Biomedical subjects

Y Isogai

Publications and source records attributed to Y Isogai.

At least 55 records · Page 3Linked to original sources

PubMed1994

A novel antitumor antibiotic, KW-2189 is activated by carboxyl esterase and induces DNA strand breaks in human small cell lung cancer cells.

KW-2189 has been selected as a lead compound for clinical trial among duocarmycin derivatives with structural similarity to CC-1065, a cyclopropylpyrroloindole. The purpose of this study was to examine the DNA-binding potency and the mechanisms of cytotoxicity of KW-2189. In order to analyze DNA-binding activity of KW-2189, plasmid pBR322 was treated with KW-2189 with or without pretreatment with carboxyl esterase, which we demonstrated to be an activating enzyme, and the products were examined by agarose gel electrophoresis and restriction enzyme analysis. Cytotoxic activity was examined by exposing a human small cell lung cancer cell line, NCI-H69 to KW-2189 with or without carboxyl esterase. Alkaline elution was performed to examine whether KW-2189 induces DNA strand breaks. DNA treated with KW-2189 and carboxyl esterase migrated faster than KW-2189-treated DNA, which migrated at the same rate as untreated DNA. In addition DNA treated with esterase-activated KW-2189 was protected from digestion by some restriction enzymes. KW-2189 showed concentration- and time-dependent growth inhibitory effect with IC50 values (drug concentration required for 50% growth inhibition) of 58 nM (96 h) to 1900 nM (1 h) in H69 cells. The IC50 values of 4-h exposure of H69 to KW-2189 with 0, 26, 130, 650 mU/ml carboxyl esterase were 460, 120, 30, and 7 nM, respectively. Time-dependent enhancement of cytotoxicity by carboxyl esterase was also observed. KW-2189 induced DNA strand breaks in H69 cells in a concentration-dependent manner around the IC50 value. We conclude that 1) KW-2189 is activated by carboxyl esterase to its active form(s), 2) activated KW-2189 has a stronger DNA-binding activity and cytotoxicity than KW-2189, 3) DNA cleavage is one of the major mechanisms of KW-2189-mediated cytotoxicity.

Antibiotics, Antineoplastic↗

PubMed1994

Correlation of altered Q-T interval and sympathetic nervous system dysfunction in diabetic autonomic neuropathy.

We examined the relationship between the Q-T interval and autonomic dysfunction in 74 diabetic patients and age-matched controls. The expected Q-T interval was standardized as a function of the R-R interval in 646 healthy controls, and the delta Q-T defined as the difference from the expected value. Propranolol increased delta Q-T, confirming this as a parameter of autonomic function. No relationship between delta Q-T and duration of disease, glucose control, retinopathy or proteinuria was observed. However, significant correlations were found between the delta Q-T and delay of nerve conduction velocity, orthostatic hypotension, altered Valsalva ratio, abnormal Valsalva overshoot, cold pressor response, decreased norepinephrine concentration and sympathetic function score in diabetic patients.

Adult↗

PubMed1994

Effects of NG-monomethyl-L-arginine, indomethacin, and aspirin on the vasodepressor response to low doses of endothelin-1 and endothelin-3 in rats.

Low doses (< or = 100 pmol/kg) of endothelin-1 (ET-1) and endothelin-3 (ET-3) elicited a fall in mean arterial pressure (MAP) and a dose-related reduction in hindquarter vascular resistance in anesthetized rats. The depressor response to low doses of ET-1 or ET-3 was short-lived (about 10 sec) and reversible. High doses (> or = 200 pmol/kg) of ET-1 and ET-3 elicited a biphasic response; an initial fall in MAP followed by a gradual increase in MAP. The pressor response to large doses of ET-3 was less than that to large doses of ET-1. On the other hand, the depressor response to low doses of ET-3 was similar to that to low doses of ET-1. Both ET-1 and ET-3 at low doses exhibited primarily a vasodilatory activity. Pretreatment with NG-monomethyl-L-arginine (L-NMMA), a compound that inhibits nitric oxide (NO) production by endothelial cells, attenuated the hypotensive and hindquarter vasodilating effects of low doses of these isopeptides, indicating that the hindquarter vasodilating responses to these peptides depend upon the release of NO from endothelial cells. On the other hand, pretreatment with either aspirin or indomethacin did not alter the hypotensive or the hindquarter vasodilating effects of either ET-1 or ET-3, indicating that cyclooxygenase products may not be involved in the vasodepressive mechanisms of these peptides. L-NMMA attenuated the vasodilating effects of these peptides, but did not completely inhibit the response, suggesting that NO production by endothelial cells plays only a partial role in the vasodilation of ET in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

A young case with multi-infarct dementia associated with lupus anticoagulant.

A 39-year-old man was admitted because of an abrupt onset of right-side weakness and dysarthria. During the 2 years before admission, he had suffered from insomnia, depressed mood and progressive memory disturbance. Neurological and psychiatric examination revealed severe intellectual impairment in addition to the neurological deficits. Neuroradiological examinations revealed multiple brain infarcts. He had no risk factor for stroke except for lupus anticoagulant. He was diagnosed as having multi-infarct dementia associated with antiphospholipid antibodies. This case suggests that it is necessary to investigate antiphospholipid antibodies in addition to neuroradiological examination when relatively young patients present with unexplained cognitive or behavioral symptoms.

Adult↗

PubMed1994

[Relationship between behavioral problems and cognitive status in Alzheimer type and mixed Alzheimer and vascular dementia].

To investigate the relationship between troublesome behavior and cognitive status in Alzheimer type dementia (DAT), and to know whether the addition of cerebrovascular ischemia modifies that relationship, we studied behavioral and cognitive data from a clinical series of 57 DAT patients (mean age: 83.4 yrs) and 31 patients with mixed Alzheimer and vascular dementia (MIX) (mean age: 83.4 yrs). All subjects were ambulatory and were recruited from among patients having been admitted to our affiliated nursing home. None of them had any serious systemic diseases. The Dementia Behavior Disturbance scale (DBD), originally developed by Baumgarten et al, and the Mini-Mental State (MMS) were used for the evaluation of behavioral problems and cognitive status, respectively. In the DAT group, a significant correlation was recognized between DBD and MMS scores. In the MIX group, however, DBD scores did not correlate with MMS scores. Among patients having MMS scores greater or equal to 20, those with MIX had higher DBD scores (mean 19.3) than those with DAT (mean 13.7), although MMS scores in these two subgroups were comparable. These findings suggest that in DAT, behavioral problems increase in conjunction with cognitive impairments. However, with the addition of cerebrovascular ischemia to Alzheimer pathology, behavioral impairments may progress independently of cognitive decline, with more frequent presentation of troublesome behaviors in the early stage of dementia.

Aged↗

PubMed1993

Physiology and morphology of spiking local interneurons in the terminal abdominal ganglion of the crayfish.

Not only nonspiking local interneurons but also spiking local interneurons in the terminal abdominal ganglion of the crayfish (Procambarus clarkii Girard) contribute to form the motor output of the uropod. In this study, 14 spiking local interneurons are identified by their gross morphology and physiological properties including the sensory inputs from the uropod and premotor output onto the uropod motor neurons on both sides. Morphologically, they are divided into three groups based on the position of their somata: anterior, medial, and posterior. The main branches of interneurons in each group are usually extended on the side contralateral to the soma, or they have profuse bilateral branches. Physiologically, all of them receive excitatory inputs from the afferents innervating the exopodite on the side ipsilateral their main branches. They are usually silent, and spike only in response to sensory stimulation. The majority of them (11 out of 14 neurons) have output effects on the uropod motor neurons that elicit reciprocally closing pattern. They increased the activity of the closer motor neurons and decreased the activity of the opener motor neurons. Only one interneuron inhibits the closer motor neurons. The remaining two interneurons coactivate both the antagonistic motor neurons. Since the reciprocal closing pattern of the uropod motor neurons is elicited in response to sensory stimulation of the uropod, spiking local interneurons may initiate this local reflex circuit. They detect the initiation of the stimulus and convey signals from the sensory to the motor side.

Animals↗

PubMed1993

Specific modification of structure and property of myoglobin by the formation of tetrazolylhistidine 64(E7). Reaction of the modified myoglobin with molecular oxygen.

Tetrazole-myoglobin (Tet-Mb), a site selectively modified myoglobin with tetrazole anion (-CN4-) covalently attached to the imidazole N epsilon of the distal histidine 64(E7) (see Fig. 1; Kamiya, N., Shiro, Y., Iwata, T., Iizuka, T., and Iwasaki, H. (1991) J. Am. Chem. Soc. 113, 1826-1829), exhibited unique properties in the reduction from ferric to ferrous states and in the reaction of its deoxy form with O2. The redox potential of Tet-Mb is obtained to be -193 mV, which is much lower than that of unmodified (native) myoglobin (50 mV), possibly due to the electrostatic interaction between the heme iron and the tetrazole group. The ferrous deoxy form of Tet-Mb was rapidly oxidized to its ferric form in the reaction with O2 at room temperature through an intermediary formation of its oxy form and with the generation of O2-. The oxy form of Tet-Mb can be detected by the optical spectral measurement at -12 degrees C, the rapid scan measurement at room temperature, and the electron spin resonance measurement of its cobalt-substituted derivative (Tet-Mb(Co2+)) at 77 K. In the kinetic measurement of the O2 binding reaction to Tet-Mb, its association and dissociation rate constants in the bimolecular reaction were 6.1 x 10(7) M-1 s-1 and 2200 s-1, respectively, showing that the tetrazole modification of His-64 extremely accelerates its association and dissociation rates. Taken together with the extremely fast autoxidation rate (53 h-1) obtained, these kinetic results suggested that the channel of O2 from the solvent region to the protein interior is open enough to pass the external ligand. The structure is discussed in relation to those of some genetic mutants. Taking these properties, we demonstrated that Tet-Mb can catalyze O2 consumption to generate O2-, coupled with the NADH-supported enzymatic reduction system of cytochrome P-450cam under an aerobic condition.

Amino Acid Sequence↗

PubMed1993

Intersegmental ascending interneurons controlling uropod movements of the crayfish Procambarus clarkii.

The premotor effects of intersegmental ascending interneurons upon uropod motor neurones in the crayfish Procambarus clarkii (Girard) are examined with intracellular recording and staining techniques. We show that many ascending interneurones can affect the activity of the antagonistic opener and closer motor neurones in the terminal ganglion. Based upon soma position, ascending interneurones are divided into three groups of rostral, medial, and caudal interneurones. Twenty-four ascending interneurones are characterized physiologically according to their inputs from the tailfan and their output effects on the uropod motor neurones of both sides. Each interneurone is identifiable as a unique individual by means of overall shape, soma position, number of main branches, the commissure in which primary neurites cross the midline, axon position in the 5th-6th abdominal connective and physiological responses. They are classified into six classes; coactivating, coinhibiting, reciprocally closing, reciprocally opening, variably effective, and not effective interneurones, according to their premotor effects on the uropod motor neurones. These ascending interneurones seem to act as multifunctional units conveying sensory information from the tailfan to the anterior abdominal ganglia and, at the same time, influencing the uropod motor pattern in the terminal abdominal ganglion.

Animals↗

PubMed1993

Superoxide-producing cytochrome b. Enzymatic and electron paramagnetic resonance properties of cytochrome b558 purified from neutrophils.

Molecular properties of superoxide (O2-)-producing cytochrome b558 purified from neutrophils were investigated focusing on the mechanism of the catalytic reaction. The purified cytochrome, which was depleted of FAD, exhibited high O2(-)-generating activity with consumption of NADPH in the presence of microsomal NADPH-cytochrome P-450 reductase. Exogenous additions of CO, CN-, or N3- had no effect on the enzymatic activity. Potentiometric titration of the ferric-ferrous couple of the cytochrome showed that the midpoint reduction potential was -255 mV at pH 7.4. When the reaction of the reduced cytochrome with O2 was analyzed by stopped flow and rapid scanning spectrophotometry, the ferrous form was found to be converted to the ferric form at a rate constant of 9.3 x 10(6) M-1 s-1 at 10 degrees C without showing formation of an oxygenated intermediate. EPR measurement of the ferric cytochrome at 10 K showed that the electronic spin state was in a low spin with g values of 3.2, 2.05, and 1.5. These results suggest that the heme in a six-coordinated low spin state catalyzes one electron reduction of O2 without ligation of O2 to the heme iron during the catalytic cycle.

Animals↗

PubMed1993

Characterization of superoxide dismutase-insensitive cytochrome c reductase activity in HL-60 cytosol as NADPH-cytochrome P450 reductase.

A flavoprotein dehydrogenase assayed for the activity of electron transfer from NADPH to cytochrome c was highly purified from the cytosolic fraction of differentiated human promyelocytic leukemia HL-60 cells. The purified enzyme had an apparent molecular mass of 68 kDa by sodium dodecyl sulfate gel electrophoresis and an equimolar amounts of flavin mononucleotide and flavin-adenine dinucleotide. The purification factor of the enzyme with respect to the cytosolic fraction was close to 1100 and the recovery of activity was approximately 18%. Reduction of cytochrome c by NADPH indicated Michaelis-Menten kinetics with a Km value of 1.50 microM for NADPH. When cytochrome c was the varied substrate, a Km value of 4.10 microM was obtained. NADH was not an effective electron donor for cytochrome c reduction and NADPH-dependent reduction of nitroblue tetrazolium was negligibly small. The purified enzyme alone did not exhibit superoxide production, and NADPH oxidase activity was not markedly stimulated upon incubation of the reductase with cytochrome b558 purified from porcine neutrophils. The purified flavoprotein gave a positive cross-reactivity to polyclonal antibodies raised to microsomal NADPH-cytochrome P450 reductase, indicating structural homology between these enzymes. The catalytic properties of the purified NADPH-cytochrome c reductase have similarities to those of liver NADPH-cytochrome P450 reductase.

Antibodies, Monoclonal↗

PubMed1993

Type 1 (insulin-dependent) diabetic patient with remarkable infiltration of lymphocytes to the islets.

We report the case of a 62-year-old woman who was admitted to our hospital with diabetic ketoacidosis. Her urinary C-peptide was 3.5 micrograms/day, HLA typing was DR9, and serum was positive for islet cell antibodies. There was no significant increase in the major viral titer. Pancreatic head tumor was suspected, and pancreaticoduodenectomy was performed. The pathology of this tumor was polycystic adenoma. We examined the surgical specimen from around the tumor histologically. The pancreatic islets had decreased in number. The immunohistochemical staining of islets for insulin, glucagon and somatostatin showed that the number of B cells had decreased remarkably, while A and D cells were preserved. Marked lymphocytic infiltration was observed in the islets. The majority of lymphocytes were helper/inducer and suppressor/cytotoxic T cells, which did not express HLA-DR antigen or interleukin-2 receptor. No NK cells were present in the islets. The present case, which was examined histologically in detail, is consistent with the previously proposed hypothesis that autoimmunity might play an important role in the pathogenesis of insulin-dependent diabetes mellitus.

Adenoma↗

PubMed1993

Social and economic impact on youth-onset diabetes in Japan.

OBJECTIVE: To investigate the social and economic backgrounds of youth-onset insulin-treated diabetes mellitus in Japan. RESEARCH DESIGN AND METHODS: We conducted a case-control study on 35 diabetic patients with age at onset of 19.5 +/- 5.1 yr and duration of diabetes 14.9 +/- 6.7 yr. Sex- and age-matched (within 5 yr) siblings were selected as control subjects. Thirty-five matched pairs were asked to complete a questionnaire, including employment status and educational achievement. RESULTS: Overall, diabetic patients were more likely to encounter job refusal in their lives than sibling control subjects (20 vs. 0%), and most patients (6/7) who had an experience of job refusal told job interviewers about their diabetes. Although the full-time employment rate and unemployment rate did not differ significantly between patients and control subjects, income levels were lower among patients than in the sibling (1600 vs. 2500 thousand yen). A multivariate analysis indicated that patients had lower incomes than control subjects after adjusting for the effect of physical disability. Educational achievements in the patients were similar to those in the siblings. CONCLUSIONS: These results suggested that diabetic patients had several social and economic problems in Japan. Further studies in more subjects are required to grasp the social and economic impact on diabetes precisely, and minimize the social handicaps on diabetic patients.

Absenteeism↗

PubMed1993

[Heart failure due to metabolic heart disorders].

The classification of myocardial diseases, proposed by the WHO/ISFC task force in 1980, distinguishes specific heart muscle diseases from myocardial diseases of unknown origin, termed cardiomyopathies. In this article, specific heart muscle diseases caused by metabolic disturbances are reviewed. The disorders were categorized into 4 types: 1. endocrine disorders; 2. storage or infiltration disorders, such as amyloidosis, hemochromatosis and familial storage disorders; 3. nutritional disorders, such as Kwashiorkor, beri-beri, obesity and alcoholic and electrolyte disorders; and 4. Diabetic heart. Since the first type disorders have been covered by a separate review, the other 3 types were covered in this article. A common clinical picture of these disorders is chronic congestive heart failure. The pathogenesis and laboratory findings of these disorders are briefly discussed.

Amyloidosis↗

PubMed1993

[Double meningoencephalitis with herpes simplex virus and rubella virus].

A 47-year-old man suffered from a headache, fever and memory disturbance. He was admitted to Morimoto Hospital. Neurological examination revealed disturbance of memory of recent events. Cranial nerves were normal. Muscle strength of the extremities was normal, except for Barré's sign of the right upper extremity. Deep tendon reflexes were exaggerated bilaterally, and extensor plantar response of the left side was elicited. Sensory examination showed no abnormality. Cerebellar sign was not recognized. Meningeal sign was slightly but clearly showed. CT scan demonstrated brain swelling at the right insular cortex region followed by severe hydrocephalus with dilatation of the lateral and the third ventricles. Cerebrospinal fluid showed high CSF pressure (250 mmH2O), pleocytosis (C.C. 359/mm3) and elevated protein level (213 mg/dl). Virological examination revealed herpes simplex virus (HSV) (CF) 32x, HSV-1 IgG (EIA) 4,050X, rubella virus IgE (EIA) 6,060X, cytomegalovirus (CMV) IgG (EIA) 1,130X in serum and HSV (CF) 1X, HSV-1 IGg (EIA) 1,430X, rubella virus IgG (EIA) 1,480X, CMV IgG (EIA) 587X in CSF. The ratio of serum/CSF of HSV and rubella virus titers by EIA methods were 2.83 and 4.10, respectively. He was treated by acyclovir 1,000 mg/day and gamma globulin, but his condition get worse acutely and died at 15th hospital days. This case was considered as a meningoencephalitis caused by simultaneous HSV and rubella virus infection.

Antibodies, Viral↗

PubMed1993

[Spontaneous splenic rupture in a case of non-Hodgkin's lymphoma].

A 58-year-old man admitted to hospital as an emergency with pain in the left hypochondrium. The initial physical examination revealed hypotension, giant splenomegaly and ascites but no lymphadenopathy was found. Laboratory findings at admission included hemoglobin level of 9.2g/dl, leucocyte count of 22, 100/microliters with 2% of lymphoma cell and platelets count of 66,000/microliters. A presumptive diagnosis of ruptured spleen was made. Splenectomy was performed after 7 hours from admission. The spleen was infiltrated by malignant lymphoma. Three weeks after surgery, left neck and abdominal lymphoadenopathy were recognized, therefore systemic chemotherapy was started. The leukemic change was one of important factors for the mechanisms of spontaneous splenic rupture in malignant lymphoma.

Antineoplastic Agents↗

PubMed1992

Effect of captopril on isoproterenol-induced cardiac hypertrophy and polyamine contents.

It is well known that isoproterenol (ISO) a nonselective beta adrenoceptor agonist induces cardiac hypertrophy. It can be assumed that, in addition to its direct cardiac effect, ISO has a cardiac trophic effect via stimulation of the renin angiotensin system. Synthesis of polyamines is facilitated in cardiac hypertrophy and polyamine levels are rapidly elevated prior to an increase in heart weight. In the present study, we investigated whether captopril (30 mg/kg body weight, daily) could attenuate cardiac hypertrophy and elevation of cardiac polyamine levels in rats, which effects were elicited by a chronic (1- or 2-weeks) and repeated administration of a small dose (0.5 mg/kg body weight) of ISO. Cardiac hypertrophy was assessed by an increase in the wet weight and RNA content of the heart. Polyamines were analyzed by HPLC. Captopril alone did not affect either heart weight/body weight ratio or cardiac contents of polyamines and nucleic acids at the end of the second week. In isoproterenol-treated rats, the above parameters, except for putrescine content on day 14, were significantly increased on both day 7 and day 14. Captopril slightly attenuated ISO-induced cardiac hypertrophy and significantly prevented the ISO-evoked increase in the contents of RNA, spermidine, and spermine at the end of the second week. These results suggest that the ISO-evoked increase in cardiac polyamines was mediated, at least in part, by the renin angiotensin system, which was stimulated by ISO.

Animals↗

PubMed1992

Interstitial nephritis associated with glomerulonephritis in a patient with Hashimoto's disease and idiopathic portal hypertension.

A middle-aged women with hypothyroidism, idiopathic portal hypertension and nephrotic syndrome is presented. This unusual clinical appearance could not be explained as SLE by serological examinations. Pathohistological examinations showed "Banti's liver", Hashimoto's thyroiditis and diffuse proliferative glomerulonephritis with severe tubulo-interstitial nephritis. Immunohistochemical studies revealed IgA deposits in glomeruli. Electron microscopic study disclosed peculiar lucent areas of rarefaction with osmiophilic particles in tubular basement membranes. This tubulointerstitial nephritis was considered to be related to the immunological mechanism involving thyroid gland, liver and kidney disorders. This case thus had a clinically rare combination of these three.

Female↗

PubMed1992

Fabry's disease.

A 20-year-old man presented with generalized acquired anhidrosis and heat intolerance which was confirmed by a sweat test. Other clinical features included severe pain of the extremities and cutaneous angiokeratomas. On electronmicroscopy, granules specific for Fabry's disease were observed in the endothelial cells. Biochemical examination revealed a decreased level of serum alpha-galactosidase A. These findings confirmed the diagnosis of Fabry's disease.

Adult↗