Biomedical subjects
Publications and source records attributed to H Ishida.
Malignant thymoma was found in an 8-year-old Japanese boy with growth hormone (GH) deficiency who had received GH therapy for 3 years and 5 months. There may be a possible relationship between the occurrence of malignant thymoma and GH therapy.
The purpose of this study was to investigate the effect of starvation on the cellular function of rat parotid glands in relation to the diurnal variation of amylase secretion from the tissue. Salivary amylase secreted from the glands of rats starved for 24 h showed diurnal variation, with two peaks at 13 and 21 h. The peak at 21 h was more notable than that in fed rats, because of the accumulation of a large amount of amylase in the tissue due to starvation. Maximal binding (Bmax) values of [3H]dihydroalprenolol in the parotid membrane of starved rats also showed diurnal variation, with marked peak at 13 and 21 h. However, phosphorylation of nuclear non-histone proteins in starved rat parotid glands showed diurnal variation, with peaks at 17 and 1 h. This phasing was delayed by 4 h in comparison to that of fed rats, suggesting that the delay of diurnal variation of amylase secretion commences at least a few days after the beginning of starvation. These results indicate that changes in salivary amylase secreted from parotid glands of rats starved for 24 h coupled with those in the number of beta-adrenoceptors in the tissue show the same diurnal variation as observed in fed rats. Starvation of rats for 24 h does not appear to influence the response of parotid gland cells to stimuli.
In order to investigate a possible role of GABA in the regulation of insulin secretion, we have studied the effect of GABA on insulin secretion from the isolated perfused rat pancreas in vitro and on the changes in the cytoplasmic Ca2+ of Beta-cells from the isolated rat islets. When glucose is present, GABA caused a dose dependent inhibition of the first phase of arginine-induced insulin secretion during the range of 10-1000 microM, but GABA did not affect arginine-induced insulin secretion in the absence of glucose. GABA inhibited not only the first phase but also the second phase of glucose-induced insulin secretion. A GABAB-receptor agonist, baclofen, also inhibited both phases of insulin secretion induced by 16.7 mM glucose. Furthermore, GABA inhibited the rise in cytoplasmic Ca2+ of Beta-cells in response to 16.7 mM glucose. These studies indicate that GABA decreases Beta cell secretory activity mainly in response to glucose. These inhibitory effects of GABA on insulin secretion may be mediated through GABAB-receptor and the inhibition of the rise in cytoplasmic Ca2+.
The anti-inflammatory mechanism of iodine-enriched egg was investigated in mice by means of arachidonic acid-induced ear inflammation. The lipid fraction of iodine-enriched egg was capable of suppressing the increase in ear weight induced by arachidonic acid in a dose-dependent manner. The lipid fraction was further separated into neutral and polar lipid fractions. Of these two fractions, only the neutral lipid fraction was capable of suppressing LT-C4 production in arachidonic acid inflammation. Neither the neutral nor polar lipid fractions of ordinary egg, however, showed any anti-inflammatory effect. These results suggest that the anti-inflammatory activity of iodine-enriched egg is present in the neutral lipid fraction, and its mechanism is assumed to be inhibition of LT-C4 production.
The conversion of lyso-platelet activating factor (lyso-PAF) to PAF in cultured paranasal sinus mucosa obtained from normal human subjects was studied. The PAF concentration in the medium was determined after addition of lyso-PAF. PAF became detectable at 10 minutes after the addition of 10(-8)M lyso-PAF, and reached a maximum concentration (3.25 x 10(-9)M) at 20 minutes. The PAF level then gradually declined to become undetectable at 60 minutes after addition of lyso-PAF. Thus PAF is very unstable having a half-life calculated to be 12.8 minutes with an elimination constant of k = 0.05377 minutes-1. In contrast, lyso-PAF is known to be a stable metabolite of PAF as well as a precursor of PAF. The results obtained from this study suggest that the turnover of lyso-PAF to PAF may play a role in evoking prolonged inflammation in target organs or tissues.
Endothelin is a well known vasoconstrictive peptides produced by endothelial cells and has been reported to regulate the systemic circulation. The authors investigated changes in endothelin in plasma and the surface of wounds induced with thermal injury using an experimental ear burn model in mice. At 0, 15, 30, 60, 120 and 180 minutes after thermal injury the plasma endothelin-like immunoreactant levels were 1.50 +/- 0.21, 1.86 +/- 0.36, 2.81 +/- 0.55, 2.62 +/- 0.27, 1.54 +/- 0.14 and 1.25 +/- 0.19 fmol/ml (N = 8), respectively. Endothelin-like immunoreactant levels in the plasma increased gradually until 30 minutes after the thermal injury. Endothelin-like immunoreactant content in the ear before thermal injury and at 60 minutes after injury were 7.04 +/- 0.64 and 8.61 +/- 1.24 fmol/ear (N = 8), respectively. The change in endothelin-like immunoreactant after thermal injury originated from endothelin 1,2; that is, the endothelin-1,2 content of the burned ear increased significantly 15 and 60 minutes after thermal injury to 12.52 +/- 0.68 and 11.58 +/- 1.04 fmol/ear, respectively, compared with 1.78 +/- 0.91 fmol/ear (N = 8) obtained before injury. These results suggested that endothelin 1,2 existed in the region of the wound caused by thermal injury.
Pancreatic islets from the streptozocin-induced non-insulin-dependent diabetes mellitus (NIDDM) rat model showed a diminished insulin response to 16.7 mmol/L glucose, but the insulin response to arginine remained intact. To evaluate the importance of intracellular calcium concentration ([Ca2+]i) in the diminished insulin response to glucose, the [Ca2+]i of pancreatic beta cells was investigated using fura-2. Glucose produced heterogeneous responses of [Ca2+]i, which were in beta-cell clusters of both the control and NIDDM groups. Many cells showed initial slight decreases of [Ca2+]i, which were followed by gradual and large increments of [Ca2+]i after glucose stimulation of beta cells in the control group. On the other hand, the increase of [Ca2+]i in response to glucose was markedly diminished in beta cells of the NIDDM group compared with controls. The average lag time to [Ca2+]i elevation of beta cells in the NIDDM group was significantly longer than that of the control group. Arginine produced marked increases of [Ca2+]i, in contrast to the effect of glucose stimulation in the NIDDM group. These results suggest that the diminished and delayed [Ca2+]i increases in beta cells of NIDDM rats in response to glucose stimulation are responsible for the selectively impaired insulin response to glucose in the rat model of NIDDM.
A sticker-type skin-surface temperature indicator, commercially available in Japan, has been utilized to monitor temperature changes in replanted digits. In clinical application, the authors evaluated several shortcomings in some of these devices. For example, the 10-mm diameter indicator is too small for numbers to be seen clearly. The 18-mm diameter indicator is too large to patch onto the finger pulp. To improve this device, the authors used only the number 33 from the 18-mm diameter indicator and applied it to several study subjects. Judgments about the circulatory status of the replanted digit can be made on the basis of the indicator color. The 18-mm diameter indicator, now modified to use only the number 33, is in common use for all the authors' digital replantation cases. Clinicians' ability to see critical temperature changes has been markedly improved, even under poor lighting conditions.
The erythrocyte deformability, membrane fluidity, mean corpuscular volume (MCV), and lipid compositions of erythrocyte membrane were investigated to evaluate the possible role in disturbed hepatic microcirculation in alcoholic liver disease. Erythrocyte deformability was assessed in 37 alcoholic patients and 20 normal subjects. Erythrocyte deformability determined by the filtration method was found to be decreased significantly in alcoholic patients. Erythrocyte membrane fluidity in alcoholic liver disease analysed by fluorescence recovery time after photobleaching was decreased significantly. The decrease of erythrocyte membrane fluidity in alcoholic patients correlated significantly with a decrease of erythrocyte deformability (r = -0.65, P < 0.02). The increased MCV in alcoholic liver disease also correlated with a decrease of erythrocyte deformability significantly (r = 0.652, P < 0.02). The lipid compositions of erythrocyte membrane were abnormal in alcoholic liver disease; the phosphatidylcholine:sphingomyelin ratio was increased (P < 0.001) and unsaturated:saturated fatty acid ratio was decreased (P < 0.01). We conclude that, in alcoholic liver disease, the decreased erythrocyte deformability was closely associated with changes of membrane fluidity and MCV. It was also associated with abnormalities of membrane lipid compositions. It is speculated that these abnormalities of erythrocytes result in further reduction of sinusoidal blood flow in alcoholic liver disease, and consequently disturb metabolic functions of the liver.
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We compared the in vitro antibacterial activity of DV-7751a against gram-positive and -negative bacteria with those of quinolones currently available. MICs for 90% of the strains tested (MIC90s) against clinical isolates of methicillin-susceptible and -resistant Staphylococcus aureus and Staphylococcus epidermidis were 0.20, 0.39, 0.20, and 0.78 micrograms/ml, respectively. Moreover, MIC50s for DV-7751a against ofloxacin-resistant methicillin-resistant S. aureus were 4-, 8-, 16-, 32-, and 64-fold lower than those for tosufloxacin and sparfloxacin, levofloxacin, ofloxacin and fleroxacin, ciprofloxacin, and lomefloxacin, respectively. DV-7751a inhibited the growth of all strains of Streptococcus pneumoniae, Streptococcus pyogenes, and Peptostreptococcus spp. at 0.39, 0.39, and 0.78 micrograms/ml, respectively, and was 4- to > 16-fold more active against enterococci at the MIC90 level than the other quinolones tested. The activity of DV-7751a against Pseudomonas aeruginosa was roughly comparable to those of levofloxacin and sparfloxacin at the MIC90 level and was two- to fourfold less than that of ciprofloxacin. DV-7751a showed activity comparable to those of levofloxacin and ciprofloxacin against the other glucose-nonfermenting bacteria Haemophilus influenzae, Neisseria gonorrhoeae, and Moraxella catarrhalis (MIC90s of 0.025, 0.20, and 0.10 micrograms/ml, respectively). DV-7751a activity was not affected by medium, inoculum size, or the addition of human serum but was decreased under acidic conditions and in human urine, as were the other quinolones tested. Time-kill curve studies demonstrated the rapid bactericidal action of DV-7751a against S. aureus, S. pneumoniae, Escherichia coli, and P. aeruginosa. The frequency of spontaneous resistance to DV-7751a was less than or equal to those of the reference drugs. DV-7751a inhibited the supercoiling activity of DNA gyrases from S. aureus, E. coli, and P. aeruginosa at concentrations comparable to those of levofloxacin and sparfloxacin.
An antiarrhythmic agent, disopyramide, was found to enhance the insulin secretory capacity of Wistar rat pancreatic islets with a half-maximal concentration of 23.3 microM. Employing a patch-clamp technique, disopyramide was found to inhibit ATP-sensitive K+ (KATP) channel activity in rat pancreatic beta-cells in primary culture without altering the unitary conductance. Half-maximal inhibition was achieved by the addition of 3.6 microM disopyramide to the intracellular bathing solution in the inside-out mode, 11.0 microM to the extracellular bathing solution in the outside-out mode, and 87.4 microM in the cell-attached mode. The binding of [3H]glibenclamide to pancreatic islets was inhibited by unlabeled glibenclamide but not by unlabeled disopyramide. Based on these observations, it is concluded that disopyramide blocks pancreatic KATP channels via binding to a site(s) distinct from the sulfonylurea receptor. This effect may be causatively involved in disopyramide-induced hypoglycemia.
Most patients with common variable immunodeficiency (CVI) have normal numbers of circulating B cells but low concentrations of serum Ig. To determine if the hypogammaglobulinemia is caused by an intrinsic B cell defect, we studied B cell function of 22 CVI patients. Cultured B cells from all CVI patients underwent normal proliferation and synthesized normal quantities of IgE in the presence of anti-CD40 and IL-4. If cultured with anti-CD40 and IL-10, four patterns of Ig isotype synthesis were observed. Six CVI patients produced normal amounts of IgM, IgG, and IgA. Four patients produced normal quantities of IgM and IgG. Of the remaining 12 patients who failed to synthesize IgG and IgA, 8 produced normal and 4 synthesized decreased amounts of IgM. Analysis of the IgG subclasses produced by 10 patients with IgG-secreting B cells revealed that IgG4 was the most affected subclass, followed by IgG2; synthesis of IgG3 and IgG1 remained normal. Similarly, in the six IgA producing patients, IgA2 was more often affected than IgA1. The hierarchy of Ig isotype and subclass synthesis corresponds to Ig heavy chain constant region gene location on chromosome 14. Thus, circulating B cells of CVI patients are committed to synthesize one or more Ig isotypes or subclasses, and under proper conditions can proliferate, mature into Ig-secreting cells, and undergo class switch to IgE.
We investigated the effects of 1,25-dihydroxyvitamin D3[1,25-(OH)2D3], on osteoprogenitor cell differentiation and bone nodule formation at various stages of differentiation by evaluating the effects on long term cultures of fetal rat calvaria (RC) cells. RC cells were plated at 3 x 10(4) cells/35-mm dish in alpha-minimal essential medium containing 15% fetal bovine serum, ascorbic acid, and beta-glycerophosphate (beta-GP), conditions under which bone nodules form. 1,25-(OH)2D3 inhibited bone nodule formation in a dose-dependent manner with total inhibition occurring at 1-10 nM and half-maximal inhibition occurring at approximately 0.06 nM. 1,25-(OH)2D3 also significantly stimulated RC cell growth in a dose-dependent manner in both the presence and absence of ascorbic acid. Addition of 1 nM 1,25-(OH)2D3 at different times after the start of culture inhibited nodule formation when added before and up to the early multilayering stage (up to day 11 of culture), but had no effect on nodule number when added later. When 1,25-(OH)2D3 was added at the start of the culture period and removed at the early multilayering stage, nodule formation was also inhibited. Pulses of 48-h duration also inhibited nodule formation, with maximal effect occurring between days 3 and 11. Thus, 1,25-(OH)2D3 inhibited osteoprogenitor cell differentiation during the earlier stages of culture before visible bone nodule formation occurred and the effect was not reversible upon removal of 1,25-(OH)2D3. In cultures grown to the multilayering stage in medium without ascorbic acid and beta-GP and then changed to medium with ascorbic acid and beta-GP, 1,25-(OH)2D3 inhibited when present before, but not after, the addition of ascorbic acid and beta-GP. Two other vitamin D3 metabolites, 24,25-dihydroxyvitamin D3 [24,25-(OH)2D3] and 1,24,25-trihydroxyvitamin D3 [1,24,25-(OH)3D3] had inhibitory effects similar to 1,25-(OH)2D3. The effects were dose dependent for each metabolite tested and correlated with the biological effectiveness of these metabolites in other systems: i.e. 1,25-(OH)2D3 was more effective than 1,24,25-(OH)3D3 which in turn was more effective than 24,25-(OH)2D3. The data show that 1,25-(OH)2D3 inhibits osteoprogenitor cell differentiation at an early stage and at a time during which cell growth is stimulated.
Methylglyoxal is directly mutagenic to Salmonella typhimurium TA100 and its mutagenicity is markedly enhanced in the presence of hydrogen peroxide. We found that methylglyoxal in phosphate buffer was decomposed easily by hydrogen peroxide at room temperature to yield acetic acid and formic acid as major products and diacetyl as a minor product; acetyl radical was detected in the solution by ESR spectroscopy by the use of a spin-trapping reagent, 5,5-dimethyl-1-pyrroline N-oxide. Furthermore, guanosine was converted into N2-acetylguanosine by a combination of methylglyoxal and hydrogen peroxide in 0.1 M phosphate buffers (pH 6.1 to 7.4). This acetylation may be related to the enhancement of methylglyoxal mutagenicity by hydrogen peroxide. Other alpha-ketoaldehydes such as glyoxal and phenylglyoxal also yielded the corresponding acids and alpha-dicarbonyls upon reaction with hydrogen peroxide under the same conditions as above. These acids would have been produced through Baeyer-Villiger reaction or coupling of acyl radical with hydroxy radical, and dicarbonyls by dimerization of acyl radicals. In addition, when phenylglyoxal was used, the generation of benzoyl radical and the conversion of guanosine to N2-benzoylguanosine were observed. However, it remains to be established whether the generation of acyl radicals is directly involved in the N-2 acylation of guanosine.
Iodine-labelled fatty acids have been proposed as new tracers of cardiac metabolisms. However, it is not clear how these tracers would reflect the intracellular metabolism. Therefore, we measured the uptake and release of iodine 125-labelled phenylpentadecanoic acid (IPPA), its beta-methyl substitute (BMIPP) and 201Tl in cultured myocytes of mouse embryos, and compared these values to intracellular adenosine triphosphate (ATP) content after metabolic inhibitions of oxidative phosphorylation by sodium cyanide (CN), glycolysis by 2-deoxyglucose (2-DG) or fatty acid beta-oxidation by lactate. The uptake and release of BMIPP was not changed by any inhibitors suggesting BMIPP would not be metabolized in the myocytes. The uptake of IPPA was significantly reduced by 2DG and 60-80% of IPPA was metabolized to hydrophilic catabolites. The correlation of BMIPP and IPPA uptake to intracellular ATP content were high (r = 0.89, p < 0.05; r = 0.86, p < 0.1), but there was poor correlation of 201Tl to ATP values (r = 0.53, n.s.). These results suggested that iodine-labelled fatty acids could be used as better tracers of myocardial metabolism than 201Tl.
For use in a differential assay of human alpha-amylases, a variety of 6(5)-S-substituted p-nitrophenyl alpha-maltopentaoside derivatives (6-54) were systematically synthesized via the key intermediate, p-nitrophenyl O-(2,3-di-O-acetyl-6-S-acetyl-4-O-benzoyl-6-thio-alpha-D-glucopyranosyl) - (-->4)-tris[O-(2,3,6-tri-O-acetyl-alpha-D-glucopyranosyl)-(1-->4)]-2,3,6 -tri-O-acetyl-alpha-D-glucopyranoside (4), which was easily prepared from p-nitrophenyl alpha-maltopentaoside (G5P) in four steps. The sulfoxide and sulfone derivatives were prepared by oxidizing the corresponding sulfides with m-chloroperbenzoic acid.
In order to investigate the pathophysiology of the diabetic osteopenia observed in non-insulin-dependent diabetes mellitus, the circulating levels and the bone contents of bone gamma-carboxyglutamic acid-containing protein (osteocalcin) were determined in rat models of non-insulin-dependent diabetes mellitus, neonatally streptozotocin-induced rats and in genetic Wistar fatty rats. In Wistar fatty rats the plasma level of osteocalcin was 8.1 +/- 0.8 nmol/l, significantly lower than the value of 17.3 +/- 0.9 nmol/l in their lean littermates (p < 0.001). Bone length, bone strength, and weight of powdered bone in Wistar fatty rats were significantly decreased compared to control rats (p < 0.001, p < 0.02 and p < 0.001, respectively). Bone content of osteocalcin per femur in Wistar fatty rats was also significantly decreased compared to controls (p < 0.001). In addition, plasma osteocalcin in neonatally streptozotocin-induced diabetic rats was 2.9 +/- 0.3 nmol/l, which was also significantly decreased compared to the value of 5.6 +/- 0.5 nmol/l in their controls (p < 0.001). Since it has been established that the plasma level of osteocalcin is well related to bone formation and turnover, the low plasma values in these animal models suggest that bone formation and turnover are decreased in non-insulin-dependent diabetes mellitus. Low bone formation and turnover are, therefore, postulated to be one of the pathophysiological characteristics of the skeletal tissue in non-insulin-dependent diabetes mellitus, and to be at least in part responsible for the occurrence of this complication.