Teruya Yoshimi

Serum thrombopoietin levels in patients with chronic hepatitis and liver cirrhosis

OBJECTIVES:Thrombocytopenia is a common manifestation of cirrhosis. The aim of this study was to examine the relationship between serum thrombopoietin concentrations, circulating platelet levels, and the stage of hepatic fibrosis in patients with chronic viral hepatitis.METHODS:The study included 48 patients with chronic viral hepatitis (14 with stage 1 fibrosis; five with stage 2 fibrosis; three with stage 3 fibrosis; 26 with cirrhosis) and 30 healthy volunteers. Serum thrombopoietin levels were measured using an enzyme-linked immunosorbent assay. Spleen size, platelet counts, and prothrombin time were measured.RESULTS:Thrombopoietin levels of patients with fibrosis stage 1 (2.50 ± 1.60 fmol/ml) or stage 2 (1.89 ± 0.65) were significantly higher than those in patients with cirrhosis (1.21 ± 0.55) or healthy volunteers (1.26 ± 0.74). Mean platelet counts of patients with cirrhosis (8.0 ± 4.6 × 104/μl) were significantly lower than those with fibrosis stage 1 (18.6 ± 3.9) or stage 2 (16.0 ± 5.8), or healthy volunteers (24.5 ± 7.3). Patients with cirrhosis had larger spleens (30.9 ± 18.4 cm2) than those with fibrosis stage 1 (18.2 ± 6.4). Platelet counts showed a significant inverse relationship to spleen size (ρ=−0.51, p < 0.0005) and a significant positive relationship with thrombopoietin levels (ρ= 0.34, p < 0.02). Thrombopoietin levels were significantly correlated to prothrombin time (ρ= 0.45, p < 0.005).CONCLUSIONS:Serum thrombopoietin levels are elevated in patients with an early stage of chronic viral hepatitis. As the disease progresses from mild fibrosis to cirrhosis, decreased production of thrombopoietin may contribute to the further development of thrombocytopenia in cirrhosis.

Distribution and concentration of urocortin, and effect of adrenalectomy on its content in rat hypothalamus

We developed a specific and sensitive radioimmunoassay (RIA) for rat urocortin (rUcn) and investigated the tissue distribution and concentration of immunoreactive (IR-)Ucn in rats. Antiserum was obtained by immunizing rabbits with synthetic rUcn21-35 coupled with bovine thyroglobulin. 125I-[Tyr]18-rUcn19-37 was used as the tracer. The RIA detected synthetic rUcn1-40 as low as 0.4 fmol/tube, and did not cross-react with other corticotropin-releasing factor-related peptides. IR-Ucn was widely distributed in central nervous system, endocrine organs, and digestive system. Its concentration was highest in pituitary (11.0 +/- 1.36 pmol/g.w.w., mean +/- SEM, n=4). Reverse-phase HPLC revealed that hypothalamic IR-Ucn had similar chromatographic mobility to synthetic rUcn1-40. However, bilateral adrenalectomy did not influence the hypothalamic IR-Ucn content. Our results suggest that Ucn may play important roles in various tissues in normal rats, but not behave as a hypothalamic hypophysiotropic factor in mediating adrenocorticotropin secretion in adrenalectomized rats.

Daily variations of platelet aggregation in relation to blood and plasma serotonin in diabetes

The circadian rhythms of platelet aggregation in the whole blood and platelet rich plasma-PRP and plasma serotonin were studied in healthy volunteers (n = 10) and diabetic patients (type II diabetes mellitus n = 12). Platelet aggregation in the whole blood induced by collagen (2 micrograms/ml), ADP (10 microM), arachidonic acid (0.5 mM) and epinephrine (10 microM), and in PRP induced by collagen (2 micrograms/ml), ADP (5 microM), arachidonic acid (250 microM), epinephrine (10 microM) and serotonin-5-HT (1 microM) was measured at 7:30, 11:30, 17:00, 23:00, 4:00 and 7:00. In healthy subjects collagen- and ADP-induced platelet aggregation in the whole blood was significantly lower at 23:00 and 4:00 when compared to values at 7:30. In PRP normal and diabetic platelet response was the lowest during the night. Diabetic platelets exhibited an enhanced response to 5-HT starting from 17:00 until 4:00 when compared to 7:30. 5-HT-induced platelet aggregation was found to be significantly higher throughout the study in DM patients over controls in parallel to plasma 5-HT. In healthy volunteers plasma 5-HT was higher at 17:00 when compared to baseline values, whereas in DM patients plasma 5-HT was elevated starting from 17:00 until 4:00. An enhanced response of diabetic platelets to 5-HT together with elevated plasma 5-HT levels may contribute, at least partly, to the pathogenesis of diabetic vasculopathy and 5HT2 receptor blockers may be of value in DM patients.

Urocortin expression in the human central nervous system

Urocortin is a recently identified neuropeptide of the corticotrophin‐releasing factor (CRF) family in the mammalian brain and has been demonstrated to stimulate ACTH secretion from pituitary cells, but its expression in human brain tissue including the hypothalamus has not been examined. In this study, we first examined urocortin expression in the hypothalamus (20 cases) and pituitary stalks (17 cases) of human brain obtained from autopsy using immunohistochemistry and mRNA in situ hybridization.

Blood serotonergic mechanisms in type 2 (non-insulin-dependent) diabetes mellitus

Serotonin (5-hydroxytryptamine, 5HT) is believed to play a role in vasospasm and increased platelet aggregability that in turn could contribute to atherosclerosis. The present study was designed to evaluate a possible participation of serotonin in the development of vascular complications in diabetes mellitus. Whole blood and plasma serotonin, the platelet uptake and release of the amine and serotonin- induced platelet aggregation were studied in 32 patients with Type 2 diabetes. The patients were divided into three groups according to the presence and advancement of retinopathy. Mean levels of blood serotonin content were significantly lower in diabetic patients. The concentration of the amine in the plasma was markedly increased in diabetes. It was correlated with vascular changes of the retina. We established that platelets from diabetic patients took up less serotonin when compared to the control group. Concomitantly enhanced spontaneous release of 5HT from platelets was observed. The platelets of diabetic patients showed increased response to serotonin. There was a relation between serotonin-induced aggregation and the presence of retinopathy. These results suggest that serotonin may be involved in the pathogenesis of diabetic vasculopathy.

Urocortin in human placenta and maternal plasma

Plasma immunoreactive (IR-) urocortin (Ucn) and corticotropin-releasing factor (CRF) levels in pregnant women were measured by their specific radioimmunoassays after extraction. Although plasma IR-CRF levels were increased in pregnant women as compared to men and non-pregnant women, there was no difference of plasma IR-Ucn levels among groups. Ucn mRNA was detected in cytotrophoblasts and syncytiotrophoblasts by in situ hybridization. A reverse-phase high-performance liquid chromatography (HPLC) showed the major peak of IR-Ucn in placenta and plasma that had similar chromatographic mobility to synthetic Ucn1-40. These data suggest that Ucn is produced and processed into the same form of synthetic Ucn in placenta, but not secreted into maternal blood.

High Incidence of Positive Autoantibodies against Thyroid Peroxidase and Thyroglobulin in Patients with Sarcoidosis

OBJECTIVE Although abnormalities of the humoral immune system, such as increased immunoglobulin production, are known in sarcoidosis, the relationship between sarcoidosis and autoimmune disorders is uncertain. We studied the incidence of thyroid autoantibodies and the prevalence of Hashimoto’s thyroiditis in patients with sarcoidosis.

Effect of Urocortin and Its Interaction with Adrenocorticotropin (ACTH) Secretagogues on ACTH Release

We examined the effect of urocortin (Ucn) on the adrenocorticotropin (ACTH) release from cultured rat anterior pituitary cells and AtT 20 cells. Synthetic rat (r)Ucn was not soluble in 0.1 N HCl but soluble in alkaline solvents with diminished corticotropin-releasing activity. rUcn dissolved in 0.1 M sodium phosphate buffer as a stock solution maintained its bioactivity and had the equal corticotropin-releasing activity with rat/human corticotropin-releasing factor (r/hCRF). rUcn stimulated the adrenocorticotropin release via CRF-receptors accompanied by the additive effect with r/hCRF, the synergistic effect with arginine vasopressin and the dose-dependent inhibition of a potent CRF-receptor antagonist.

Improvement of proteinuria in a case of hepatitis B-associated glomerulonephritis after treatment with interferon

Disappearance of proteinuria was observed in a patient with hepatitis B-associated chronic glomerulonephritis after treatment with leukocyte interferon. The decrease of proteinuria was preceded by the disappearance of both deoxyribonucleic acid polymerase activity and hepatitis B e antigen from the patients sera.

Changes in fibrinolytic parameters in male patients with type 2 (non-insulin-dependent) diabetes mellitus

We examined changes in fibrinolytic parameters in male patients with diabetes mellitus (DM) and controls. DM patients were divided into three groups: patients without retinopathy, patients with simple retinopathy, and patients with proliferative retinopathy. Plasma levels of t-PA (tissue plasminogen activator) and t-PA-PAI-1 (plasminogen activator inhibitor-1) complex increased with increase in age, but those of PAI-1 (total and free) did not change in controls. On the other hand plasma levels of PAI-1 decreased with increase in age in DM patients. Plasma levels of t-PA, t-PA-PAI-1 complex, free and total PAI-1 increased with increase in body mass index in controls, but no significant changes were shown in these parameters in DM patients. When compared with controls, plasma levels of t-PA, t-PA-PAI-1 complex and PAI-1 were lower in DM patients. Plasma levels of UK (urokinase) and Lp(a) were higher in DM patients. ELT (euglobulin clot lysis time) was significantly shorter in DM patients than in controls. Patients without retinopathy showed increased fibrinolytic activities compared with those with retinopathy due to the increased levels of t-PA in plasma. These results seem to indicate that blood vessels release larger amounts of t-PA at the early stage of DM, then release being impaired at its advance stage. It is also suggested that the regulatory control mechanisms of fibrinolytic activity associated with mechanisms of fibrinolytic activity associated with change in age and body mass index are different between patients with DM and normal people.