Biomedical subjects
Publications and source records attributed to H Okazaki.
Fibrostatins, potent inhibitors of prolyl hydroxylase, were isolated as orange crystals from the culture broth of strain No. 23924, which was identified as Streptomyces catenulae subsp. griseospora. In vitro inhibitory activity (ID50 value) of fibrostatins A, B, C, D, E and F against prolyl hydroxylase of chick embryos was 23, 39, 29, 180, 10 and 14 microM, respectively.
The structures of six inhibitors of prolyl hydroxylase, fibrostatins A, B, C, D, E and F produced by a strain of Streptomyces, were deduced to be 1, 2, 3, 4, 5 and 6, respectively, from chemical and spectroscopic evidence, especially from extensive 13C NMR studies including selective decoupling and low power selective decoupling experiments monitored by 13C-1H long-range couplings. These compounds are the first naturally occurring 2,6,7- or 3,6,7-tri-substituted or 2,3,6,7-tetra-substituted 5-hydroxy-1,4-naphthoquinone inhibitors possessing N-acetyl-L-cystein-S-yl moieties in the molecule.
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To determine the utility of injection of polymers to obliterate the pancreatic duct, we examined this method and others viz, pancreatico-duodenostomy, duct ligation, and the open duct method. We performed the pancreatic duct treatment on the left portion of the pancreas in dogs without any transplantation. The right portion of the pancreas was removed. We used Neoprene and Ethibloc as injected materials. One month after the operation, the polymer injected dogs showed the same endocrine function as the duct ligated and open duct ones. However, three months after the operation, endocrine function of the polymer injected dogs improved and was better than that of the other two groups which showed no changes. The endocrine function of the polymer injected dogs had remained stable for one year and was close to that of the optimal function of pancreatico-duodenostomy. Furthermore, after operation in the polymer injected dogs, the elevated serum amylase descended to normal level. This occurred much less rapidly in the other groups. The fibrosis of the polymer injected dogs' pancreas was completed by 3 months, while the dogs in the other groups still had some degenerated exocrine tissues. Rapid destruction of exocrine tissues, induced by the injection of the polymer, appears to encourage reconstruction of endocrine tissue.
This paper describes the pathological findings in two cases of delayed contralateral hemiparesis following herpes zoster arteritis. Both died of cerebral haemorrhage and a necrotizing angiitis was found involving the major vessels of the ipsilateral cerebral hemisphere. No feature of granulomatous arteritis or of encephalitis was found. It is likely that the virus spreads along intracranial branches of the ophthalmic nerve supplying the major arteries and causes the inflammatory reaction by direct invasion of vascular muscle.
The AG-CDC tests were performed in parallel with C-CDC tests for studying sensitization of DST patients. Fourteen of 56 DST patients were positive by the AG-CDC tests after DST. Ten of 14 were also positive by both tests after DST. In 8 of 14 patients AG-CDC antibodies continued to be detectable even after C-CDC antibodies became undetectable as time passed and with plasmapheresis. Thus, AG-CDC tests are more sensitive compared to C-CDC tests and can extend the detection rate of DST-sensitized patients. Except for two DST patients (highly sensitized), 12 of 14 DST-sensitized patients were given transplants from specific blood donors at the time when their C-CDC tests became negative. One graft failed, another one had impaired function, and ten of them functioned. It should be noted that DST patients were transplanted successfully with or without plasmapheresis across a positive AG-CDC test if the titer was less than 1:4 at the time of transplant. All four DST recipients who developed antibodies detected only by AG-CDC tests after DST experienced severe accelerated rejections. In contrast, two of eight patients who were positive by both tests had "severe" accelerated rejections. The incidence of severe accelerated rejections was shown to be highly associated with the presence of AG-CDC antibodies. These facts suggest that AG-CDC antibodies may damage kidney grafts and result in severe accelerated rejections; and that AG-CDC tests are useful for predicting occurrence of severe accelerated rejections in DST recipients.
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Using radioligand binding techniques and human frontal cortex, we determined the equilibrium dissociation constants (KDs) of 25 antidepressants at the serotonin S1 (probably the S1A subtype) and serotonin S2 receptors using [3H]WB4101 and [3H]ketanserin, respectively. At the serotonin S1 receptor, the most and least potent antidepressants were trazodone (KD = 60 nM) and bupropion (KD = 170 microM), respectively. At the serotonin S2 receptor, the most and least potent antidepressants were amoxapine (KD = 0.6 nM) and bupropion (KD = 90 microM), respectively. Analysis of the data revealed a relationship between structure and serotonin S1 affinity for some tricyclic antidepressants. Buspirone, a new anxiolytic agent, possessed high affinity for the serotonin S1 receptor (KD = 3.8 nM).
A 59-year-old woman with a metastatic adenocarcinoma of unknown origin and no metabolic abnormalities developed a diffuse encephalopathy, with generalized triphasic waves seen on the electroencephalogram. Postmortem examination revealed widespread, multifocal perivascular carcinomatosis of the cerebral cortices. Triphasic waves have been described with dementing processes, subdural hematomas, and cerebrovascular disease, but they are more commonly seen with metabolic encephalopathies. This case demonstrates an additional nonmetabolic cause of triphasic waves.
Characterization and quantitation of the spatial distribution of pathological abnormalities along the length of nerves may be helpful in understanding the underlying mechanisms of diabetic polyneuropathy. To this end, by examining transverse sections of nerve roots and proximal-to-distal levels of lower limb nerves in 9 controls and 15 diabetic patients with polyneuropathy, we have determined the myelinated fiber (MF) number, size distribution, median diameter, and variability of density (MFs/mm2) among frames and among fascicles. Even in cases with mild polyneuropathy, fiber loss, a decrease in the median diameter, and an increase in the variability of density among frames and among fascicles began in proximal nerve and extended to distal levels. Multifocal fiber loss along the length of nerves and sprouting provide the best explanation for these findings. The pattern is dissimilar from that observed in diffuse metabolic disease of Schwann cells, neuronal degeneration, and dying-back neuropathy, but like that found in experimental ischemic neuropathy induced by embolization of nerve capillaries.
Pirenzepine, a potent antimuscarinic agent with apparent selectivity for a subtype (M1) of muscarinic receptors, was used in tritiated form to characterize its binding to human brain tissue. Specific [3H]pirenzepine binding showed rapid association and dissociation. From kinetic and competitive binding experiments, its KD was 5.5 nM and 9 nM, respectively. Regional distribution of [3H]pirenzepine binding determined in parallel with [3H]quinuclidinyl benzilate binding, a nonselective muscarinic antagonist, indicated a significant correlation for the maximum number of binding sites for the two radioligands in 13 brain regions, with the highest amount of binding for each in the putamen and the least in the cerebellum. Binding for [3H]pirenzepine averaged 57% of that for [3H]quinuclidinyl benzilate, with a range of 20% (cerebellum) to 77% (frontal cortex). Most antidepressants and neuroleptics tested had affinities for [3H]pirenzepine binding sites that were not significantly different from their previously reported values obtained with the use of [3H]quinuclidinyl benzilate.
The binding of [3H]neurotensin to membranes from human brain at 0 degrees C was specific, saturable, and reversible. In the frontal cortex, the equilibrium dissociation constant (KD) for [3H]neurotensin determined from the ratio of rate constants (k-1/k1), saturation isotherms, and inhibition binding experiments was 0.80, 2.0, and 2.0 nM, respectively, and the maximum number of binding sites (Bmax) from the saturation isotherms and the competitive binding experiments was 2.4 and 2.2 pmol/g of tissue, respectively. Hill coefficients for binding were equal to 1, indicating the presence of single, noncooperative binding sites. Inhibition of specific binding of [3H]-neurotensin by several analogs of neurotensin showed that [Gln4]neurotensin and neurotensin(8-13) had the highest affinities for these binding sites in human frontal cortex, with each analog being approximately 13-fold more potent than neurotensin. In addition, these data showed that the carboxy-terminal portion of neurotensin played an important part in the binding of this neuropeptide in human brain, a result described for other species. Regional distribution of binding sites was different from that reported for animal brains. Of the 33 different regions investigated, the uncus and substantia nigra showed the highest specific binding of [3H]neurotensin, whereas such areas as the pineal body, medulla, and corpus callosum had few binding sites.
A female infant was found to have an abnormal karyotype with mosaicism: 45,XX,-21/46,XX,r(21) (p11.2 q22.3). She showed a slightly decreased level of superoxide dismutase (SOD) activity in erythrocytes, polymorphonuclear and mononuclear leukocytes. The cuprozinc SOD (SOD-1) activity of leukocytes was 70-80% of normal level, while their manganese SOD (SOD-2) activity was within the normal range. The relationship between the chromosomal aberration and the SOD activity is discussed in relation to the gene dosage effect.
The incidence, secular trend and survivorship of amyotrophic lateral sclerosis in the Rochester, Minn., population has been investigated over a 60-year period, 1925 through 1984. The crude average annual incidence rate was 2.0 per 100,000 population. The rate, age- and sex-adjusted to the US 1970 white population, was 2.4 per 100,000 population (3.0 for men and 2.0 for women), with a male to female ratio of 1.5:1. Incidence rates after 1955 showed a small but nonsignificant increase compared to those of the former 30-year period. Median age at onset was 67.5 years; the incidence rates increased significantly with advancing age, but without a peak. Median survivorship was 23.8 months, and younger patients had a better prognosis than patients with an advanced age at onset. No change in duration of survivorship was observed over the period studied. Two of the 44 patients (4.5%) had a family history of amyotrophic lateral sclerosis.