Biomedical subjects
Publications and source records attributed to H Harada.
As a result of severe hemorrhagic shock in guinea pigs, the blood flow in the capillaries of the stria vascularis was blocked, but that of the spiral ligament was unaffected. It is therefore postulated that the thick layer of basal cells and fibrocytes around the stria vascularis and the capillaries leaving the stria vascularis plays an important role in the formation of blood sludging.
The synthesis and the structure-activity relationships of renin inhibitors designed from the angiotensinogen transition state are described. These inhibitors contained residues modified at P1-P1', P2, and P4-P3. Decrease in the size of side chain alkyl group in norstatine analog at P1 diminished the inhibitory activities of the compounds. Compound 5j, which contained valine residue instead of histidine residue at P2, inhibited potently cathepsin D (IC50 = 6.0 x 10(-9) M) and pepsin (IC50 = 3.5 x 10(-7) M) to the same extent as renin (IC50 = 8.5 x 10(-10) M), and thus was not specific for renin. The reduction of the beta-carbonyl group to methylene group in beta-carbonylpropionyl residue at P4-P3 decreased the potency about 2 orders against human renin (5i: IC50 = 1.1 x 10(-7) M vs. 1: IC50 = 2.4 x 10(-9) M). These results confirmed the rationality of our analysis of the interaction between an orally potent human renin inhibitor 1 and the active site of human renin using modeling techniques, showing that 1 fits the active site of renin favorably. The experimental details of the synthesis are presented.
The experimental details for the synthesis of human renin inhibitors are described. In order to avoid metabolic degradation of the Phe-His (P3-P2) amide bond in transition-state analogs, structurally modified acyl residues (P4-P3) were incorporated into the inhibitors. Compound 1a, which contained 2-(1-naphthylmethyl)-3-(N-phenethylcarbamoyl)propionyl residue (P4-P3) with a retro-inverso amide bond, L-histidine, and norstatine isoamylamide residue (P1-P1) as a transition-state mimic, had potent human renin inhibitory activity, and it lowered blood pressure when administered orally to common marmosets.
Reactions of 4-methyl-2(3H)-thiazolones (5) with various N-alkoxycarbonyl pyridinium salts (6a--f) led to (N-alkoxycarbonyl dihydropyridyl)thiazolones (7a--f), oxidation of which yielded a new class of 5-pyridylthiazolones (8a--f). These reactions were applied to the synthesis of other azaarylthiazolones. Some of these azaarylthiazolones, particularly 5-(4-pyridyl)thiazolones (8b, c) and 5-(4-quinolyl)thiazolones (14a,b), showed positive inotropic activity with little chronotropic effect on guinea pig left atria.
We found the presence of hepatitis C virus (HCV) infection in liver tissues of hepatocellular carcinoma (HCC) patients who had antibodies to HCV but no serological markers for hepatitis B virus infection by the sensitive reverse transcription/polymerase chain reaction (R/PCR) method. The primers used were derived from the non-structural (NS) 3 and/or the structural (C/E) region. Amplified cDNA sequences of HCV were detected in either cancerous or non-cancerous portion of liver tissues from four out of eight HCC patients with primers of NS3 region. Similar but less efficient results were obtained with primers of C/E region. These results indicate that HCV persists in the liver tissue of HCC. A possible role of persistent infection of HCV for the development of HCC is discussed.
1. Accumulation of 2,4,6-trichlorophenyl-4'-aminophenyl ether (CNP-amino) in carp was investigated for 14 days. CNP-amino in carp could be divided into free CNP-amino [CNP-amino(I)] and bound CNP-amino [CNP-amino(II)]. 2. The bioconcentration factors (BCF) of CNP-amino(I + II) in carp were 90 +/- 38 (mean +/- SD, n = 3) for muscle, 402 for liver, 501 for kidney and 5368 for gallbladder after 14 days exposure. 3. 2,4,6-Trichlorophenyl-4'-acetamide phenyl ether (CNP-acetamide) was detected as metabolites of CNP-amino in muscle and viscera of carp.
1. Bioconcentration and excretion of diazinon, IBP, malathion and fenitrothion were studied for carp (Cyprinus carpio L.). 2. The concentrations of these pesticides in muscle and viscera of the carp reached plateaus in 12-48 hr exposure. 3. The average values of bioconcentration factors (BCF) for diazinon were 20.9 in muscle, 60.0 in liver, 111.1 in kidney and 32.2 in gallbladder over the 168 hr exposure period. Similarly, those values were 4.3-26.7 for IBP, 2.7-17.3 for malathion, and 36.0-157.1 for fenitrothion. 4. The excretion rate constants of malathion (hr-1) were 0.13 for muscle, 0.12 for liver, 0.08 for kidney and 0.06 for gallbladder. Those of diazinon, IBP and fenitrothion (g.ng-1.hr-1) were 0.002-0.024 for muscle, 0.001-0.020 for liver, 0.0004-0.004 for kidney and 0.002-0.023 for gallbladder, respectively.
A 41-year-old woman was hospitalized for evaluation of diabetes mellitus and hypertension. The hormonal and radiological examinations revealed that she had pheochromocytoma of bilateral adrenal gland and medullary carcinoma of thyroid gland. Therefore, she was diagnosed as having Sipple's syndrome. She had no definite familial history, but her two sisters, already dead, had been strongly suspected of having had pheochromocytoma. First, bilateral adrenalectomy was performed and secondly, total thyroidectomy, excision of parathyroid and cervical lymph node dissection were performed. Histopathological diagnosis was pheochromocytoma of bilateral adrenal gland, medullary carcinoma of thyroid gland and chief cell hyperplasia of parathyroid gland. We report a case of Sipple's syndrome, which probably is the 88th case in Japan, with the review of the previous Japanese literature.
We report two cases of Philadelphia (Ph1) chromosome positive acute mixed lineage leukemia (AMLL) with breakpoint cluster region (bcr) (M-BCR-1) rearrangement. A 31 year-old-man (case 1) and a 42 year-old-woman (case 2) were admitted to our hospital for further evaluation of leucocytosis with atypical blasts. Each case was diagnosed as having bilineal type of AMLL because: (1) blasts in each case consisted of larger myeloid cells positive for myeloperoxidase and small lymphoid cells positive for PAS, and blasts in case 2 were positive for TdT; (2) blasts in case 1 expressed B lymphoid associated antigen; (3) Southern analysis in each case showed clonal rearrangements of both the immunoglobulin heavy chain and the T cell receptor beta gene. These two cases demonstrated the Ph1 chromosome and rearrangement of the bcr (M-BCR-1) gene, but none of splenomegaly, basophilia, and additional chromosome abnormalities were observed. In addition, after achieving remissions, they didn't revert to chronic phase of chronic myelogenous leukemia (CML) and showed normal neutrophil alkaline phosphatase scores, and the Ph1 chromosome disappeared completely in case 1 and coexisted with the normal chromosome in case 2. These findings suggest that diagnosis of both cases should not be CML blast crisis (BC) but Ph1 positive acute leukemia, and Ph1 positive AMLL may be a distinct clinical entity to be distinguished from CML-BC.
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The occurrence of aortic dissection in 2 or more family members is rare. Such occurred, however, in the brothers and elder sister described herein. Case 1: A 54-year-old male had chronic Type I dissecting aortic aneurysm with severe aortic insufficiency and abdominal aortic aneurysm. Case 2: A 57-year-old female had chronic Type II dissecting aortic aneurysm with severe aortic insufficiency. Case 3: A 49-year-old male had chronic Type IIb dissecting aortic aneurysm. Two cases (Case 1 & 3) of them had surgical interventions. The histology showed cystic medial necrosis of aorta. Neither of these 3 patients or other family members had skeletal or ocular features of the Marfan syndrome. The metacarpal indices of them were well within normal. Their parents are cousins. It is, therefore, likely that the occurrence of dissecting aneurysm in the above three cases was due to an underlying hereditary disease. Thus familial dissecting aneurysm is suggested.
We analyzed the chest CT findings in nine patients with biopsy-proven eosinophilic granuloma. Multiple cystic lesions with relatively thin walls seems characteristic of this disease. Small nodular lesions and increased density were observed in many cases. Pleural or subpleural lesions were found in all cases. In seven cases, the distribution of the lesions were predominantly in the upper or upper and middle lung fields. In the remaining two cases however, lesions were found homogeneously throughout the whole lung. In order to analyze the site of the lesions in the secondary pulmonary lobule, a specimen obtained from an open lung biopsy was inflated and fixed using fixative by Heitzman's method. Observation of the slices of the specimen by dissection microscope and their soft X-ray radiographs demonstrated that the lesion existed in the central area of acini. However, CT of the patient before open lung biopsy didn't showed centriacinar distribution. The disparity is because a certain number of lesions lobule is necessary to identify the centriacinar pattern by CT.
In order to know the entities of platelet defect in pernicious anemia, we investigated platelet functions in ten cases with pernicious anemia. Three of the cases had total gastrectomy. Five cases showed thrombocytopenia and four cases revealed prolongation of Ivy bleeding time. Decreased adhesiveness was observed in three cases. Various abnormalities in platelet aggregation were observed. However, almost all of the cases showed remarkable improvement of decreased platelet functions after the therapy of Vitamin B12 injection. The results of adenine nucleotides in platelets and the release of them following collagen or epinephrine aggregation were analysed in comparison with normal platelets. The ADP was definitely decreased and the ATP/ADP ratio was increased. In addition, the release of ATP and ADP at collagen or epinephrine induced aggregation was markedly decreased, and after the therapy of Vitamin B12, the decrease of adenine nucleotide release remarkably increased. In summary, the acquired defects of platelet function in pernicious anemia are regarded as a secondary storage pool disease, and its defects improve after Vitamin B12 therapy.
A case of pulmonary embolism associated with diabetes insipidus is reported in an 18-year-old male. The patient, who had been treated with DDAVP for diabetes insipidus and hydrocortisone for hypocorticism for two years after first operation for the removal of craniopharyngioma, was admitted with recurrence of that tumor. Diabetes insipidus immediately after second operation was controlled with intermittent drip infusion of a small amount of aqueous pitressin under monitorings of body weight hourly using a patient weighing system to keep the weight changes within +/- one kilogram. Serum and urine electrolytes levels, osmolarity, and free water clearance were also monitored every three hours to maintain water-electrolytes balances appropriately. Postoperative course had been uneventful except that CSF rhinorrhea occurred 7 days after operation. The patient was, then, kept in bed with horizontal plane to avoid further leakage of CSF. Two days later, he developed chest pain suddenly with tachypnea, tachycardia, and general cyanosis. The arterial-BGA showed PaO2 of 53.5mmHg and PaCO2 of 35.3mmHg in room air. The definite diagnosis of pulmonary embolism was made by technetium microaggregate lung perfusion scans and by pulmonary angiograms. The patient was treated with heparin, 15000IU/day, and urokinase, 720000IU/day. The symptoms due to pulmonary embolism had improved gradually within a couple of weeks. Recent articles have shown an unexpected high incidence of deep vein thrombosis and pulmonary embolism in neurosurgical patients associated with the elevation of blood coagulability. Brain tumors, especially suprasellar mass with hypothalamic dysfunction have been suggested to cause thromboembolic disorders frequently. The clinical course was described and factors causing pulmonary embolism on this patient was discussed.
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