells but was clearly elevated upon cAMP stimulation and was slightly decreased by TPA in cAMP-stimulated cells. Expression of the electron carrier adrenodoxin (ADX), which is a part of the cytochrome P450scc enzyme system, was very low in nonstimulated cells but was dramatically elevated in FK- and 8-Br-cAMP-stimulated cells, whereas no reduction of ADX was evident in cells costimulated with FK and TPA. Immunocytochemical studies revealed a weak staining of ADX in mitochondria of nonstimulated cells and intensive staining in highly clustered mitochondria of FK- or 8-Br-cAMP-stimulated cells. Only moderate reduction in ADX staining was evident in cells costimulated with FK and TPA. These unique cell lines can provide a useful model for the investigation of induced steroidogenesis in human granulosa cells.

Animals↗
PubMed1998

Modulation of Mdm2 expression and p53-induced apoptosis in immortalized human ovarian granulosa cells.

The activity of the tumor suppressor gene p53 is implicated in arrest of the cell cycle and the induction of apoptosis. The mdm2 oncogene is transcriptionally activated by p53, and the protein products of this gene can down-modulate biochemical activities and biological effects of p53 in a cell context-dependent manner. We have established highly steroidogenic human granulosa cell lines expressing the Ha-ras oncogene and a temperature sensitive (ts) mutant of p53 (p53val135) to test the involvement of p53-downstream genes in the modulation of apoptosis in these cells. We find that ras-transformed granulosa cells expressing p53val135 undergo apoptosis following a shift from 37 C to 32 C, a temperature at which p53val135 exerts its wild-type activity. Elevating the cellular content of cAMP at 32 C markedly enhances apoptosis. Basic fibroblast growth factor (bFGF) effectively blocks the p53/cAMP-induced apoptosis, but suppresses steroidogenesis. A naturally produced basement membrane-like extracellular matrix (ECM) containing immobilized bFGF exerts a similar antiapoptotic effect, but unlike soluble bFGF, it enhances steroidogenesis in these cells. While cAMP markedly suppresses the p53-induced Mdm2 expression, bFGF and ECM elevate Mdm2 expression 3-5-fold. These effects on Mdm2 expression are most pronounced 2-4 h after the shift to 32 C, before nuclear fragmentation is detected. Cells grown at 32 C in contact with ECM have a more developed actin cytoskeleton both in the absence and presence of cAMP stimulation, compared with cells grown on plastic dishes. We conclude that bFGF and components of the ECM can cross-talk with p53/cAMP-generated signals for apoptosis. These signals may, at least in part, be coordinated by the modulation of Mdm2 expression, which precedes the biochemical events characteristic of apoptosis. The multicomponent ECM also induced differentiation in these ras-transformed cells, while soluble bFGF inhibited differentiation, suggesting that ECM components other than bFGF stimulate differentiation. Organization of the actin cytoskeleton is likely to play an important role in the cross-talk between p53/cAMP- and bFGF/ECM-generated signals. Because the tumor suppressor gene p53 is implicated with apoptosis of primary granulosa cells and the ECM is involved in the prevention of this process, the newly established cell lines can serve as a useful model for apoptosis in highly luteinized granulosa cells.

Apoptosis↗
PubMed1998

Malignant insulinoma with extensive liver metastases presenting as disturbance of consciousness.

A 56-year-old man was referred to our hospital for evaluation of episodic disturbance of consciousness. Hypoglycemic symptoms were noted and Whipple's triad was satisfied. The 75 g OGTT and the glucagon test revealed a high baseline insulin level and hyperreactivity to glucagon. A pancreatic tumor and liver metastases were found by abdominal computed tomography (CT). Based on the finding of liver biopsy, the final diagnosis was malignant insulinoma with liver metastasis. He selected conservative treatment and no hypoglycemic crisis has occurred for one year since discharge. Early diagnosis and long-term follow-up is necessary since this tumor is slow growing.

Blood Glucose↗
PubMed1998

Usefulness of revised fasting plasma glucose criterion and characteristics of the insulin response to an oral glucose load in newly diagnosed Japanese diabetic subjects.

OBJECTIVE: To examine the usefulness of the revised criterion for fasting plasma glucose (FPG) in the diagnosis of diabetes recommended by the American Diabetic Association (ADA) (126 mg/dl, 7 mmol/l), and to characterize insulin response during the 75-g oral glucose tolerance test (OGTT) in newly diagnosed Japanese diabetic subjects. RESEARCH DESIGN AND METHODS: A series of 2,121 Japanese subjects underwent a 75-g OGTT (0-3 h) and were divided into three groups (normal glucose tolerance [NGT], impaired glucose tolerance [IGT], and diabetes mellitus [DM] according to the current World Health Organization criteria. After the cutoff values of FPG that distinguish NGT and IGT from diabetes were analyzed, the usefulness of the ADA criterion for FPG was examined by comparing diagnostic parameters (sensitivity, specificity, and accuracy) with those for the cutoff value of 140 mg/dl. To assess insulin response, both the insulinogenic index (IsIx), a marker of early secretion, and the area under the insulin response curve (AUCins), a marker of total secretion, were compared between the DM, NGT, and IGT groups. RESULTS: First, the FPG cutoff value distinguishing NGT from diabetes was 109 mg/dl. An FPG of 126 mg/dl showed a higher sensitivity (0.52 vs. 0.31), the same specificity (1.00), and a higher accuracy (0.82 vs. 0.74) than an FPG of 140 mg/dl, and it had a higher specificity (1.00 vs. 0.86) with a slightly lower accuracy (0.82 vs. 0.85) than an FPG of 109 mg/dl. Second, the FPG cutoff value differentiating IGT from diabetes was 113 mg/dl. An FPG of 126 mg/dl showed a higher sensitivity (0.52 vs. 0.31) and accuracy (0.80 vs. 0.74) and a similar specificity (0.97 vs. 1.00) compared with an FPG of 140 mg/dl, and it had a higher specificity (0.97 vs. 0.82) with the same accuracy (0.80) as an FPG of 113 mg/dl. Third, the DM group showed the lowest IsIx among the three groups at all FPG values. The AUCIns in the DM group increased along with FPG, reached the maximum level at an FPG of 110 mg/dl, and declined thereafter. AUCIns was higher in the DM group than in the NGT group at FPG values > or = 100 mg/dl. CONCLUSIONS: The revised ADA criterion for FPG of 126 mg/dl may improve diagnostic sensitivity without loss of specificity in Japanese diabetic subjects when compared with an FPG criterion of 140 mg/dl. Although early insulin secretion was impaired, total insulin secretion did not seem to be reduced in newly diagnosed Japanese diabetic subjects.

Adult↗
PubMed1998

[Recent advances in endoscopic mucosal resection for early gastric cancer].

Our indications of endoscopic mucosal resection (EMR) for early gastric cancer (EGC) as a radical treatment are as follows: 1) histology: intestinal type; 2) macroscopic type: IIa and IIc; 3) without ulcerative change. We do not put restrictions on the size of the lesion. EMR is performed on lesions which are suspected to have submucosal invasion for a diagnostic purpose. The ratio of EMR cases to the total EGC cases is increasing in recent years and amounted to about 40% of EGCs treated at the National Cancer Center Hospital in '96. From '87-'96, we had 440 cases of EGCs (intestinal type, histologically) at the National Cancer Center Hospital and National Cancer Center Hospital East. Eighty-five cases (19.3%) turned out to have submucosal invasion and judged non-curative resection. The overall rate of cut-end-free cases was 72.3%, while the overall rate of curative resection (excluding cases with submucosal invasion) was 63.0%. Though we had 37 cases of recurrence after EMR, there were no cases of death from the original disease with additional treatment or observation (due to complication or age). The cut-end-free rates of each period ('87-'90, '91-'93, '94-'96) were 53.1%, 61.3% and 81.6%, respectively. The mean diameter of the lesion of each period became larger, at 11.9 mm, 12.0 mm and 14.0 mm, respectively. To resect a larger lesion in one piece, we began EMR with cutting the mucosa around the lesion using a newly improved endoscopic device called an insulation-tipped diathermic knife (IT knife) from '95. With this IT knife, we could resect 75% of the lesions sized 11-20 mm in one piece, while we could resect 29% with the conventional method (strip biopsy). Though the results of EMR are improving in recent years, new endoscopic technics of EMR to resect easily and surely are expected.

Adenocarcinoma↗
PubMed1998

Biological markers as a predictor for response and prognosis of unresectable gastric cancer patients treated with 5-fluorouracil and cis-platinum.

We investigated the utility of examining biological markers to predict chemoresponse and survival. The subjects consisted of 39 unresectable gastric cancer patients treated with a combination of 5-fluorouracil and cis-platinum. The expression of p53, bcl-2, thymidylate synthase (TS), glutathione S-transferase pi (GST-pi), and vascular endothelial growth factor (VEGF) in the formalin-fixed biopsy samples of primary tumors before chemotherapy was examined immunohistochemically. The positive rate for VEGF, bcl-2, TS, p53, and GST-pi was 51, 10, 46, 38, and 69%, respectively. VEGF-positive cases showed a higher response rate than did negative cases (11 of 20 versus 2 of 19 cases; P = 0.0057). The cases that were negative for p53, TS, bcl-2, and GST-pi were more likely to respond to chemotherapy than the cases that were positive for these markers. The 10 cases having 4 or 5 favorable phenotypes (VEGF positive, p53 negative, bcl-2 negative, TS negative, and GST-pi negative) survived longer than the remaining 29 cases (P = 0.0069). Multivariate analysis revealed that the number of favorable phenotypes (> or = 4 versus < or = 3) had a greater impact on survival than performance status (0 versus 1 or 2), age (> 60 years versus < or = 60 years), macroscopic type (scirrhous versus nonscirrhous), histological type (intestinal versus diffuse), or tumor extent (locally advanced versus metastatic). Immunohistochemical examination of biological markers in biopsy samples may be useful in predicting the clinical outcome of unresectable gastric cancer patients treated with 5-fluorouracil and cis-platinum.

Adult↗
PubMed1997

Gene therapy for peritoneal dissemination of pancreatic cancer by liposome-mediated transfer of herpes simplex virus thymidine kinase gene.

Peritoneal dissemination is one of the most common complications of the malignancies of the digestive system, such as gastric or pancreatic cancers. Yet, no effective therapy has been established so far to alleviate this devastating and often fatal end-stage condition. Here we describe a novel approach of intraperitoneal (i.p.) lipofection of a suicidal gene to the pancreatic cancer cells in a mouse peritoneal dissemination model. A human pancreatic cancer cell line, PSN-1, was inoculated into the peritoneal cavity of nude mice. Eight days later, a herpes simplex virus thymidine kinase (HSV-TK) gene expression plasmid under a potent hybrid promoter CAG was injected as a DNA-lipopolyamine complex. Ganciclovir (GCV) was then administered for 8 days, and the mice were examined for tumor development at the 24th day after the tumor inoculation. Although all 24 control mice showed macroscopic peritoneal dissemination and solid tumors on the pancreas, 8 of the 14 mice treated with HSV-TK and GCV were free of tumors, and only a few small tumors were observed in the remaining 6 mice. Treatment-related toxicity was not observed. The semiquantitative reverse transcription polymerase chain reaction (RT-PCR) analysis suggested that the HSV-TK transgene was expressed in about 10% of tumor cells but not in the normal pancreas or in the small intestine. When the lacZ gene was transduced in place of the HSV-TK gene, the blue-stained cells were identified only in tumor nodules and not in normal organs. This preclinical study suggests the therapeutic feasibility of the i.p. lipofection-based suicidal gene/prodrug strategy for peritoneal dissemination of pancreatic cancer.

Animals↗
PubMed1997

Detection of K-ras gene mutations at codon 12 in the pancreatic juice of patients with intraductal papillary mucinous tumors of the pancreas.

BACKGROUND: The authors previously found specific mutations of the K-ras gene at codon 12 in the pancreatic juice of 67% of patients (6 of 9) with pancreatic ductal carcinoma, and the detection of these mutations was useful for diagnosis. This study was performed to detect and evaluate K-ras mutations in pancreatic juice from patients with intraductal papillary mucinous tumor of the pancreas, which is considered a low grade malignancy. The results were interpreted from the viewpoint of clinical significance. METHODS: K-ras mutations were examined using seminested polymerase chain reaction analysis combined with restriction enzyme digestion, followed by nonradioisotopic single strand DNA conformation polymorphism. RESULTS: Twelve of thirteen cases (92%) of intraductal papillary mucinous tumor of the pancreas, confirmed histologically (9 adenomas and 4 carcinomas), and 26 of 43 cases (60%) of ductal carcinoma showed specific K-ras gene mutations in the pancreatic juice. Furthermore, 4 of 22 patients (18%) with chronic pancreatitis, followed for more than 1 year without a sign of pancreatic tumor, showed K-ras mutations. In contrast, no mutations of the K-ras gene were detected in the pancreatic juice from 28 normal controls. CONCLUSIONS: K-ras mutations were found in the pancreatic juice of all but one patient with intraductal papillary mucinous tumor of the pancreas, but they were not useful for distinguishing carcinoma from adenoma. The authors concluded that K-ras mutations are not a specific marker for pancreatic neoplasms because similar mutations were detected in the pancreatic juice from patients with chronic pancreatitis. At the present time, the detection of K-ras mutations in pancreatic juice should be used clinically as an adjunct diagnostic modality for pancreatic diseases.

Adenocarcinoma, Mucinous↗
PubMed1997

Muscle histopathology in diabetes mellitus associated with mitochondrial tRNA(Leu(UUR)) mutation at position 3243.

Diabetes mellitus associated with 3243 mitochondrial tRNA(Leu(UUR)) mutation (DM-Mt3243) is a subtype of the mitochondrial multisystem syndromes, usually lacking myopathy. Muscle biopsies were obtained from 5 patients with diabetes and one patient with impaired glucose tolerance, all possessing the 3243 mutation without hallmarks of MELAS. The specimens were subjected to histochemical, biochemical, and genetic analysis. Ragged-red fibers were seen in 4 of the 6 patients (67%), and focal cytochrome c oxidase deficiency in 3 (50%). Strongly succinate dehydrogenase-reactive blood vessels was found in 5 patients (83%). The histochemical signs were present even when the mutant percentage was very low. The percentage of mutant DNA was almost always higher in muscles than in leukocytes. The combination of allele specific PCR amplification and PCR-RFLP method was useful to evaluate the mutant proportion. The mutant percentage in muscle was under 50% in 5 (83%) patients. Mitochondrial enzyme activity was deficient only in one patient. This study presents the detailed muscle histopathology in the DM-Mt3243 group. Abnormal histopathologic findings seemed similar to those noted in MELAS. However, mutant percentage in muscles was lower than that of MELAS, and respiratory chain enzyme activity was well preserved.

Acidosis, Lactic↗
PubMed1997

Diabetes mellitus associated with the 3243 mitochondrial tRNA(Leu)(UUR) mutation: insulin secretion and sensitivity.

To investigate the pathophysiology of diabetes mellitus associated with the 3243 mitochondrial tRNA(Leu)(UUR) mutation (DM-Mt3243), insulin secretion and sensitivity were studied using the 75-g oral glucose tolerance test (oGTT), 1-mg intravenous glucagon test, and euglycemic glucose clamp test. Twelve DM-Mt3243 patients were investigated (seven men and five women). Their ages ranged from 36 to 74 years, and the onset of diabetes occurred at 44.5 +/- 9.5 years (mean +/- SD). In the glucose tolerance test, nine patients (75.0%) showed lower C-peptide reactivity (CPR) than normal at 30 minutes, suggesting blunted insulin secretion. Three patients showed an impaired glucose tolerance (IGT) pattern, although they had absolute hyperglycemia at the onset of diabetes. In the glucagon test, 10 patients (76.3%) had CPR within the normal range at 6 minutes, indicating an adequate response. In the glucose clamp test, the M value was 8.70 +/- 2.35 mg/kg/min and was within normal limits in all patients. The glucose metabolized (M value) was negatively correlated with 24-hour urinary C-peptide excretion (r = .696, P < .05). Thus, plasma CPR to glucose loading was blunted in many DM-Mt3243 patients, but CPR to glucagon was relatively well preserved. This difference in the intrinsic insulin response to the two stimuli may be characteristic of DM-Mt3243. Although M values were normal in all subjects, the correlation with 24-hour urinary C-peptide excretion suggests a relationship between insulin sensitivity and insulin secretion. These two mechanisms may cooperate to maintain homeostasis in this disease. Since three patients did not progress with aging, this mutation may not always cause gradual beta-cell destruction.

Adult↗
PubMed1997

Diabetes mellitus associated with 3243 mitochondrial tRNA(Leu(UUR)) mutation: clinical features and coenzyme Q10 treatment.

Diabetes mellitus associated with mitochondrial tRNA mutation at position 3243(DM-Mt3243) is a new disease. Patients have a distinctly different picture from MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes). During observations at the Saiseikai Central Hospital, the following findings were noted in DM-Mt3243 patients: DM-Mt3243 patients are diagnosed earlier with diabetes, compared to NIDDM (non-insulin dependent diabetes mellitus) controls without family history. DM-Mt3243 patients often need insulin more often than NIDDM controls without family history. Post-treatment neuropathy and insulin edema are often found in DM-Mt3243, and the two phenomena possibly have a similar pathophysiology related to mitochondrial dysfunction. Ambiguous psychiatric disorders of functional psychosis are observed frequently in DM-Mt3243. Mild headache is common in DM-Mt3243 cases. Ambiguous neuromuscular abnormalities such as sleep disturbance, paresthesia of the legs, edema of the legs, and palpitation may be symptoms associated with mitochondrial dysfunction in DM-Mt3243. Coenzyme Q may be effective in the relief of these neuromuscular symptoms.

Adult↗
PubMed1997

Prevalence of human herpesvirus-8 in skin lesions.

A putative new herpesvirus, designated Kaposi's sarcoma-associated herpesvirus (KSHV) or human herpesvirus-8 (HHV-8) was recently identified in AIDS-related Kaposi's sarcoma. The DNA sequence of the virus is homologous to the gamma-herpesviruses such as herpesvirus Saimiri or Epstein-Barr virus, both of which are tumorigenic, suggesting that this new virus may also be oncogenic. Thus, we determined whether the virus is present in other skin lesions. DNA samples from 118 skin specimens were tested for the HHV-8 sequence by polymerase chain reaction (PCR) and Southern hybridization. The sequences were detected in 13 of 21 samples from Bowen's disease, three of 11 squamous cell carcinomas, three of 11 actinic keratoses, three of seven leucoplakia, one of six from Paget's disease, one of 12 malignant melanoma, one of seven neurofibromas, two of seven chronic dermatites and one of 14 normal skin samples. On sequencing the PCR products, new mutation points were detected. These results suggest that the virus is associated with lesions other than Kaposi's sarcoma and may be more widespread than expected (with a latent level too low to be detected), like the other herpesviruses. Some lesions. e.g. in Bowen's disease or squamous cell carcinoma, may be locally immunosuppressed, allowing the virus to replicate until the copy number is sufficient for detection.

Adolescent↗
PubMed1997

Quantitative morphology of Auerbach's plexus in rat intestinal wall undergoing ischemia.

To clarify the causes of abnormal peristalsis after free jejunum transplantation, the authors focused on Auerbach's plexus inducing peristalsis, and conducted an experimental study to investigate the relationship between the morphologic changes and intestinal ischemic time. Results showed that the sectional area per one ganglion cell was reduced statistically significantly at 2 and 4 hr of ischemic time, and subsequently remained almost constant. Therefore, it was assumed that atrophy of the ganglion cells might occur and might effect abnormal peristalsis.

Animals↗