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Biomedical subjects

S Kakumu

Publications and source records attributed to S Kakumu.

At least 55 records · Page 3Linked to original sources
PubMed1998

A lipoprotein lipase activator, NO-1886, improves endothelium-dependent relaxation of rat aorta associated with aging.

Endothelial function is closely related to development of atherosclerosis and is impaired with aging. The novel compound NO-1886, 4-diethoxyphosphorylmethyl-N-(4-bromo-2-cyanophenyl)benzamid e, is a lipoprotein lipase activator and its long term administration protects against the development of experimental atherosclerosis in animals. The aim of this study was to ascertain whether NO-1886 ameliorates the impaired endothelium-dependent relaxation of rat aorta associated with aging. NO-1886 (50 mg/kg p.o.) was administered to 7-month old rats for 3 months. Plasma lipid, glucose and insulin levels in old control rats (10 months of age) were significantly higher than those of young rats (2 months of age). NO- 1886 decreased plasma triglyceride levels (old rats, 233+/-10 mg/dl; old rats + NO-1886, 172+/-16 mg/dl, P < 0.01) and increased plasma high density lipoprotein (HDL) cholesterol level (old rats, 72+/-6 mg/dl; old rats + NO-1886, 142+/-6 mg/dl, P < 0.001) in old rats, but had no effects on plasma glucose or insulin. The endothelium-dependent relaxation of the thoracic aorta caused by histamine was significantly impaired in old rats (% relaxation at 10(-5.5) M histamine: young rats 25.4+/-3.1%; old rats 14.1+/-1.9%, P < 0.01), an effect completely prevented by NO-1886 (old rats + NO-1886; 22.8+/-2.8%, P < 0.05 vs. old rats). In contrast, NO-1886 showed no effect on the endothelium-independent relaxation by sodium nitroprusside. These results indicate that NO-1886 improves impaired endothelium-dependent relaxation of rat aorta associated with aging, possibly by correcting lipid metabolism.

Aging↗
PubMed1998

Swimming stress that causes hyperglycemia increases in vivo release of noradrenaline, but not acetylcholine, from the hypothalamus of conscious rats.

The effects of acute swimming stress (10 min) on noradrenaline release from the medial basal hypothalamus (MBH; consisting of the ventromedial and dorsomedial hypothalamus) and acetylcholine release from the lateral hypothalamic area (LHA) were investigated in freely moving rats by using in vivo microdialysis techniques. Serum glucose, noradrenaline and adrenaline concentrations were also determined. Acute swimming stress produced significant hyperglycemia, with increases in serum noradrenaline and adrenaline concentrations. The release of noradrenaline from the MBH was significantly stimulated during the swimming stress. On the other hand, the swimming stress has no significant effect on the release of acetylcholine from the LHA. These findings support the idea that hypothalamic noradrenergic neurons play an important role in the sympathoadrenal hyperglycemic response to stressful stimuli. Moreover, it is suggested that hypothalamic cholinergic neurons are not involved in the responses of serum glucose, noradrenaline and adrenaline concentrations to swimming stress.

Acetylcholine↗
PubMed1998

Risk factors for hepatocellular carcinoma and its incidence after interferon treatment in patients with chronic hepatitis C. Osaka Liver Disease Study Group.

To elucidate the risk factors for liver carcinogenesis and to examine the incidence of hepatocellular carcinoma (HCC) after interferon therapy, 1,022 chronic hepatitis C patients treated with interferon were followed by ultrasonography for 13 to 97 months (median 36 months). Sustained response with prolonged alanine aminotransferase normalization was found in 313 patients, transient response with alanine aminotransferase relapse after therapy in 304, and no response in 405. Forty-six developed HCC, of whom 5 were sustained responders, 9 were transient responders, and 32 were nonresponders. The cumulative incidence of HCC in transient responders was almost equal to that in sustained responders, and it was significantly higher in nonresponders than in sustained and transient responders (P=.0009). The seventh-year cumulative incidence rates of HCC in sustained responders, transient responders, and nonresponders were estimated to be 4.3%, 4.7%, and 26.1%, respectively. However, there was no significant difference in the cumulative incidence of HCC between patients with HCV subtype 1 and 2 (P=.14). Cox regression analysis showed that the risk of HCC development was not elevated in transient responders compared with sustained responders, but that the risk was 7.90-fold higher in nonresponders than in sustained responders (P=.008). Patients > or =55 years of age had a significantly higher risk ratio (4.65) than did those under 55 years of age (P=.006). The risk of HCC development in men was 4.35 times higher than the risk in women (P=.02). However, the degree of fibrosis was not a significant risk factor for the development of HCC (risk ratio, 3.16; P=.052). These results suggest that patients in the high-risk group of HCC after interferon therapy were those who showed no response, those who were older, and those who were male, and that such patients should be carefully followed using ultrasonography.

Adult↗
PubMed1998

Broadly reactive antibodies to hypervariable region 1 in hepatitis C virus-infected patient sera: relation to viral loads and response to interferon.

To clarify the nature of serum anti-hypervariable region 1 (HVR1) antibodies in patients infected with hepatitis C virus (HCV), we assessed the reactivity of 21 patients' sera with 42 HVR1 proteins by Western blot. HVR1 was expressed as fusion proteins with glutathione S-transferase (GST). The patients' sera reacted with variable percentages of the HVR1 proteins, and always reacted with HVR1 proteins of the different genotype. In the genotype-1b-infected patients, the percentage of genotype-1b HVR1 proteins reactive with serum correlated significantly with viral loads; the sera reactive with the higher percentages of HVR1 proteins contained the larger viral loads. In addition, it was significantly lower in the responders of interferon (IFN) therapy than in nonresponders. The competition assays indicated that multiple fractions of anti-HVR1 antibodies with different specificity in a serum reacted with different HVR1 proteins, and that, additionally, a single fraction of antibodies often reacted with more than one HVR1 protein through a similar amino acid sequence. In conclusion, serum anti-HVR1 antibodies were broadly reactive by the mechanism of both the cross-reactivity of a single fraction of anti-HVR1 antibodies with more than one HVR1 protein and the presence of multiple fractions of anti-HVR1 antibodies with different specificity in a serum. In genotype-1b-infected patients, the broad reactivity of serum anti-HVR1 antibodies correlated with viral loads and response to IFN. Further studies are necessary to elucidate the correlation among the broad reactivity of sera with multiple HVR1 proteins and clinical features of chronic hepatitis C patients.

Adult↗
PubMed1998

The effect of low intensity bicycle exercise on the insulin-induced glucose uptake in obese patients with type 2 diabetes.

OBJECTIVE: The present study was undertaken to reveal the effect of low intensity bicycle exercise on the insulin-induced glucose uptake in obese patients. SUBJECTS AND METHODS: Seven obese men with Type 2 diabetes (OBDM) and seven healthy young men (HY) participated in this study. The glucose infusion rate (GIR) was determined by glucose clamp procedure at an insulin infusion rate of 40 mU m-2 min-1 (plasma insulin concentrations: 700-800 pmol l-1). Confirming stabilized GIR, a 30-min bicycle exercise was performed during the glucose clamp which was continued for 120 min after exercise. RESULTS: Average GIR in OBDM for last 30 min prior to exercise were significantly lower than HY (28.3 +/- 1.7, 47.4 +/- 1.8 mumol kg-1 min-1 respectively, P < 0.05). GIR abruptly increased during exercise and gradually decreased after exercise to the nadir almost at the time from 30 to 60 min in recovery period in both groups. GIR in OBDM, however, gradually increased significantly over pre-exercise levels (P < 0.05), following exercise and reached the same levels compared to HY after 80 min of recovery period. CONCLUSION: These results indicated that in obese Type 2 diabetes, 30 min of low intensity bicycle exercise significantly enhances the lower level of insulin-induced glucose uptake shortly after exercise and might be useful for the treatment of post-prandial hyperglycemia.

Adult↗
PubMed1998

Different constitution of hepatitis C virus population in peripheral blood mononuclear cells and plasma in patients with type C chronic liver disease.

We searched for the presence of the plus or minus strand of hepatitis C virus (HCV) RNA in peripheral blood mononuclear cells (PBMCs) from three patients with chronic HCV infection using the strand-specific reverse transcription and polymerase chain reaction (RT-PCR) method. To examine whether the HCV population of PBMCs differs from that of plasma, a sequence of the hypervariable region (HVR) in the E2/NS1 region was analyzed. All three patients had both plus and minus strands of HCV RNA in their PBMCs. Sequence study revealed that the HCV population in PBMCs was homogeneous in all patients, while that in plasma was composed of two main clones. One of these had the same sequence as the clones seen in PBMCs, except for one patient. Our results suggest that PBMCs represent one of the extrahepatic replication sites of HCV and that tissue tropism is expressed by some of the HCV population.

Amino Acid Sequence↗
PubMed1998

Prevalence of hepatitis B, hepatitis C, and GB virus C/hepatitis G virus infections in liver disease patients and inhabitants in Ho Chi Minh, Vietnam.

The prevalence of hepatitis B virus (HBV), hepatitis C virus (HCV), and GB virus C or hepatitis G virus (GBV-C/HGV) infections was determined in 289 patients with liver disease in Ho Chi Minh City and 890 healthy inhabitants of its rural area, Dalat City, Vietnam, respectively. Serum HCV RNA and GBV-C/HGV RNA were detected by reverse transcription-polymerase chain reaction (RT-PCR). HBsAg, HCV antibodies, and GBV-C/HGV RNA were detected in 139 (47%), 69 (23%), and ten (3%) subjects, respectively, often accompanied by elevated serum levels of alanine aminotransferase. HBsAg and HCV antibodies or HCV antibodies and GBV-C/HGV RNA were detectable simultaneously in 8% and 2% of the patients, respectively. In the inhabitants, HBsAg, HCV antibodies, and GBV-C/HGV RNA were found in 51 (5.7%), nine (1.0%), and 11 (1.2%) subjects, respectively. Thus, the prevalence of HBsAg, HCV antibodies, and GBV-C/HGV RNA was significantly higher in liver disease patients than those in the general population. In the samples from 69 patients and nine inhabitants who were seropositive for HCV antibodies, HCV RNA was detectable in 42 (61%) and 4 (44%), respectively. In patients with liver disease, ten belonged to HCV genotype 1a, ten to HCV 1b, three to HCV 2a, four to HCV 2b, and two to HCV 3a by PCR with genotype-specific primers. Nine patients had mixed genotypes, and the remaining four were not classified. Of the GBV-C/HGV RNA-positive individuals, two patients and two inhabitants were positive for HBsAg, while none of the residents had HCV antibodies, although six HCV antibodies (60%) and four HCV RNA (40%) were found in patients. When a phylogenetic tree of GBV-C/HGV was constructed based on the nucleotide sequences, the 21 isolates were classified into at least two genotypes; four isolates belonged to G2, and 17 to G3. The results indicate that in Ho Chi Minh HCV infection prevails with broad distribution of genotypes together with HBV infection among patients with liver disease. This study suggests that GBV-C/HGV infection occurs independently in the two different districts in association with HCV infection.

Adolescent↗
PubMed1997

Polymorphism of extracellular superoxide dismutase (EC-SOD) gene: relation to the mutation responsible for high EC-SOD level in serum.

Extracellular superoxide dismutase (EC-SOD) with amino acid substitution R213G generated by the nucleotide substitution 760C-->G in the heparin binding domain is responsible for the high EC-SOD level in serum. We identified the two DNA polymorphic sites in the coding region of EC-SOD gene related to the 760C-->G and determined the allele frequencies. The polymorphism were A and G at nucleotide position (nt.) 241 and C and T at nt. 280 near the N-terminal. The haplotype frequencies in Japanese were 241A280C: 0.45, 241G280T: 0.37, and 241G280C: 0.18. The haplotype of 241A280T did not exist. The mutation 760C-->G must occur on the allele having the haplotype of 241G280T.

Extracellular Space↗
PubMed1997

Serum levels of IL-10, IL-15 and soluble tumour necrosis factor-alpha (TNF-alpha) receptors in type C chronic liver disease.

We previously reported that the number of TNF-alpha-producing cells was increased in the liver of patients with type C chronic liver disease. To understand further the pathophysiology of this change, we examined serum levels of two soluble TNF receptors, TNF-alphaRI (p55) and -alphaRII (p75), and IL-10, all of which act as TNF-alpha buffer, and IL-15, a novel cytokine sharing many immunological activities with IL-2, using ELISA methods. We studied control individuals and patients with type C chronic liver disease, including asymptomatic hepatitis C virus (HCV) carriers with persistently normal serum ALT values, and those with chronic hepatitis (CH), liver cirrhosis (LC) and hepatocellular carcinoma (HCC). Both types of sTNF-alphaR closely correlated with disease progression. Patients with LC and HCC had significantly elevated levels for sTNF-alphaRII compared with the other patient groups and controls. Serum IL-10 levels were significantly greater in all chronic liver disease groups than in controls. With respect to IL-15, the values were high in CH, LC and HCC compared with those of controls. Notably, HCC patients showed highest values for both IL-10 and IL-15, with significant differences from the other patient groups. Serial determinations revealed that interferon (IFN) treatment for CH patients resulted in the suppression of circulating IL-10 and IL-15 levels along with decrease in serum aminotransferase values. Both cytokines remained at decreased levels after cessation of therapy in patients who went into clinical and virological remission. On the other hand, treatment did not affect serum levels of sTNF-alphaRs. These findings indicate that serum levels of these molecules correlated with disease progress in chronic HCV infection, and that IL-10 and IL-15 may reflect the degree of inflammation in the liver. It is also suggested that both cytokines may be related to the development of HCC.

Adult↗
PubMed1997

Production of interleukins 10 and 12 by peripheral blood mononuclear cells (PBMC) in chronic hepatitis C virus (HCV) infection.

We previously reported that interferon-gamma (IFN-gamma) production by PBMC in response to HCV core protein was increased in patients with type C chronic liver disease. To understand better the pathophysiology of this disease, we evaluated production of IL-10 and IL-12 by PBMC from 41 patients with chronic HCV infection, including asymptomatic HCV carriers with persistently normal serum ALT values. IL-10 is known to inhibit many effector functions of the immune system, suppressing Th1-type cell development, while IL-12 stimulates differentiation of Th1-type cells, facilitating cell-mediated immunity. IL-10 production was determined by culturing lymphocytes with concanavalin A (Con A), while IL-12 was produced by monocytes in the presence of Staphylococcus aureus Cowan 1 (SAC) with or without recombinant HCV core protein, respectively. The cytokine levels in culture supernatants were measured by ELISA. Spontaneous IL-10 production was greater in patients with chronic hepatitis (CH) (229 +/- 119 pg/ml, P < 0.01) and liver cirrhosis (LC) (185 +/- 88 pg/ml, P < 0.05) than in controls (119 +/- 27 pg/ml), while it was decreased during IFN treatment (70 +/- 25 pg/ml). Both HCV core protein and Con A enhanced IL-10 production by cells from HCV-infected patients. IL-12 was not detectable in medium alone cultures, and SAC-induced IL-12 production did not differ between various patient groups and controls. Simultaneous addition of HCV protein resulted in an increase of IL-12 production in chronic liver disease compared with SAC-alone cultures. Addition of IL-10 to the cultures equally suppressed IFN-gamma production for both controls and patient groups, but the enhancing effect of IL-12 on IFN-gamma production was significantly less in LC than in controls and other patient groups. The findings suggest that secretion of IL-10/IL-12 by cells from control individuals and various patient groups may be different, and that the cytokines might show different effects on IFN-gamma production by some cells.

Adult↗
PubMed1997

Humoral immune response to the hypervariable region of hepatitis C virus differs between genotypes 1b and 2a.

Antibody to the hypervariable region (HVR) of HCV is thought to have neutralizing activity. The HCV genotype is known to affect the clinical course of infection. The antibody response to HVR and its relationship to the virologic and clinical characteristics were investigated in 21 patients with chronic hepatitis C. HVRs amplified by polymerase chain reaction from serum HCV were expressed as glutathione S-transferase fusion proteins. From 8 to 34 clones per serum sample were obtained (375 clones total), and the anti-HVR antibody in serum was assessed by Western blot. Both the incidence of fusion proteins positive for anti-HVR antibody and the activity of antibody were significantly higher in 6 patients with genotype 2a than in 15 patients with genotype 1b. This result suggests that the quantity of humoral response to HVR affects the clinical outcome of infection with these two HCV genotypes.

Adult↗
PubMed1997

Cyclosporine therapy affects aminotransferase activity but not hepatitis C virus RNA levels in chronic hepatitis C.

Interferon (IFN) therapy is of proven efficacy in chronic hepatitis C, but it is not universally effective and is often limited by side effects. Cyclosporine A (CsA) is a potent immunosuppressant widely used in organ transplantation. We conducted a pilot study to determine whether CsA therapy could affect aminotransferase activity and hepatitis C virus RNA levels in patients with chronic hepatitis C. Cyclosporine A was administered to 10 patients (mean age of 59 years; male:female = 9:1) who did not respond to IFN therapy previously and who had elevated serum alanine aminotransferase (ALT) values for at least 6 months. All patients were positive for HCV-RNA by RT-PCR with genotype 1b. Their mean duration of hepatitis was 15 years. Oral CsA was given for 3 months in a dose that was increased at 1 month intervals from 1.5-2.0 to 2.0-3.0 and 3.0-4.0 mg/kg per day. All patients completed the treatment schedule, although two patients developed mild non-symptomatic hypertension. Serum ALT levels gradually decreased in all but one patient. The mean percentage decrease was 59.5% at the end of therapy (from 153 +/- 82 to 62 +/- 48 IU/L; P < 0.02). The ALT levels fell to the normal range in five patients, although once therapy was discontinued the enzyme levels tended to return to pretreatment levels. Serum aspartate aminotransferase and g-glutamyl transpeptidase levels similarly decreased. The serum HCV-RNA titre, determined by competitive RT-PCR, did not change in any patient throughout the study period. There were no appreciable alterations in other laboratory tests, such as serum creatinine levels and lymphocyte subsets, except for an increase in serum alkaline phosphatase levels. These findings suggest that CsA, even in a relatively low dose, reduces serum aminotransferase levels without serious side effects in patients with chronic hepatitis C, although an antiviral effect was not noted.

Administration, Oral↗
PubMed1997

Earlier loss of hepatitis C virus RNA in interferon therapy can predict a long-term response in chronic hepatitis C.

To distinguish responders from non-responders early in interferon (IFN) treatment would be beneficial in patients with chronic hepatitis C. Those patients unlikely to respond would be spared the cost and hazard of prolonged treatment. Forty-three chronic hepatitis C patients who had received IFN-alpha therapy (6-9 MU; six times weekly for 2 weeks followed by thrice weekly for 22 additional weeks) were randomly enrolled into the present study. Serially obtained sera were retrospectively tested for HCV-RNA by reverse transcription-polymerase chain reaction (Amplicor HCV) with a low limit detection of approximately 10(2) copies/mL. Genotypes were determined by type-specific primers. Sixteen subjects were defined as sustained responders (SR), who showed sustained loss of viraemia with normalized alanine aminotransferase values for at least 6 months of follow-up after completion of therapy. The other 27 subjects were non-responders (NR), whose viraemia persisted during follow-up. Pretreatment serum HCV-RNA levels (P < 0.0001) and the genotype (P < 0.01) were significant predictors for sustained response to IFN therapy. Hepatitis C virus RNA was detectable in only one (6%) SR and in 23 (85%) NR at the second week of therapy (P < 0.0001) and was detected in none of the SR subjects and in 18 (67%) NR at the fourth week of therapy (P < 0.0001). Pretreatment viral load was correlated with the time until loss of viraemia. Multivariate analysis revealed that loss of viraemia at the second week of therapy was the strongest predictor for a long-term response, followed by the initial viral load and loss of viraemia at the fourth week of therapy. These findings suggest that it is possible to predict a long-term response to IFN as early as at the second and fourth weeks after the start of therapy by identifying the presence or absence of HCV-RNA with a sensitive assay.

Adult↗
PubMed1997

Serial quantitation of serum core protein and viral RNA of hepatitis C virus after interferon therapy: increase in viral loads in biochemical responders.

OBJECTIVES: Interferon (IFN) therapy is often ineffective in eradicating hepatitis C virus (HCV). Some patients show normal serum ALT levels for a long time after IFN therapy despite the presence of HCV. These patients are considered not virological responders but biochemical responders. We investigated the changes in the amount of HCV after IFN therapy in biochemical responders. METHODS: Nine biochemical responders and 11 nonresponders were studied. Serum HCV amount was measured by fluorescence enzyme immunoassay for HCV core (pg/ml) and Amplicor HCV Monitor test for HCV RNA (logarithms of copy numbers per milliliter). RESULTS: In biochemical responders, core protein and HCV RNA were increased significantly at 1 month after IFN therapy (291 +/- 191 pg/ml and 5.4 +/- 0.9, respectively; p < 0.05 for both) and at 1 yr (324 +/- 189 pg/ml and 5.6 +/- 0.7, respectively; p < 0.01 for both) compared with pretreatment values (122 +/- 114 pg/ml and 4.8 +/- 0.9, respectively). The change ratios of core protein at 1 month and 6 months after therapy to the pretreatment values were significantly higher in biochemical responders (3.2 +/- 2.4 and 2.9 +/- 2.3, respectively) than in nonresponders (0.9 +/- 0.7 and 1.1 +/- 0.8, respectively) (p < 0.05 for both). Similarly, the change ratios of HCV RNA at 1 month and 1 yr after IFN therapy were significantly higher in biochemical responders (9.9 +/- 14.6 and 12.8 +/- 15.1) than in nonresponders (0.6 +/- 0.5 and 1.2 +/- 1.2) (p < 0.05 for both). CONCLUSIONS: HCV amount increased significantly after IFN therapy in biochemical responders, whereas it did not change notably in nonresponders.

Alanine Transaminase↗