A case study of adult T-cell lymphoma in a kidney transplant patient.
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Adult↗
Biomedical subjects
T Hanafusa
Publications and source records attributed to T Hanafusa.
Experimental incineration of low level radioactive samples.
To determine the volume reduction potential for incineration of radioactivity in low-level radioactive waste, an incineration experiment was performed at the Okayama University Radioisotope Center (OURIC). Solid low-level radioactive samples (LLRS) were prepared for 15 routinely used radionuclides (45Ca, 1251, 32p, 33p, 35S, 59Fe, 123I, 131I, 67Ga, 99mTc, 111In, 3H, 14C, 51Cr, and 201Tl). For each radionuclide, incinerated one at a time, the smoke duct radioisotope concentration was less than 1/10 of the regulatory concentration limit (The Japanese law concerning prevention of radiation hazard due to radioisotopes, etc.). The radionuclide-containing combustible and semi-combustible LLRS were incinerated at the AP-1 50R furnace erected at OURIC, and the distribution of radioactivity inside and outside the furnace was measured. In the experimental incineration of LLRS containing these 15 radionuclides, the fractions released (RF) in the gas phase of the final smoke duct ranged from 0.165 to 0.99. The radioactivities remaining in the incineration residue were 99mTc, 87%; 59Fe, 83.1%; 45Ca, 75%; 51Cr, 62.1%; 33P, 62.0%; 32P, 61.1%; 67Ga, 57.7%; 35S, 26.0%; 111In, 21.1%; 201Tl, 16.6%; 123I, 11.9%; 131I, 8.2%; 125I, 2.4%; 14C, 0.39%; 3H, 0.04%. In the incineration of LLR S containing 35S, the rate of adhesion to the furnace wall was lower at high-temperature (809 degrees C) incineration than at low-temperature (376 degrees C) incineration. For LLRS containing one of the three radioiodines, 123I, 125I, or 131I, no such difference was observed between low (372 degrees C) and high (827 degrees C) temperature incineration (RF varied from 0.82 to 0.94).
Incineration↗
Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients.
Adiponectin is a novel, adipose-specific protein abundantly present in the circulation, and it has antiatherogenic properties. We analyzed the plasma adiponectin concentrations in age- and body mass index (BMI)-matched nondiabetic and type 2 diabetic subjects with and without coronary artery disease (CAD). Plasma levels of adiponectin in the diabetic subjects without CAD were lower than those in nondiabetic subjects (6.6+/-0.4 versus 7.9+/-0.5 microg/mL in men, 7.6+/-0.7 versus 11.7+/-1.0 microg/mL in women; P<0.001). The plasma adiponectin concentrations of diabetic patients with CAD were lower than those of diabetic patients without CAD (4.0+/-0.4 versus 6.6+/-0.4 microg/mL, P<0.001 in men; 6.3+/-0.8 versus 7.6+/-0. 7 microg/mL in women). In contrast, plasma levels of leptin did not differ between diabetic patients with and without CAD. The presence of microangiopathy did not affect the plasma adiponectin levels in diabetic patients. Significant, univariate, inverse correlations were observed between adiponectin levels and fasting plasma insulin (r=-0.18, P<0.01) and glucose (r=-0.26, P<0.001) levels. In multivariate analysis, plasma insulin did not independently affect the plasma adiponectin levels. BMI, serum triglyceride concentration, and the presence of diabetes or CAD remained significantly related to plasma adiponectin concentrations. Weight reduction significantly elevated plasma adiponectin levels in the diabetic subjects as well as the nondiabetic subjects. These results suggest that the decreased plasma adiponectin concentrations in diabetes may be an indicator of macroangiopathy.
Adiponectin↗
Stable overexpression of the glucose-6-phosphatase catalytic subunit attenuates glucose sensitivity of insulin secretion from a mouse pancreatic beta-cell line.
Glucose-6-phosphatase (G-6-Pase) hydrolyzes glucose-6-phosphate to glucose, reciprocal with the so-called glucose sensor, glucokinase, in pancreatic beta cells. To study the role of G-6-Pase in glucose-stimulated insulin secretion from beta cells, we have introduced rat G-6-Pase catalytic subunit cDNA and have established permanent clones with 3-, 7- and 24-fold G-6-Pase activity of the mouse beta-cell line, MIN6. In these clones, glucose usage and ATP production in the presence of 5.5 or 25 mM glucose were reduced, and glucose-stimulated insulin secretion was decreased in proportion to the increased G-6-Pase activity. In addition, insulin secretory capacity in response to d-fructose and pyruvate was unchanged; however, 25 mM glucose-stimulated insulin secretion and intracellular calcium response were completely inhibited. In the clone with 24-fold G-6-Pase activity, changes in intracellular NAD(P)H autofluorescence in response to 25 mM glucose were reduced, but the changes with 20 mM fructose and 20 mM pyruvate were not altered. Stable overexpression of G-6-Pase in beta cells resulted in attenuation of the overall glucose-stimulated metabolic responses corresponding to the degree of overexpression. This particular experimental manipulation shows that the possibility exists of modulating glucose-stimulated insulin release by thoroughly altering glucose cycling at the glucokinase/G-6-Pase step.
Adenosine Triphosphate↗
Recombinant human betacellulin promotes the neogenesis of beta-cells and ameliorates glucose intolerance in mice with diabetes induced by selective alloxan perfusion.
Betacellulin (BTC), a member of the epidermal growth factor family, is expressed predominantly in the human pancreas and induces the differentiation of a pancreatic acinar cell line (AR42J) into insulin-secreting cells, suggesting that BTC has a physiologically important role in the endocrine pancreas. In this study, we examined the in vivo effect of recombinant human BTC (rhBTC) on glucose intolerance and pancreatic morphology using a new mouse model with glucose intolerance induced by selective alloxan perfusion. RhBTC (1 microg/g body wt) or saline was injected subcutaneously every day from the day after alloxan treatment. The intraperitoneal glucose tolerance test revealed no difference between rhBTC-treated and rhBTC-untreated glucose-intolerant mice at 2-4 weeks. However, glucose tolerance was significantly improved and body weight was significantly increased in rhBTC-treated mice compared with untreated mice at 8 weeks. Islet-like cell clusters, consisting mainly of beta-cells, were increased in the pancreas and were localized in contact with the ductal lining cells and sometimes with acinar cells. In conclusion, administration of rhBTC improved glucose tolerance in this mouse model by increasing beta-cell volume, primarily through accelerated neogenesis from ductal lining cells.
Animals↗
A proposal of three distinct subtypes of type 1 diabetes mellitus based on clinical and pathological evidence.
To better understand the pathogenesis of type 1 diabetes, our group performed a pathological examination on the pancreas tissue of recent-onset type 1 diabetics and analysed their clinical characteristics. These studies led us to speculate that there are three distinct subtypes of type 1 diabetes mellitus: autoimmune, nonautoimmune fulminant and nonautoimmune nonfulminant (or nonautoimmune chronic). The autoimmune type 1 diabetes mellitus comprises about 60% of the patients and is characterized by insulitis and over-expression of class I MHC molecules in the islet cells, a high prevalence of diabetes-related autoantibodies, and a progressive loss of beta-cell function after the onset of diabetes. The nonautoimmune nonfulminant type 1 diabetes mellitus includes about 30% of the patients, shows neither insulitis nor over-expression of class I MHC antigen in the islet cells, and has a low prevalence of diabetes-related autoantibodies and a relatively slow progression of beta-cell loss after the onset of diabetes. The nonautoimmune fulminant type 1 diabetes comprises about 10% of patients and shows neither insulitis nor over-expression of class I MHC molecules, but is characterized by lymphocytic infiltration in the exocrine pancreatic tissue, elevated serum pancreatic enzyme levels, absence of diabetes-related autoantibodies and a remarkably aggressive course of disease. The appropriate classification of type 1 diabetes would increase our understanding of the pathogenesis of the disease and would allow to develop therapeutic means based on this understanding.
Autoantibodies↗
[Insulin resistance and cytokine, cytokine receptor].
Insulin resistance is associated with many common diseases including diabetes mellitus, hyperlipidemia and hypertension, and plays an important role for determining their clinical courses. Obesity is a multifactorial syndrome characterized by an excessive adipose tissue accumulation, and is associated with acquired insulin resistance. Adipose tissue, acting as one of the endocrine organs, has been revealed to produce and secrete some bioactive molecules, "adipocytokines", which regulate cell growth and/or metabolic pathways. Tumor necrosis factor(TNF)-alpha is also synthesized by adipocytes, and is involved in the expression of peripheral insulin resistance. This review deals with molecular mechanisms of the TNF/TNF receptor system promoting insulin resistance, and its prevention by the insulin-sensitizing drugs, thiazolidinediones.
Adipocytes↗
[PPARs, cancer cells and inflammation].
The peroxisome proliferator-activated receptor-gamma (PPAR gamma) is a ligand-dependent nuclear receptor that has been implicated in the modulation of aspects of development and homeostasis, including adipocyte differentiation and glucose metabolism. Recent reports indicate that PPAR gamma is also expressed at significant level in several other tissues, including macrophages, monocytes and aortic smooth muscle and cancer cells. In this point of view, PPARs are susceptible to mediated the modulation of immune cell activation and tumor cell differentiation. If a major role for PPARs in tumor cell differentiation is manifested, PPARs may also provide a link between nutrition and certain types of cancers.
Animals↗
[A case of mumps pneumonia complicated with acute respiratory failure].
A 38-year-old male with swollen parotid glands was admitted to our hospital with dyspnea on effort. Positive serum IgM antibody for mumps supported a diagnosis of mumps. Computed tomography (CT) scan showed a ground-glass appearance in both lower lungs. On the third day of hospitalization, bronchoalveolar lavage demonstrated an elevation of both the total cell (2.0 x 10(6)/cc) and the lymphocyte count (83%), as well as a decrease of the CD 4+/CD 8+ ratio (0.4). Bronchial biopsy specimens revealed infiltration of lymphocytes in both the bronchiolar walls and the alveolar septa. These data were suggestive of mumps pneumonia. The patients suffered acute respiratory failure on the seventh day of hospitalization, which improved after 3 days of high-dose methyl prednisolone therapy. This is the first report of adult mumps pneumonia in Japan. As a result of the examination of the bronchoalveolar lavage and a bronchial biopsy of viral pneumonia which had been reported in the past, mumps pneumonia was a corresponding opinion to other viral pneumonia.
Acute Disease↗
[Thyroid crises and myxedema crises].
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Emergencies↗
Structure/function studies of hepatocyte nuclear factor-1alpha, a diabetes-associated transcription factor.
Mutations in the transcription factor hepatocyte nuclear factor-1alpha (HNF-1alpha) cause maturity-onset diabetes of the young type 3 (MODY3), a form of diabetes mellitus characterized by autosomal dominant inheritance, early onset, and pancreatic beta-cell dysfunction. We have examined the effects of five diabetes-associated mutations (L12H, G191D, R263C, P379fsdelCT, and L584S585fsinsTC) on HNF-1alpha function including DNA binding ability, intracellular localization, and transactivation activity. L12H, P379fsdelCT, and L584S585fsinsTC mutations were found in patients with a clinical diagnosis of MODY, while G191D and R263C mutations were identified in patients diagnosed with type 2 diabetes. These mutations had diverse effects on the functional properties of HNF-1alpha. Comparison of the functional data with clinical information suggested that transactivation activity of mutant HNF-1alpha in beta cells like MIN6 may be the primary determinants of the phenotypic differences observed among diabetic patients with HNF-1alpha mutations.
Adolescent↗
Human insulin gene is a target gene of hepatocyte nuclear factor-1alpha (HNF-1alpha) and HNF-1beta.
Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes characterized by autosomal dominant inheritance, early-onset, and impaired insulin secretion. The type 3 and type 5 forms of MODY result from mutations in the genes encoding the transcription factor, hepatocyte nuclear factor (HNF)-1alpha and HNF-1beta, respectively. The mechanism by which mutations in one allele of the HNF-1 gene impair pancreatic beta cell function is unclear. We studied the effects of wild-type and four mutant (L12H, R263C, P379fsdelCT, and L584S585fsinsTC) HNF-1alpha, which were identified in Japanese subjects with MODY3 on human insulin gene transcription. Both wild-type (WT) HNF-1alpha and HNF-1beta bound to the oligonucleotide containing the A3 element sequence in the human insulin promoter and transactivated the insulin-luciferase reporter gene by 30- and 31-fold, respectively. In contrast, binding of L12H, R263C and L584S585fsinsTC-HNF-1alpha to the probe was impaired. Transactivation activity by the four mutant HNF-1alpha was reduced (4.3 to 43.3% of WT). These data suggest that the insulin gene is a candidate target gene of HNF-1alpha/HNF-1beta and the impairment of insulin gene transcription by mutations in the HNF-1 gene might be involved in the pathogenesis of MODY.
Animals↗
Replication of hepatitis B virus which carries foreign DNA in vitro.
Targeting a specific DNA sequence to the desired tissues is an important step in gene therapy. The hepatitis B virus (HBV) is the only DNA virus that has hepatocyte specificity. We attempted to construct an HBV-based vector for targeting the liver. We observed the replication and secretion of virus particles in an HBV construct that lacks X gene and carries an extra 63 bp DNA fragment in vitro. Replication was observed in the cell line HuH-7 but not HepG2. From this construct, we designed an HBV-based vector that could carry foreign DNA. HBV based vectors provide for the possibilities of generating therapeutic agents for individual patients. Our host vector system may be used to clear out the HBV from the HBV carrier or chronic hepatitis B patients by introducing a genetically engineered HBV into these patients.
Base Sequence↗
Immunological abnormalities in islets at diagnosis paralleled further deterioration of glycaemic control in patients with recent-onset Type I (insulin-dependent) diabetes mellitus.
AIMS/HYPOTHESIS: To determine whether the clinical heterogeneity observed in the development of Type I (insulin-dependent) diabetes mellitus correlates with immunohistochemical differences observed at diagnosis. METHODS: Patients (n = 17) with recent-onset diabetes clinically considered to be insulin dependent (Type I), underwent pancreatic biopsy for immunohistological analysis. These patients were divided into two groups based on the presence or absence of islet immunological abnormalities (insulitis or hyperexpression of MHC class I antigens or both). The patients were also HLA typed and tested for islet cell antibodies and antibodies to glutamic acid decarboxylase (GAD-Ab). All patients were followed monthly for 2 years and their fasting plasma glucose, haemoglobin A1c and daily insulin doses were recorded. The clinical course of patients with islet immunological abnormalities was compared with that of patients without those abnormalities. RESULTS: Patients with and without islet immunological abnormalities did not differ with regard to HLA type or islet cell antibodies. Antibodies to glutamic acid decarboxylase correlated with the presence of insulitis and MHC class I hyperexpression. These local immunological abnormalities were also associated with higher haemoglobin A1c values (p < 0.05) and a trend towards greater insulin requirements. Further, patients with the islet abnormalities had higher fasting plasma glucose concentrations 2 years after the biopsy than at the time of the biopsy (p < 0.05). CONCLUSION/INTERPRETATION: The heterogeneous clinical course observed following diagnosis in patients with Type I diabetes correlates with islet immunological abnormalities. Insulitis and hyperexpression of MHC class I correlate with deteriorating glycaemic control.
Adolescent↗
Three new mutations in the hepatocyte nuclear factor-1alpha gene in Japanese subjects with diabetes mellitus: clinical features and functional characterization.
AIMS/HYPOTHESIS: Mutations in the hepatocyte nuclear factor-1alpha gene are a common cause of the type 3 form of maturity-onset diabetes of the young. We examined the clinical features and molecular basis of hepatocyte nuclear factor-1alpha (HNF-1alpha) diabetes. METHODS: Thirty-seven Japanese subjects with early onset Type II (non-insulin-dependent) diabetes mellitus and 45 with Type I (insulin-dependent) diabetes mellitus were screened for mutations in this gene. Functional properties of mutant HNF-1alpha were also investigated. RESULTS: Three new mutations [G415R, R272C and A site of the promoter (+ 102G-to-C)] were found. Insulin secretion was impaired in the three subjects. Insulin and glucagon secretory responses to arginine in the subject with the R272C mutation were also diminished. Molecular biological studies indicated that the G415R mutation generated a protein with about 50% of the activity of wild-type HNF-1alpha. The R272C mutation had no transactivating or DNA binding activity and acted in a dominant negative manner. The + 102 G-to-C mutation in the A site of the promoter activity was associated with an increase in promoter activity and it had 42-75% more activity than the wild-type sequence. CONCLUSION/INTERPRETATION: Mutations in the HNF-1alpha gene may affect the normal islet function by different molecular mechanisms.
Adult↗
Augmented growth response to IGF-1 via increased IRS-1 in Chinese hamster ovary cells expressing kinase-negative insulin receptors.
AIMS/HYPOTHESIS: Although both increased cell growth and impaired insulin signalling have been associated with diabetes, this association has not been investigated. Insulin-like growth factor-1 (IGF-1), a structural and functional analog of insulin, may play a part in the aberrant insulin receptor-mediated signalling observed in diabetes. METHODS: To investigate the consequence of this impaired signalling on cell proliferation and transformation, we transfected Chinese hamster ovary cells with cDNA encoding a kinase-defective insulin receptor. RESULTS: In these mutant cells, the mitogenic and metabolic effects of insulin were reduced compared with control cells (p < 0.05) and this was due to a dominant negative effect. In contrast, these mutant cells showed a higher mitogenic response to IGF-1 than control cells, although IGF-1 receptor expression was similar in both cell lines. There was no statistically significant difference in mitogenic response, however, to platelet-derived growth factor, basic fibroblast growth factor and heparin-binding epidermal growth factor-like growth factor. Variables of the IGF-1 signalling pathway, including tyrosine phosphorylation of insulin receptor substrate-1 and activation of mitogen-activated protein kinase and phosphatidyl inositol 3 kinase, were also augmented in mutant cells. Insulin receptor substrate-1 message and protein abundance were higher in mutant than in control cells. Moreover, mutant cells had a higher mitogenic potential in low-serum-containing medium, suggesting that these cells have a transformed phenotype. CONCLUSION/INTERPRETATION: These findings suggest that an impaired insulin signalling may upregulate insulin receptor substrate-1 and that this, in turn, leads to increased IGF-1 signalling, a phenomenon that is possibly associated with increased cell growth in diabetes.
Adaptor Proteins, Signal Transducing↗
Fas and Fas ligand expression in inflamed islets in pancreas sections of patients with recent-onset Type I diabetes mellitus.
AIMS/HYPOTHESIS: Type I (insulin-dependent) diabetes results mainly from T-cell-mediated autoimmune destruction of pancreatic beta cells. Cytotoxic T lymphocytes destroy target cells via a perforin-based or Fas-based mechanism. Our previous study indicated that the Fas-Fas ligand (FasL) pathway is required for the development of autoimmune diabetes in the NOD mouse. We now investigated whether or not the Fas-FasL system is involved in the beta-cell destruction in human Type I diabetes. METHODS: We immunohistochemically analysed pancreas biopsy specimens of 13 recent-onset patients. RESULTS: Pancreatic islets were identified but showed various degrees of reduction in beta-cell volume in all patients. Out of 13 patients 6 had insulitis. In these 6 patients Fas was expressed in both the islets and infiltrating cells but not in either cell type in the 7 other patients without insulitis. Double immunostaining showed that Fas was positive in 92.2 to 97.7 % of beta cells but only in 17.6 to 46.7 % of alpha cells in Fas-positive, insulin-remaining islets. We found FasL was expressed exclusively in islet-infiltrating cells in patients with insulitis. Double immunostaining revealed that the most prevalent phenotype of FasL-positive cells was CD8, which was followed by macrophages and CD4. CONCLUSION/INTERPRETATION: The interaction between Fas on beta cells and FasL on infiltrating cells might trigger selective apoptotic beta-cell death in inflamed islets, leading to immune-mediated Type I diabetes. [Diabetologia (1999) 42: 1332-1340]
Adolescent↗
Different expression patterns of nitric oxide synthase isozymes in various gynecological cancers.
The expression of nitric oxide synthase (NOS) in human gynecological cancers, including ovarian cancers, uterocervical cancers, and endometrial cancers for example, was examined by the reverse transcriptase/polymerase chain reaction, coupled with Southern hybridization and by immunohistochemistry. Nitric oxide synthase II (NOS II), an inducible form, was expressed in more than 90% of the cancers. Nitric oxide synthase I (NOS I), a neuronal form, was expressed in 58% of all the ovarian cancers, in which the serous type is found more frequently (5 out of 7) than the mucinous type (2 out of 6), and in all clear-cell cancers. The frequency of NOS I expression in uterocervical cancers and endometrial cancers was relatively low. Nitric oxide synthase III (NOS III), an endothelial form, was detected in 25% of ovarian and 33% of endometrial cancers, while no expression was detected in uterocervical cancers. In terms of cancer types, all clear-cell adenocarcinomas and most of the serous-type adenocarcinomas expressed both NOS I and NOS II, while most uterine squamous carcinomas and endometrial adenocarcinomas expressed only NOS II. However, there was no correlation between the frequency of NOS expression and patients' age or the clinical stage of the disease. Since NO increases vascular permeability and blood flow, the high frequency of NOS expression in gynecological cancers may serve to stimulate and promote tumor growth.
Blotting, Southern↗