Mutant insulin syndrome: identification of two families with [LeuA3]insulin and determination of its biological activity.
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Biomedical subjects
Publications and source records attributed to K Miyamura.
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CDDP is often dose-limited owing to its nephrotoxicity. Urinary NAG was measured to evaluate the nephrotoxicity of CDDP in 18 patients (DIV: 12 patients, Intra-Peritoneal: 6 patients) with or without Fosfomycin. The gradual increase in urinary NAG activity was noted on repeating the therapy. 24 hour NAG excretion was correlated with that of urinary beta 2-microglobulin. However, urinary NAG was not correlated with Ccr 24 or BUN. Though Ccr 24 and BUN were normal, urinary NAG and beta 2-microglobulin markedly increased during CDDP therapy. Fosfomycin administration significantly decreased urinary NAG, which was increased by CDDP. These results indicate that: The measurement of urinary NAG and beta 2-microglobulin are most useful in estimating the nephrotoxicity of CDDP. Fosfomycin decreases the nephrotoxicity of CDDP.
A procedure for effective application of ultrafiltration is described for preparation of serum catecholamine samples suitable for a sensitive radioreceptor assay. Each of the fresh serum samples unsuitable for the direct receptor assay was dialyzed by applying centrifugal force into a capsule-shaped porous core whose surface was tightly covered with a molecular filtration membrane. Interfering macromolecular serum components were left outside the capsule during the centrifugation or forced dialysis. The ultrafiltrate in the capsule was readily recovered by another centrifugation, and was found satisfactory as an assay specimen. In the radioreceptor assay system adapted to detect 30 pg per assay tube, epinephrine added to fresh serum to make the final concentration approximately 1 X 10(-8) mol/L was recovered semiquantitatively. Serum catecholamine level determined was equivalent to beta-adrenergic receptor reactivity that could be expressed in terms of (-)-epinephrine concentration.
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Different isolates of enterovirus type 70 (EV70) taken between 1971 and 1981 were studied by molecular biological methods to elucidate their evolutional change. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed that only a few isolates had a slight alteration in mobility in some viral proteins. On the contrary, oligonucleotide mapping of virion RNA could clearly delineate the molecular changes among isolates. The number of base changes of isolates became greater as the years elapsed. In addition, the number of base changes among recent isolates from different areas of the world was much greater than those among early isolates. Thus, when the isolates were arranged three-dimensionally according to the number of base changes between each other, the constellation of the strains gave rise to a conical shape. The central axis of the figure was the time of isolation of the strains. The early isolates clustered near the top of the conical figure and the recent isolates tended to disperse divergently at the bottom. The figure indicated that all EV70 strains were derived from a common ancestor, and its top would be the time of emergence of the original strain. It was estimated to be around 1966, 3 years prior to the first epidemic in Accra, Ghana. From the results, it was presumed that EV70 would have emerged at a single focus in Africa as a novel human virus. After having circulated there for a few years, the virus spread to the other parts of the world. Based on the difference in the oligonucleotide spots between the recent isolates and early isolates, the base changes of EV70 that occurred during 10 years was estimated to be 320, about 4% (0.4% a year on the average) of the bases of the total RNA genome.
The persistence of neutralizing antibody (NA) against three types of poliovirus acquired after two doses of trivalent live attenuated poliovirus vaccine (LPV) has been followed up for ten years in individual vaccinees. Sixty-seven children were bled once a year over a five year period following the primary vaccination. More than 80% of them retained NA against all three types of poliovirus. Thirty-two individuals whose NA titres were 1:16 or over for types 1 and 2 and 1:4 or over for type 3 at the fifth year were further followed up for a further five years and it was shown that during this period some of them had a naturally-acquired antibody rise, mostly against type 3 virus. At the sixth to eighth year after the primary vaccination, one further dose of the trivalent vaccine was administered to the children whose NA titres were down to 1:8 or less and the effect of booster vaccination on NA was followed. Other subjects were revaccinated with LPV and their fecal excretion of the vaccine virus was investigated. The results showed that a decrease in serum antibody level could be a good indicator of the local resistance of the alimentary tract and that reinfection could occur if serum NA had decreased to 1:8 or less, which allowed a virus excretion in the stools.
A crude replication complex prepared from enterovirus 70-infected cells was used to study the temperature-sensitive characteristic of the virus. The complex showed a temperature sensitivity in the in vitro incorporation of radiolabeled ribonucleoside triphosphate. The endonuclease itself did not account for the restricted RNA synthesis at the nonpermissive temperature. Analyses of the in vitro products by both gel electrophoresis and sucrose density gradient centrifugation showed that the complex synthesized three types of viral RNA only when incubated for a short period of time at the nonpermissive temperature. When the replication complex was treated with a detergent (deoxycholic acid), incorporation of ribonucleoside triphosphate into RNA at the permissive temperature was reduced to the level of that at the nonpermissive temperature. In addition, the in vitro RNA synthesis by the enterovirus 70 replication complex at the permissive temperature required a higher concentration of ATP than of other ribonucleoside triphosphates, whereas such a preference for ATP was not found in the reaction at the nonpermissive temperature. The results indicate that the initiation step of RNA synthesis by the complex is blocked at the nonpermissive temperature. The possible implications of these findings are discussed.
The genetic relationship between two enteroviruses causing the acute hemorrhagic conjunctivitis (AHC) syndrome was examined by the RNA-RNA hybridization technique. Nucleotide sequence homology between the J670/71 strain of enterovirus type 70 (EV70) and the EH 24/70 strain of Singapore epidemic conjunctivitis (SEC) virus was found to be only 2% or less of the total RNA genome, while more than 90% homology was detected between the prototype (J670/71) and other isolates of EV70. The results indicate that the SEC virus, an agent of conjunctivitis epidemics in limited areas of southeast Asia and India since 1970, was distinguished serologically and genetically from EV70, which caused pandemics of AHC over the African and Eurasian continents from 1969 to 1972.
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High and rising neutralizing antibody titers (NATs) to enterovirus type 70 (EV70) were detected in the serum and cerebrospinal fluid (CSF) of patients with polio-like motor paralysis accompanying acute hemorrhagic conjunctivitis (AHC) in an outbreak of AHC in 1981 in Bombay, India. Fifty-four (88.5%) of 61 patients with AHC with or without neurologic disease had serum NATs of greater than or equal to 1:16, and some paired sera from these patients showed significant increases in NAT. Serum from noninfected control subjects had no significant neutralizing antibody to EV70. Thirty-six (94.7%) of 38 CSF specimens from 30 patients with spinal or a combination of spinal and cranial motor paralysis associated with AHC had NATs ranging from 1:2 to 1:256. No neutralizing antibody was found in CSF specimens from patients with AHC alone or in those from non-infected control subjects, and a reduced ratio of serum NAT to CSF NAT was detected in patients with neurologic disease. Therefore, it is highly likely that intrathecal synthesis of antibody occurred in response to direct invasion of the central nervous system by EV70. The results represent strong laboratory evidence of the neurovirulence of EV70.
A 47-yr-old woman who had previously received methimazole (MMI) treatment for hyperthyroidism was found to have glucagon binding autoantibodies in plasma. She had never received glucagon. The binding substances were detected in plasma at the time of a glucagon RIA. [125I]Glucagon binding was inhibited only by porcine glucagon and porcine glicentin, and dissociated at acid pH. The substances proved to be glucagon binding antibodies (immunoglobulin G, L-chain K-type), as determined by ammonium sulfate and radioprecipitation. There were no clinical manifestations related the presence of these autoantibodies. In a survey of 91 patients with thyroid disease, 3 patients whose plasma bound [125I]glucagon were identified among 41 with hyperthyroidism who were receiving MMI treatment. Such binding was not found in plasma from untreated hyperthyroid patients, those receiving propylthiouracil or those with chronic thyroiditis. These findings suggest that the development of glucagon antibodies in hyperthyroidism may be associated with MMI treatment.
Differences in glucose intolerance within various occupational groups, i.e. laborers, clerks, and managers, and the related environmental factors were studied in ca. 9000 male workers of a certain factory. Age-and weight-adjusted prevalence rates of glucose intolerance were 3.2% in the laborers, 5.8% in the clerks, and 9.3% in the managers. In the managers, the total intake of calories was excessive for the amount of exercise expended; food intake was relatively low in complex carbohydrates and high in animal fats. The clerks were characterized by a high sugar intake. The low prevalence of glucose intolerance in the laborers was ascribed to the greater amount of exercise. Assigned work hours, however, probably affected the prevalence of diabetes in the laborers, which was 2.1% in subjects who worked all three shifts, but 0.9% in subjects working only day shifts. Thirty laborers from all 3 shifts consented to give urine specimens during their working time (8 hr), after the same amount of food and exercise in all of them. Urinary excretion of HGH and VMA during the midnight shift was significantly higher (p less than 0.05) than that during the day shift although urinary 170HCS was significantly low (p less than 0.01) at midnight. There were no significant changes in urinary CPR excretion between day and night shifts. These data indicate the importance of environmental factors, such as exercise, nutrition and stress, in glucose intolerance.
Very little information is available related to possible differences in immunological characteristics of IDDM among Asian populations, though it has been reported that IDDM is associated with Bw54-DR4 and B17-DR3 in Japanese and Chinese, respectively. There is virtually no report related to comparative studies on Bf-DM association among Asian populations, while Bf-DM association is reported to be stronger than HLA-DM association in Caucasians. In the present paper, the results of our studies on anti-thyroid antibodies (ATA) of IDDM in Japanese, Chinese and Filipinos are presented. In Japanese, the incidence of ATA positive was higher in IDDM with a duration of less than one year (35.7%) than that in the patients with a duration of one year or more (12.5%). But, there was no such a duration dependent decrease in the incidences of ATA among Chinese or Filipino IDDM. The frequency of BfSS in Filipinos is lower than in Japanese or Chinese. However, no association was found between Bf phenotypes and IDDM in Asian populations. These results indicate that autoimmunity is transient in Japanese IDDM, but persistent in Chinese and Filipinos, and that it is too early to postulate in general that Bf-IDDM association in general populations is stronger than HLA-IDDM association.
The incidence of vascular disorders was investigated in two groups of diabetics. One group (group-U) comprised 408 diabetics who were inhabitants of an urban district. The other group (group-R) consisted of 148 diabetics who were inhabitants of a rural district. The annual incidence rates of myocardial infarction and cerebrovascular disease in group-R were about twice as high as the respective rates in group-U. The prevalence rates of hypertension and ECG-abnormalities in group-R were also significantly higher than those in group-U (p less than 0.01). However, there was no appreciable difference between the two groups with respect to the incidence of proteinuria or proliferative retinopathy. Any significant difference between the two groups in age, obesity index, Hb-A1, T. Chol., TG. or HDL-C levels was not recognized. The duration of diabetes was relatively short in group-R. These findings suggest that the high incidence of myocardial infarction and cerebrovascular disease in group-R is not influenced by the difference in Hb-A1 or serum lipid levels, and that these vascular disorders are probably associated with hypertension and ECG-abnormalities.