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

We previously reported that the number of TNF-α-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-αRI (p55) and -αRII (p75), and IL-10, all of which act as TNF-α 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-αR closely correlated with disease progression. Patients with LC and HCC had significantly elevated levels for sTNF-αRII 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-αRs. 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.     

A 56 Year-Old Female with Congenital Hepatic Fibrosis Diagnosed by Laparoscopy

Abstract: We describe a 56-year-old woman with congenital hepatic fibrosis. Blood tests and liver scanning with Tc-99m-labelled galactosyl human serum albumin revealed mild liver dysfunction. Per-rectal portal scintigraphy with iodine-123 iodoamphetamine showed severe abnormalities in the portal circulation, and the portal pressure measured during percutaneous transhepatic portography was high (350 mmH₂O). Idiopathic portal hypertension was suspected. Laparoscopy disclosed diffuse, intense dendritic white markings around the liver. Congenital hepatic fibrosis was confirmed on histologic examination of a biopsy specimen obtained during laparoscopy. In summary, we report a rare and relatively elderly case of CHF, in which laparoscopy was useful in the diagnosis. (Dig Endosc 1999; 11: 174–178)     

Differences in the clinical characteristics of Pneumocystis jirovecii pneumonia in immunocompromized patients with and without HIV infection

Background and objective: The incidence of Pneumocystis jirovecii pneumonia (PCP) in patients with predisposing immunodeficiencies other than AIDS is growing. Knowing the different characteristics and outcomes of PCP according to HIV status would help physicians manage and treat patients with PCP. Methods: The medical charts of all patients with a proven first episode of PCP, diagnosed between 1997 and 2007 were retrospectively reviewed, and clinical and laboratory data abstracted. Results: Of the 35 patients with PCP, 18 were HIV‐positive and 17 were HIV‐negative with other immunosuppressive conditions. HIV‐negative patients were significantly older than HIV‐positive patients. The WCC (10 952 ± 5669 vs 9750 ± 3133/µL; P = 0.015), neutrophil counts (9631 ± 5421 vs 5680 ± 2628/µL; P = 0.01) and CD4+ lymphocyte counts (329 ± 502 vs 47 ± 50/µL; P < 0.001) were significantly higher in HIV‐negative patients. Six of the 17 HIV‐negative patients had a CD4+ lymphocyte count >300/µL. Serum IgG levels were lower in HIV‐negative patients (943 ± 379 vs 1635 ± 657 mg/dL; P = 0.017). Mortality was higher in HIV‐negative (52.9%) than in HIV‐positive patients (0%). On univariate analysis, risk factors for mortality from PCP were the presence of underlying pulmonary disease (odds ratio 4.000, 95% CI: 1.501–10.658) and HIV‐negative status (odds ratio 2.125, 95% CI: 1.283–3.518). Conclusions: The characteristics and outcomes of PCP differ significantly depending on HIV status. The existence of underlying pulmonary diseases may be associated with the prognosis of HIV‐negative patients with PCP.     

Clinical characteristics of Japanese patients with familial obstructive sleep apnoea syndrome

Background and objective: Craniofacial structure and body fat are key factors that predispose to upper airway obstruction while asleep, and these phenotypes can be genetically inherited. Neither the clinical characteristics of familial obstructive sleep apnoea syndrome (OSAS) nor the definitive morphological factors responsible for familial occurrence have been well identified. This study compared the clinical and cephalographic characteristics of Japanese patients with familial OSAS, non‐familial OSAS and healthy controls, to clarify the mechanisms underlying familial OSAS. Methods: The study recruited 28 patients with familial OSAS, comprising 14 index cases and 14 first‐degree relatives affected with OSAS, and compared these with age‐ and sex‐matched patients with non‐familial OSAS (n = 32) and healthy subjects (n = 33). Data on clinical status were collected, including the presence of hypertension, BMI and daytime sleepiness measured on the Epworth sleepiness scale. Respiratory function was evaluated by the AHI, % periods in which SpO₂ fell 90% or below and lowest value of SpO₂ on polysomnograms. Information on the first witnessed age of habitual snoring during sleep was collected via interview with patients and/or their family members. A detailed cephalometric assessment was made of each study subject. Results: Patients with familial OSAS had lower mean BMI than did patients with non‐familial OSAS. The first witnessed age of habitual snoring was younger in the familial cases than the non‐familial cases. Cephalometric variables showed that the posterior airway space and the distance between the gonion and the gnathion were significantly smaller in the familial group than in the other two groups. Conclusions: Familial OSAS occurred at a younger age than non‐familial OSAS due to minor anomalies of craniofacial morphology.     

PHARMACOKINETIC STEREOSELECTIVITY OF TROGLITAZONE,AN ANTIDIABETIC AGENT,IN THE KK MOUSE

Troglitazone, an oral antidiabetic agent, is an equal mixture of four stereoisomers involving two asymmetric centres. In the present study, the stereoselectivity of in vitro epimerization in plasma and organ homogenate and in vivo plasma disposition in the KK mouse, an animal model of non-insulin-dependent diabetes, was examined. In the incubation experiments at 37 °C, there was a fivefold to eightfold acceleration of epimerization at the 5 position of the thiazolidine ring in KK mouse plasma compared with that in buffer. However, no inversion at the 2 position of the chroman ring was observed. In addition, there was an approximately 1·3-fold difference in the epimerization rates among stereoisomers at the 2 position of the chroman ring. However, there were no differences in the values of the equilibrium constants of epimerization, and the ratio of epimerization among stereoisomers at the 5 position of thiazolidine ring was almost unity. The acceleration of epimerization is thought to be due to the high degree of protein binding because of the relationship between the initial epimerization rate and the dilution ratio of the plasma. Although acceleration of epimerization was also observed in the 20% homogenates of liver, kidney, and intestine of the KK mouse, the degree of stereoselectivity was lower than in plasma. The analysis of the plasma disposition after intravenous administration of troglitazone stereoisomers, using a kinetic model, indicated that the metabolic clearance in the liver showed a 2·5-fold maximum difference among stereoisomers and that the stereoselectivity of epimerization was low. ©1997 by John Wiley & Sons, Ltd.     

Determination of Protein Binding of Troglitazone Stereoisomers by Fluorometric Titration

Determination of the protein binding of troglitazone is difficult because of its high adsorption to filters and membranes and the instability of the stereoisomers. We attempted to assess the protein binding of four stereoisomers of troglitazone in the plasma and albumin from several species by the method using fluorescent probes. The inhibition constants (K_i) for the stereoisomers of troglitazone were obtained from the decreases in fluorescence intensity of dansylsarcosine caused by competitive inhibition. Each stereoisomer of troglitazone displaced dansylsarcosine, a typical specific fluorescent probe for the diazepam binding site on human serum albumin (HSA). The highest binding affinity for dansylsarcosine was observed with HSA (dissociation constant, K_d,1 = 0·5 μM), while it was lowest in the mouse (K_d,1 = 18 μM). The K_i values for KK and ddY mouse plasma and mouse and rat albumin were in the range 2–15 μM, and there were no large variations among stereoisomers, the maximum differences being twofold. For human plasma and albumin, the displacement could not be accounted for by a simple competitive inhibition. Comparison between unbound fraction ( f_u) values calculated from thus obtained K_i values and those of a mixture of the four stereoisomers determined by high-performance frontal analysis showed that the f_u values obtained by fluorometric titration were higher, while the relative differences among the stereoisomers in terms of animal species and strain were comparable for the two methods. Small differences in protein binding among stereoisomers of troglitazone may not be the major reason for their stereoselective pharmacokinetics. © 1997 John Wiley & Sons, Ltd.     

Real-world Experience of Carotid Artery Stenting in Japan: Analysis of 7,134 Cases from JR-NET1 and 2 Nationwide Retrospective Multi-center Registries

The present study aimed to demonstrate the “real-world” experiences of carotid artery stenting (CAS) in Japan using Japanese Registry of Neuroendovascular Therapy (JR-NET) 1 and 2, retrospective nationwide multi-center surveillances. JR-NET1 and 2 registries are retrospective surveillances conducted between January 2005 and December 2007 and January 2008 and December 2009, respectively, in Japan regarding neuroendovascular therapy. A total of 7,134 procedures (1,943 for JR-NET1 and 5,191 for JR-NET2) were included in this study and retrieved data were analyzed retrospectively. Treatment results of two surveillance periods were similar. In JR-NET2 registry, total of 5,191 lesions were treated by CAS and 5,008 of 5,191 procedures (96.5%) were performed by the board-certified surgeons of Japanese Society of Neuroendovascular Therapy. The rate of technical success was extremely high (99.99%), and the rate of clinically significant complication was low (3.2%). These results were comparable to a previous large study in Japan. Multivariate logistic analysis revealed that age [odds ratio (OR), 1.04 per year; 95% confidence interval (CI), 1.02–1.07; p = 0.0004), symptomatic lesion (OR, 1.87; 95% CI; p = 0.0004), and the use of closed-cell type stent (OR, 0.58; 95% CT, 0.32–1.00; p = 0.05) were independently associated with clinically significant complications. It was revealed that good clinical results were achieved in patients who underwent CAS in Japan. It is expected that the evolution of devices and increasing experiences of surgeons would lead to further improvement of the clinical results, and further investigation would be required to clarify the optimal treatment strategy and therapeutic efficacy of CAS, especially in symptomatic lesions.