Biomedical subjects
Publications and source records attributed to H Furuta.
A 68 year-old woman underwent replacement of the descending thoracic aorta with a cryopreserved aortic homograft for the treatment of a Stanford B dissecting aneurysm. After surgery, the patient made an uneventful recovery without recurrent infection. In such cases, the use of aortic homografts to replace aortic segments is a promising and effective therapeutic option.
Maturity-onset diabetes of the young (MODY) is a genetically heterogeneous monogenic disorder characterized by autosomal dominant inheritance, onset usually before 25 yr of age, and abnormal pancreatic beta-cell function. Mutations in the hepatocyte nuclear factor(HNF)-4alpha/MODY1, glucokinase/MODY2, and HNF-1alpha/MODY3 genes can cause this form of diabetes. In contrast to the glucokinase and HNF-1alpha genes, mutations in the HNF-4alpha gene are a relatively uncommon cause of MODY, and our understanding of the MODY1 form of diabetes is based on studies of only a single family, the R-W pedigree. Here we report the identification of a second family with MODY1 and the first in which there has been a detailed characterization of hepatic function. The affected members of this family, Dresden-11, have inherited a nonsense mutation, R154X, in the HNF-4alpha gene, and are predicted to have reduced levels of this transcription factor in the tissues in which it is expressed, including pancreatic islets, liver, kidney, and intestine. Subjects with the R154X mutation exhibited a diminished insulin secretory response to oral glucose. HNF-4alpha plays a central role in tissue-specific regulation of gene expression in the liver, including the control of synthesis of proteins involved in cholesterol and lipoprotein metabolism and the coagulation cascade. Subjects with the R154X mutation, however, showed no abnormalities in lipid metabolism or coagulation except for a paradoxical 3.3-fold increase in serum lipoprotein(a) levels, nor was there any evidence of renal dysfunction in these subjects. The results suggest that MODY1 is primarily a disorder of beta-cell function.
The prohormone convertase SPC2 (PC2) participates in the processing of proinsulin, proglucagon, and a variety of other neuroendocrine precursors, acting either alone or in conjunction with the structurally related dense-core granule convertase SPC3 (PC3/PC1). We have generated a strain of mice lacking active SPC2 by introducing the neomycin resistance gene (Neor) into the third exon of the mSPC2 gene. This gene insertion results in the synthesis of an exon 3-deleted form of SPC2 that does not undergo autoactivation and is not secreted. The homozygous mutant mice appear to be normal at birth. However, they exhibit a small decrease in rate of growth. They also have chronic fasting hypoglycemia and a reduced rise in blood glucose levels during an intraperitoneal glucose tolerance test, which is consistent with a deficiency of circulating glucagon. The processing of proglucagon, prosomatostatin, and proinsulin in the alpha, delta, and beta cells, respectively, of the pancreatic islets is severely impaired. The islets in mutant mice at 3 months of age show marked hyperplasia of alpha and delta cells and a relative diminution of beta cells. SPC2-defective mice offer many possibilities for further delineating neuroendocrine precursor processing mechanisms and for exploring more fully the physiological roles of many neuropeptides and peptide hormones.
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The active form of vitamin B12 (methylcobalamin) has been reported to be effective on sleep-wake rhythm disorders. Previous studies, however, were performed under open trial, and the effect of vitamin B12 has not been properly evaluated. The aim of this double-blind study was to investigate the efficacy of methylcobalamin on delayed sleep phase syndrome (DSPS). Methylcobalamin (3 mg/day) or placebo was administered for 4 weeks. The subjects were 50 patients with DSPS aged 13-55 years (26.8 +/- 1.3), 27 of whom received the active drug while 23 received the placebo. No significant differences were observed between the 2 groups in subjective evaluations of mood or drowsiness during the daytime or in night sleep by sleep-log evaluation. These results indicate that 3 mg methylcobalamin administered over 4 weeks is not an effective treatment for DSPS.
A case of X-linked autoimmune enteropathy was successfully treated with cyclosporine A (CsA) or tacrolimus (FK506) and developed extremely high serum levels of IgE during the immunosuppressive therapy. Serum IgE levels increased from 190 to 1,000-2,500 IU/ml with CsA therapy and as high as 80,000 IU/ml with subsequent FK506 therapy. Serum IgG2 and IgG4 levels were slightly elevated compared to serum IgE levels. Thereafter, serum IgE levels progressively decreased in parallel with a reduced dosage of FK506. Total serum IgG levels and peripheral eosinophil counts, however, showed no significant changes during the course. These observations suggest that both CsA and FK506, potent immunosuppressants, could paradoxically enhance some immune responses, possibly through the action of CsA-/FK506-resistant immune systems.
Hepatocyte nuclear factor-4 alpha (HNF-4 alpha) is a member of the nuclear receptor superfamily, a class of ligand-activated transcription factors. A nonsense mutation in the gene encoding this transcription factor was recently found in a white family with one form of maturity-onset diabetes of the young, MODY1. Here, we report the exon-intron organization and partial sequence of the human HNF-4 alpha gene. In addition, we have screened the 12 exons, flanking introns and minimal promoter region for mutations in a group of 57 unrelated Japanese subjects with early-onset NIDDM/MODY of unknown cause. Eight nucleotide substitutions were noted, of which one resulted in the mutation of a conserved arginine residue, Arg127 (CGG)-->Trp (TGG) (designated R127W), located in the T-box, a region of the protein that may play a role in HNF-4 alpha dimerization and DNA binding. This mutation was not found in 214 unrelated nondiabetic subjects (53 Japanese, 53 Chinese, 51 white, and 57 African-American). The R127W mutation was only present in three of five diabetic members in this family, indicating that it is not the only cause of diabetes in this family. The remaining seven nucleotide substitutions were located in the proximal promoter region and introns. They are not predicted to affect the transcription of the gene or mRNA processing and represent polymorphisms and rare variants. The results suggest that mutations in the HNF-4 alpha gene may cause early-onset NIDDM/MODY in Japanese but they are less common than mutations in the HNF-1 alpha/MODY3 gene. The information on the sequence of the HNF-4 alpha gene and its promoter region will facilitate the search for mutations in other populations and studies of the role of this gene in determining normal pancreatic beta-cell function.
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We report an 85-year-old woman with postinfarction interventricular septal perforation. She underwent successful emergent surgical treatment by a slightly modified method based on David-Komeda's procedure. Perforation in this case occurred four days after acute myocardial infarction. Preoperative Qp/Qs was 2.58, and pulmonary artery pressure was 34/25 mmHg. The area of infarction was large, and the perforation was the linear type 2.5 cm long near the apex. A probe was not able to pass through the perforation due to its complicated configuration. A double Xenomedica patch was sutured on the left side of the interventricular septum without excising the infarcted area. The suture line was placed on healthy myocardium apart from the infarcted area. The Xenomedica patch was sandwiched between the closure line of the ventriculotomy. Four days after surgery, residual shunt was observed by echocardiogram, but this subsequently disappeared on the 17th postoperative day. The patient was discharged from our hospital on the 57th postoperative day, and is now doing quite well.
To evaluate the usefulness of the radial artery (RA) as a graft material for coronary artery bypass grafting (CABG), the histologic studies of the RA were performed. Specimens were obtained from both sides of 10 RAs during the operations. The degree of arteriosclerosis was evaluated by two methods. The one was microscopic examination by a pathologist, while the other was used by NIH Image 1.57 system. Using this system, the pathological index of arteriosclerotic change was expressed as a ratio (Rx: internal luminal area/tunica media area) of the cross section. From the pathological view the tunica media of RA was rich in smooth muscle cells and poor in elastic fiber. And there was little arteriosclerosis in this artery. The mean Rx of the proximal side of RA was 0.177 +/- 0.033 and that of the distal side was 0.258 +/- 0.132. There was no significant difference between the two, but the proximal side of the RA was slightly larger than the distal. These results showed that RA has a low grade of arteriosclerosis. This was confirmed on microscopic examination. According to these results, the RA can be expected to be a suitable bypass material for CABG.
The disease non-insulin-dependent (type 2) diabetes mellitus (NIDDM) is characterized by abnormally high blood glucose resulting from a relative deficiency of insulin. It affects about 2% of the world's population and treatment of diabetes and its complications are an increasing health-care burden. Genetic factors are important in the aetiology of NIDDM, and linkage studies are starting to localize some of the genes that influence the development of this disorder. Maturity-onset diabetes of the young (MODY), a single-gene disorder responsible for 2-5% of NIDDM, is characterized by autosomal dominant inheritance and an age of onset of 25 years or younger. MODY genes have been localized to chromosomes 7, 12 and 20 (refs 5, 7, 8) and clinical studies indicate that mutations in these genes are associated with abnormal patterns of glucose-stimulated insulin secretion. The gene on chromosome 7 (MODY2) encodes the glycolytic enzyme glucokinases which plays a key role in generating the metabolic signal for insulin secretion and in integrating hepatic glucose uptake. Here we show that subjects with the MODY3-form of NIDDM have mutations in the gene encoding hepatocyte nuclear factor-1alpha (HNF-1alpha, which is encoded by the gene TCF1). HNF-1alpha is a transcription factor that helps in the tissue-specific regulation of the expression of several liver genes and also functions as a weak transactivator of the rat insulin-I gene.
The disease maturity-onset diabetes of the young (MODY) is a genetically heterogeneous monogenic form of non-insulin-dependent (type 2) diabetes mellitus (NIDDM), characterized by early onset, usually before 25 years of age and often in adolescence or childhood, and by autosomal dominant inheritance. It has been estimated that 2-5% of patients with NIDDM may have this form of diabetes mellitus. Clinical studies have shown that prediabetic MODY subjects have normal insulin sensitivity but suffer from a defect in glucose-stimulated insulin secretion, suggesting that pancreatic beta-cell dysfunction rather than insulin resistance is the primary defect in this disorder. Linkage studies have localized the genes that are mutated in MODY on human chromosomes 20 (MODY1), 7 (MODY2) and 12 (MODY3), with MODY2 and MODY3 being allelic with the genes encoding glucokinase, a key regulator of insulin secretion, and hepatocyte nuclear factor-1alpha (HNF-1alpha), a transcription factor involved in tissue-specific regulation of liver genes but also expressed in pancreatic islets, insulinoma cells and other tissues. Here we show that MODY1 is the gene encoding HNF-4alpha (gene symbol, TCF14), a member of the steroid/thyroid hormone receptor superfamily and an upstream regulator of HNF-1alpha expression.
Complementary DNA clones encoding human hexokinase III were isolated from a liver cDNA library. There was 84.7% identity between the amino acid sequences of human and rat hexokinase III. RNA blotting showed the presence of hexokinase III mRNA in liver and lung. Fluorescence in situ hybridization localized the human hexokinase III gene (HK3) to chromosome 5, band q35.2.
Based on reactivity to antibodies against known myosin heavy chains, expression of a novel fast myosin heavy chain (MHC) gene was suspected in the thyroarytenoid (TA) muscle of the rat larynx. The 3' ends of MHC transcripts in the TA were amplified by RT-PCR using a primer to a highly conserved MHC sequence and to the poly(A) tail. The resultant products were cloned and fourteen PCR products were screened by dot-blotting with oligonucleotides specific for known skeletal muscle MHC genes. A clone that reacted weakly to the 2B oligo was sequenced and found to encode a novel fast MHC transcript, termed 2L, that appears to represent an eighth vertebrate skeletal muscle MHC gene. By homology analysis, the 2L sequence is most similar to the extraocular MHC, suggesting a possible evolutionary relationship between MHCs associated with the branchial arches.
The ATP-sensitive potassium channel of insulin-secreting pancreatic beta-cells is a complex of Kir6.2, a member of the inwardly rectifying potassium channel superfamily, and the sulfonylurea receptor. We have isolated cDNA clones encoding rat Kir6.2. Co-expression of rat Kir6.2 and sulfonylurea receptor in human embryonic kidney cells generated a potassium current with the properties of the beta-cell ATP-sensitive potassium channel. A quantitative reverse transcriptase-polymerase chain reaction assay indicated that Kir6.2 and sulfonylurea receptor mRNAs were abundantly expressed in rat islets and that expression of Kir6.2 mRNA was reduced by >70% in islets from Zucker diabetic fatty male rats, whereas there was no significant change in sulfonylurea receptor mRNA levels. Thus, decreased expression of Kir6.2 could contribute to the beta-cell dysfunction which characterizes diabetes mellitus in this animal model.
UNLABELLED: Sjögren syndrome (SS) is a common disorder in adults and involves both glandular and extraglandular systems. We report here four cases of childhood SS complicated by chronic thyroiditis, interstitial nephritis or sweat gland inflammation. Additionally, in one of these cases, the central nervous system was involved. All of these complications are common in adult cases. CONCLUSION: Childhood SS is a systemic "ductilitis" or "exocrinopathy" with complications which are commonly observed in adult cases.
Genetic factors contribute to the development of NIDDM, and genes involved in regulating pancreatic beta-cell function and insulin's effects on glucose metabolism are good candidates for being NIDDM susceptibility loci. However, testing candidate genes for linkage to NIDDM depends on the identification of highly informative DNA polymorphisms in or near the candidate locus. Here we describe an approach for identifying highly polymorphic markers near candidate genes that utilizes the emerging physical map of the human genome. A sequence-tagged site from the candidate gene is used to screen the Centre d'Etude du Polymorphisme Humain megabase-insert yeast artificial chromosome library, which contains information on the physical localization of >3,000 genetically mapped simple sequence repeat DNA polymorphisms. Thus, identification of a yeast artificial chromosome containing the candidate locus will in many instances also identify a physically linked simple sequence repeat DNA polymorphism that can be used as a marker for the candidate gene in linkage studies. We have used this approach to identify a marker for the islet amyloid polypeptide gene on chromosome 12. The physical mapping of this gene to a yeast artificial chromosome showed that it was in the same yeast artificial chromosome as the gene encoding liver glycogen synthase, another possible NIDDM susceptibility gene. Affected sib pair studies using a simple sequence repeat DNA polymorphism physically linked to the islet amyloid polypeptide and liver glycogen synthase genes showed no evidence for linkage with NIDDM, indicating that they are not major genes contributing to NIDDM susceptibility.
Total aortic root replacement was performed on 19 cases since December 1979 to May 1995. They were devided in two groups. First 7 cases were operated by original Bentall procedure with inclusion technique (group A). Succeeding 12 cases were operated by Carrel patch method or Cabrol procedure without inclusion maneuver. There were 2 operative deaths in group A (28.6%) and was one death in group B (8.3%) respectively. The operation time and the extracorporeal circulation time were significantly shorter in group A than that in group B. Anastomotic leakage was noted in 2 cases of group A. One of them required reoperation and another one with coronary ostial leakage died of congestive heart failure. We concluded that non-inclusion method for aortic root replacement was superior to conventional inclusion technique and reimplantation of both coronary ostia with Carrel patch method was the best tactics especially for Marfan syndrome in terms of long term results.