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Biomedical subjects

J Nakamura

Publications and source records attributed to J Nakamura.

At least 145 records · Page 8Linked to original sources
PubMed1999

An aldose redutase inhibitor prevents the intimal thickening in coronary arteries of galactose-fed beagle dogs.

AIMS/HYPOTHESIS: Although increased polyol pathway activity has been implicated in the pathogenesis of diabetic microangiopathy, the relation with diabetic macroangiopathy remains unclear. Galactose feeding is known to stimulate the polyol pathway and to develop abnormalities similar to those in diabetic microangiopathy. Our study was conducted to investigate whether an activation of polyol pathway by long-term treatment with galactose produced morphological changes in coronary arteries of dogs and the effect of an aldose reductase inhibitor, epalrestat, was also studied. METHODS: Dogs received either normal chow or chow containing 30% galactose with or without epalrestat given orally (20 or 50 mg x kg(-1)). After 44 months, morphometric analyses of coronary arteries were carried out and the galactitol contents in aortas were measured. RESULTS: The ratio of areas of the intimal layer to those of the medial layer, an indicator of intimal thickening, was statistically significantly increased in galactose-fed dogs compared with control dogs. Galactose-fed dogs had a remarkable accumulation of galactitol in their aortas. These morphological and biochemical deficits were reduced by treatment with epalrestat. CONCLUSION/INTERPRETATION: This report morphologically shows diabetes-like macrovascular abnormalities in galactosaemic animals, suggesting that polyol pathway hyperactivity is closely related to the development of diabetic macroangiopathy, which could be prevented by aldose reductase inhibition.

Aldehyde Reductase↗
PubMed1999

Actions of adenosine A2A receptor antagonist KW-6002 on drug-induced catalepsy and hypokinesia caused by reserpine or MPTP.

RATIONALE: Current treatment of Parkinson's disease (PD) is based on dopamine replacement therapy, but this leads to long term complications, including dyskinesia. Adenosine A2A receptors are particularly abundant in the striatum and would be a target for an alternative approach to the treatment of PD. OBJECTIVES: The purpose of this study is to examine the efficacy and potency of the novel selective adenosine A2A receptor antagonist (E)-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dhydro- 1H-purine-2,6- dione (KW-6002) in ameliorating the motor deficits in various mouse models of Parkinson's disease. METHODS: We evaluated the efficacy and potency of KW-6002 and other reference compounds in the selective adenosine A2A receptor agonist 2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamidoadenosin e (CGS 21680)-, haloperidol- or reserpine-induced catalepsy models. The effect of KW-6002 on reserpine or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride(MPTP)-induced hypolocomotion was also examined. RESULTS: The ED50s of KW-6002 in the reversal of CGS21680-induced and reserpine-induced catalepsy were 0.05 mg/kg, PO and 0.26 mg/kg, PO, respectively. Compared to the ED50 of other adenosine antagonists and dopamine agonist drugs, KW-6002 is over 10 times as potent in these models. KW-6002 also ameliorated the hypolocomotion (minimum effective dose; 0.16 mg/kg) induced by nigral dopaminergic dysfunction with MPTP or reserpine treatment. Combined administrations of subthreshold doses of KW-6002 and L-dopa (50 mg/kg, PO) exerted prominent effects on haloperidol-induced and reserpine-induced catalepsy, suggesting that there may be a synergism between the adenosine A2A receptor antagonist KW-6002 and dopaminergic agents. CONCLUSIONS: To our knowledge, KW-6002 is the most potent and orally active adenosine A2A receptor antagonist in experimental models of Parkinson's disease, and may offer a new therapeutic approach to the treatment of Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1999

Photodynamic therapy using mono-L-aspartyl chlorin e6 for rabbit experimental hepatoma.

Photodynamic therapy and photodynamic diagnosis using photosensitizers have yet to be clinically employed for hepatoma. Mono-L-aspartyl chlorin e6, a chlorin derivative with high tumor affinity developed as a second-generation photosensitizer, enables rapid tumor detection after administration, without light-shielding. This study examined the potential of photodynamic therapy, using this photosensitizer, for hepatoma in rabbits. VX2 tumor cells were transplanted into the liver of Japanese white rabbits, and the animals were administered 2.5 mg/kg of mono-L-aspartyl chlorin 36 1 week later. Accumulation of mono-L-aspartyl chlorin e6 in hepatoma was observed over time with an epifluorescence stereoscope, and the efficacy of continuous photodynamic therapy following photodynamic diagnosis was examined. A diode laser system was used for treatment, and efficacy was examined in a control group and four other groups that were irradiated at different times following administration. Efficacy in suppressing tumor growth, tumor necrosis rates, and efficacy in suppressing pulmonary metastasis were studied. For all these aspects, treatment was significantly more effective in the group irradiated 5 minutes after administration than in groups irradiated at later times. Liver function testing in all groups revealed no distinct disorders. Photodynamic therapy with mono-L-aspartyl chlorin e6 may be suitable for clinical use in therapy for hepatoma.

Analysis of Variance↗
PubMed1999

Automated and simultaneous identification of microsatellite instability by fluorescence-based polymerase chain reaction (PCR) in four loci.

Genomic instability is sometimes due to impairment of DNA repair systems, which results in a change in the number of microsatellite repeats in tumor cells, produced by slippage during DNA replication. Such abnormal repeats are manifested as microsatellite instability (MSI). We have devised a simple assay using four-color fluorescence for the detection of MSI by an automatic sequencer. Using this method, MSI and loss of heterozygosity (LOH) at four microsatellite loci can be identified simultaneously. We have also developed an algorithm and software for automated analysis of MSI and LOH with this method. Using our method for the detection of MSI in four microsatellite loci and the algorithm and software that we developed, 18 (94.7%) of 19 patients with hereditary nonpolyposis colorectal cancer (HNPCC), meeting the Amsterdam Minimum Criteria, were found to exhibit MSI.

Colorectal Neoplasms, Hereditary Nonpolyposis↗
PubMed1999

Effect of vitamin E and allylamine on the proliferation of cultured aortic smooth muscle cells from streptozotocin-induced diabetic rats.

To investigate the effect of vitamin E on the proliferation activity of vascular smooth muscle cells (SMCs) in diabetes mellitus, [3H]-thymidine incorporation was measured in cultured SMCs isolated from normal and streptozotocin-induced diabetic rats treated with or without vitamin E and/or allylamine. Untreated diabetic rats demonstrated significantly elevated concentrations of serum total cholesterol, triglycerides and malondialdehyde (MDA). Allylamine caused a further increase in serum MDA. Treatment with vitamin E decreased the serum concentrations of triglycerides and MDA in both allylamine-treated and -untreated diabetic rats. [3H]-Thymidine incorporation in cultured SMCs from diabetic rats was significantly increased compared with that from normal rats. SMCs from allylamine-treated diabetic rats showed an enhanced increase in thymidine incorporation compared with that from untreated diabetic rats. The increase in thymidine incorporation in SMCs from untreated and allylamine-treated diabetic rats was significantly reduced by the treatment with vitamin E. These observations suggest that vitamin E has a preventive effect on the proliferation of vascular SMCs in diabetes, and that this effect may be mediated through an enhancement of free radical scavenging.

Allylamine↗
PubMed1999

2-Chloroadenosine reverses hyperglycemia-induced inhibition of phosphoinositide synthesis in cultured human retinal pigment epithelial cells and prevents reduced nerve conduction velocity in diabetic rats.

The effect of the adenosine (AD) analog 2-chloroadenosine (C-AD) on glucose-induced inhibition of phosphoinositide synthesis was studied in human retinal pigment epithelial (RPE) cells by monitoring the level of the phosphatidylinositol (PI) synthase substrate, cytidine diphosphate diglyceride (CDP-DG). In high-aldose reductase (AR)-expressing RPE 91 cells, C-AD decreased CDP-DG at 5 mmol/L glucose and reversed the increase by 20 mmol/L glucose. AD deaminase (ADA), which inactivates endogenously released AD, potentiated the hyperglycemia-induced increase in CDP-DG. Theophylline, an AD-A1 and AD-A2 receptor antagonist, caused an increase in CDP-DG at 20 mmol/L glucose. C-AD did not alter CDP-DG in low-AR-expressing RPE 45 cells, but did decrease CDP-DG after cells were conditioned in 300 mmol/L glucose for 1 week (which induces AR). The mechanism by which AD regulates PI synthase in cells with high AR activity is unknown, but it is independent of Gi or Gs proteins, adenylate cyclase and phospholipase C (PLC) activation, myo-inositol (MI) uptake, or MI efflux. Administration of C-AD to streptozotocin-induced diabetic rats prevented the slowing of motor nerve conduction velocity (MNCV). Thus, AD derivatives, which reverse a glucose-induced deficit in phosphoinositide metabolism, might serve as a useful pharmacological tool to intervene in hyperglycemia-induced diabetic complications.

2-Chloroadenosine↗
PubMed1999

Activation of Kupffer cells and caspase-3 involved in rat hepatocyte apoptosis induced by endotoxin.

BACKGROUND/AIMS: Sepsis and lipopolysaccharides (LPS) cause mild to severe hepatic dysfunction. In this study, Kupffer cell activation, involvement of TNFalpha and caspases downstream of the TNFalpha receptor were examined in hepatocyte apoptosis induced by LPS. METHODS: In in vivo experiments, male Sprague-Dawley rats were injected intravenously with LPS, and small amounts of the blood and liver were sampled to evaluate apoptosis. Kupffer cells were inactivated by pretreatment with gadolinium chloride for 2 days. In in vitro experiments, hepatocytes and Kupffer cells were separately isolated from rat livers using collagenase perfusion. RESULTS: LPS induced time-dependent and dose-dependent increases in the number of TUNEL-positive cells, which coincided with the apoptotic features of hepatocytes demonstrated by electron microscopy and DNA ladder. Activation of caspase-3-like proteases was observed with an increase in the number of apoptotic hepatocytes. Immunostaining with activated caspase-3-specific antibody showed that caspase-3 was activated only in the cytoplasm of TUNEL-positive hepatocytes. Inactivation of Kupffer cells by gadolinium chloride was concomitantly accompanied by the prevention of caspase-3 activation, hepatocyte apoptosis and liver injury induced by LPS. The co-culture system of hepatocytes and Kupffer cells, but neither cell culture system, individually, showed LPS-induced hepatocyte apoptosis. Kupffer cell-conditioned medium induced hepatocyte apoptosis, whereas addition of anti-TNFalpha antibody to Kupffer cell-conditioned medium did not. Additions of acetyl-DEVD-CHO, acetyl-YVAD-CHO, and acetyl-IETD-CHO to Kupffer cell-conditioned medium decreased the number of apoptotic hepatocytes. CONCLUSIONS: These results suggest that the activation of Kupffer cells, TNFalpha and caspases downstream of TNFR1 were involved in hepatocyte apoptosis induced by LPS.

Alanine Transaminase↗
PubMed1999

Cataract surgery training using pig eyes filled with chestnuts of various hardness.

This method uses pig eyes filled with cooked chestnuts serving as pseudonuclei with the goal of teaching dividing techniques of phacoemulsification and aspiration. The pseudonuclei simulate the various degrees of human lens nuclear sclerosis. The chestnuts are trimmed to lens size. After lens extraction through a self-sealing straight incision from the pig eyes, the chestnuts are inserted in the capsular bag through the incision, which is then sutured. These preparatory procedures were initially performed by experienced surgeons but after practicing phacoemulsification technique several times, inexperienced surgeons were able to complete the entire procedure, allowing them to practice phaco chop, divide and conquer, and nondividing phacoemulsification.

Animals↗
PubMed1999

Species difference in radioactivity elimination from liver parenchymal cells after injection of radiolabeled proteins.

To elucidate the cause for the different levels of hepatic radioactivity among mammals after injection of protein radiopharmaceuticals, the metabolism of radiolabeled proteins and the fate of their radiometabolites in the parenchymal cells of rat liver were investigated and compared with those of mice. We used galactosyl-neoglycoalbumin (NGA) as a carrier protein, and NGA was labeled with 111In via 1-(4-isothiocyanatobenzyl)ethylenediaminetetraacetic acid (SCN-Bz-EDTA) or 1-[p-(5-maleimidopentyl)aminobenzyl]ethylenediaminetetraacetic acid (EMCS-Bz-EDTA) and with 125I via direct iodination. All radiolabeled NGAs exhibited rapid accumulation in liver parenchymal cells after intravenous injection into rats. Radioactivity was eliminated following NGA-125I injection at similar rates from rat and mouse liver. In contrast, both 111In-labeled NGAs demonstrated much slower elimination of radioactivity in rat when compared with mouse liver. Analyses of radioactivity in bile and liver indicated that both SCN-Bz-EDTA and EMCS-Bz-EDTA rendered mono-amino acid adducts as the final radiometabolites, which were generated in rat liver within 1 h postinjection. Subcellular distribution studies suggested that these radiometabolites were copurified with lysosome in rat liver. Because similar results were observed in mice previously, the difference between rats and mice in radioactivity elimination from liver parenchymal cells would be predominantly attributable to the different efflux rate of the 111In-labeled metabolites from the lysosome between these species. Such differences in the efflux rates of radiometabolites from the lysosome among mammals may also account for the different hepatic radioactivity levels of radiolabeled proteins between animal and clinical studies.

Albumins↗
PubMed1999

Immunoaffinity/gas chromatography/high-resolution mass spectrometry method for the detection of N(2),3-ethenoguanine.

Etheno adducts are formed after exposure to a number of carcinogens, including vinyl chloride, as well as endogenously as a result of lipid peroxidation. A sensitive and selective assay for N(2), 3-ethenoguanine (epsilonGua) was developed using immunoaffinity (IA) columns made with polyclonal antibodies to epsilonGua followed by gas chromatography/electron capture negative chemical ionization/high-resolution mass spectrometry (GC/ECNCI/HRMS) analysis of its pentafluorobenzyl derivative. These IA columns were specific for epsilonGua and did not bind guanine, deoxyguanosine, 1, N(6)-ethenoadenine, or 1,N(2)-ethenoguanine. The level of recovery of standards from the IA columns was 107 +/- 7% and throughout the entire method (using nucleoside enzymatic digestion) with or without DNA was 72 +/- 6%. Four different hydrolysis/digestion procedures were compared, nucleoside enzymatic (EZ), neutral thermal hydrolysis (NT), formic acid hydrolysis (FA), and HCl hydrolysis. All hydrolysis methods with subsequent IA chromatography produced linear standard curves with r(2) values of 0.999 or better. The level of epsilonGua in chloroethylene oxide-treated calf thymus DNA (CEO-ctDNA) was 38 +/- 2, 42 +/- 3, and 49 +/- 2 fmol of epsilonGua/microg of DNA using EZ, NT, and FA, respectively. These numbers remained consistent when the amount of DNA processed was doubled or tripled. These numbers were comparable to the previously published value of 55 +/- 8 fmol of epsilonGua/micrograms of DNA for the same DNA using HCl hydrolysis, cation exchange cleanup, and LC/MS analysis [Yen, T. Y., et al. (1996) J. Mass Spectrom. 31, 1271-1276]. Additionally, HCl hydrolysis of rat liver DNA from control and vinyl fluoride-exposed rats gave similar epsilonGua results when compared to those from enzymatic digestion using this method. This method gave a detection limit of 5 epsilonGua adducts/10(8) normal dGuo nucleosides in 150 micrograms of DNA using EZ and somewhat lower detection limits using NT and HCl hydrolysis. The method is more sensitive and selective than previously used methods for the quantitation of this adduct.

Animals↗
PubMed1999

Characterization of ocular pharmacokinetics of beta-blockers using a diffusion model after instillation.

PURPOSE: To characterize the ocular pharmacokinetics of beta-blockers (timolol and tilisolol) after instillation in the albino rabbit using a mathematical model that includes a diffusion process. METHODS: The disposition of fluorescein isothiocyanate-dextran (FITC-dextran, molecular weight 4400), timolol, and tilisolol was determined in tear fluid and aqueous humor after instillation or ocular injection in rabbits. The in vivo penetration parameters were estimated by fitting the concentration-time profiles to the Laplace equations based on a diffusion model using MULTI(FILT) program. The in vitro permeability of drugs was measured across cornea using a two-chamber diffusion cell. RESULTS: Concentration-time profiles of drugs in the tear fluid after instillation showed a monoexponential curve. Although a monoexponential curve was observed in the aqueous humor concentration of FITC-dextran after injection into the aqueous chamber, timolol and tilisolol showed a biexponential curve. On the basis of these results, an in vivo pharmacokinetic model was developed for estimation of penetration parameters. The in vitro partition parameters were higher than those of the in vivo parameters. CONCLUSIONS: The ocular absorption of timolol and tilisolol was characterized using an in vivo pharmacokinetic model and in vivo penetration parameters.

Absorption↗
PubMed1999

Aldehyde dehydrogenase genotypes and male alcohol use disorders: a case-control study in Khon Kaen, north-east Thailand.

A genetic epidemiological case-control study on aldehyde dehydrogenase 2 (ALDH2) genotype and male probable alcohol use disorders (AUD) was performed in Khon Kaen province, northeast Thailand. One hundred and twenty-four of cases (probable AUD) were obtained from male villagers aged 18-65 years using the modified Michigan Alcoholism Screening Test-Thai version. The same number of controls were selected, being matched with the cases in terms of age (+/-4 years) within the same village. Marital status, education history and past or present histories of physical illnesses were essentially the same for the cases and the controls. All of the cases and 85.5% of the controls were current drinkers, and the cases tended to drink significantly more often than the controls. Genomic DNA was extracted from fingernails and ALDH2 genotypes were determined by polymerase chain reaction technique and digested by Ksp 632I. The ALDH2 genotypes of the cases and the controls were not significantly different: 90.3% versus 91.1% normal homozygote; 8.1% versus 8.9% heterozygote; and 1.6% versus 0.0% mutant homozygote, respectively. Among the normal homozygote, the daily amount of alcohol intakes of the cases were significantly larger than that of the controls (56.2+/-40.6g vs. 8.1+/-14.1 g), the same was found among the ALDH2 deficient (55.9+/-43.4 vs. 2.2+/-5.8 g). Multivariate analysis based on the conditional logistic regression model showed no significant association of AUD with ALDH2 genotype, marital status, education history, or past history of injury, however, occupation and daily amount of alcohol intake were found to be significantly associated with AUD (OR = 10.72, 95% CI = 1.15-99.99, P = 0.037, and OR = 1.12, 95% CI = 1.06-1.18, P = 0.000, respectively). Non-farmers showed 10.7 times larger risk of developing AUD compared to farmers, and the subjects had three times more chance of developing AUD for each increase of 10 g of the daily amount of alcohol intake.

Adult↗
PubMed1999

A case of prostatic cancer metastasizing to the orbit.

PURPOSE: We report on a case of prostatic cancer with multiple bone metastases, including right orbital involvement. METHODS/RESULTS: Hormonal treatment and local irradiation to the right orbit were performed. Subjective symptoms with exophthalmos and pain disappeared. CONCLUSIONS: We report on a case of prostatic cancer metastasizing to the right orbital bone.

Adenocarcinoma↗
PubMed1999

Clinicopathological significance of poorly differentiated thyroid carcinoma.

The clinicopathological importance of a heterogeneous group of poorly differentiated thyroid carcinomas is not fully understood. Using data obtained from 303 surgically treated patients with differentiated thyroid carcinomas, the correlations between the aggressive histologic features and the clinicopathological findings, postoperative recurrences, and prognosis were retrospectively examined. In 201 cases, the carcinomas were well differentiated. The remaining 102 cases of poorly differentiated carcinomas were divided into two groups: focal-poorly differentiated (<10%) and diffuse-poorly differentiated (> or = 10%) carcinomas according to the extent of the poorly differentiated component. These poorly differentiated carcinomas were associated with high age (focal-poorly differentiated and diffuse-poorly differentiated versus well differentiated: 55 years and 59 versus 49; p < 0.0001), frequent presence of lymph node metastases (70% and 66% versus 48%; p = 0.0099) and distant metastases at diagnosis (11% and 11% versus 2%; p = 0.0098), and extrathyroidal invasion (53% and 53% versus 21%; p < 0.0001). There was independent correlation with age and the presence of extrathyroidal invasion. Cases of diffuse-poorly differentiated carcinomas showed frequent relapse (diffuse-poorly differentiated versus focal-poorly differentiated and well differentiated: 45% versus 30% and 24%; p = 0.0062) and poor prognoses (mean survival period = 9.15 versus 19.03 and 20.87 years; p < 0.0001) compared with the well and focal-poorly differentiated carcinomas. These data suggest that diffuse-poorly differentiated carcinoma is an important clinicopathological entity.

Adenocarcinoma, Follicular↗
PubMed1999

[Clinical analysis of the prognosis of severe pneumonia requiring mechanical ventilation].

To determine which factors are important in predicting the outcome of patients with severe pneumonia requiring mechanical ventilation, we compared 43 surviving pneumonic patients with 37 non-surviving pneumonic patients. The following results were obtained. The following characteristics were noted in the non-surviving patients as compared with surviving patients; 1. a worsening of performance status in the background, 2. presence of physical signs such as hypotension and trachycardia, 3. abnormal laboratory data such as leukocytosis, lymphocytopenia, hypoalbuminemia, hepatorenal dysfunction and metabolic acidosis, 4. presence of massive pulmonary infiltrations on chest roentgenograms, 5. a prevalence of resistant microorganisms for many antibiotics such as MRSA (Methicillin resistant Staphylococcus aureus). These results suggest that the most important factor affecting the prognosis of patients with severe pneumonia requiring mechanical ventilation may by the condition of the host and of the microorganisms rather than antibiotic treatment.

Aged↗
PubMed1999

[Three cases of pneumonia due to mixed infection of bacteria and Mycoplasma pneumoniae].

We reported three cases of pneumonia due to mixed infection of bacteria (2 cases: Streptococcus pneumoniae, 1 case: methicilline-sensitive Stapholococcus aureus) and Mycoplasma pneumoniae. Increased serum antibody titers of M. pneumoniae were noted in all cases. They were a 36-year-old-female with bronchial asthma, a 74-year-old-male with old pulmonary tuberculosis and a 82-year-old-male with chronic bronchitis. All cases had fever, productive cough with purulent sputum and coarse crackle by auscultation. Leukocytosis was noted in 2 cases. Chest X-ray films showed dense consolidation in all cases, 2 cases were cured by administration of cephems and 1 case was cured by administration of carbapenems and minocycline.

Adult↗