Selection of the dose of angiotensin converting enzyme inhibitor for patients with diabetic nephropathy depends on the presence or absence of left ventricular hypertrophy.

The coexistence of hypertension increases cardiovascular risks and the rate of deterioration of renal function for diabetic patients. For patients with left ventricular hypertrophy (LVH), the use of an angiotensin converting enzyme (ACE) inhibitor is known to be effective and well tolerated and to be protective against chronic renal insufficiency (CRI). However, serious adverse reactions to ACE inhibitors, such as the rapid deterioration of renal function, have been reported, making physicians hesitant to use these agents. To resolve this dilemma, we compared changes in renal function and left ventricular function and the safety and effectiveness of benazepril, an ACE inhibitor, in patients with diabetic nephropathy, with or without LVH. The age, sex, duration of diabetes, levels of blood pressure and blood glucose and rates of creatinine clearance (CrCl) were compared between 36 diabetic patients with LVH and 36 matched diabetic patients without LVH. The rates of CrCl in all patients were between 14 and 35 ml/min, and all patients received an ACE inhibitor before enrollment. The group comprised 43 men and 29 women, with a mean age of 56 +/- 4 years. These patients were divided into three groups, each of which was subdivided into a group with and a group without LVH. Group I (without LVH) or I-L (with LVH) received a half dose of benazepril (2.5 mg daily), Group II (without LVH) or II-L (with LVH) received a normal daily dose of 5 mg benazepril, and Group III (without LVH) or III-L (with LVH) discontinued the administration of the ACE inhibitor. The follow-up period was 1 year and, during the study, blood pressure was maintained at less than 140/90 mmHg. If the blood pressure control was not satisfactory, benidipine, a calcium antagonist, and/or furosemide, a loop diuretic, and/or guanabenz, a central acting antihypertensive agent, were administered. In the diabetic patients with LVH, the administration of a normal dose of benazepril inhibited the decline of renal function and cardiac function (CrCl: 24.2 +/- 1.5 to 22.0 +/- 2.5 ml/min; EF (ejection fraction): 56 +/- 3 to 54 +/- 6%) compared to the other two groups. In patients without LVH, a half dose of benazepril preserved renal function (23.4 +/- 2.6 to 22.0 +/- 3.1 ml/min; EF: 54 +/- 3 to 56 +/- 3%). Discontinuation of the administration of ACE inhibitor led to the further progression of renal dysfunction and decreases in EF in patients with or without LVH. Our results provide some indications for the use of ACE inhibitors in diabetic patients when renal dysfunction and/or cardiac hypertrophy are present.     

Evidence that fibroblasts derive from epithelium during tissue fibrosis

Interstitial fibroblasts are principal effector cells of organ fibrosis in kidneys, lungs, and liver. While some view fibroblasts in adult tissues as nothing more than primitive mesenchymal cells surviving embryologic development, they differ from mesenchymal cells in their unique expression of fibroblast-specific protein-1 (FSP1). This difference raises questions about their origin. Using bone marrow chimeras and transgenic reporter mice, we show here that interstitial kidney fibroblasts derive from two sources. A small number of FSP1(+), CD34(-) fibroblasts migrate to normal interstitial spaces from bone marrow. More surprisingly, however, FSP1(+) fibroblasts also arise in large numbers by local epithelial-mesenchymal transition (EMT) during renal fibrogenesis. Both populations of fibroblasts express collagen type I and expand by cell division during tissue fibrosis. Our findings suggest that a substantial number of organ fibroblasts appear through a novel reversal in the direction of epithelial cell fate. As a general mechanism, this change in fate highlights the potential plasticity of differentiated cells in adult tissues under pathologic conditions.     

Is technique survival on peritoneal dialysis better in Japan?

Technique failure resulting in transfer to hemodialysis (HD) remains one of the most important challenges in Longterm peritoneal dialysis (PD). In general, the proportion of patients transferring from PD to HD is much greater than the proportion transferring from HD to PD. However, technique failure rates differ considerably between and within countries. The question arises as to how technique failure rates in Japan compare with those in other countries. To address this issue, we reviewed the literature and our experience of 139 incident continuous ambulatory peritoneal dialysis (CAPD) patients from January 1995 to December 1999. Based on our review, we estimate that the 5-year technique survival rate in Japanese CAPD patients is approximately 70%, and that technique failure rate is around 7% per year. This rate is significantly lower than that in many other countries. The most common reasons for technique failure in Japan are peritoneal membrane failure, ultrafiltration loss, and inadequate dialysis. Another factor contributing to the low technique failure rate in Japan is an extremely low peritonitis rate. This may be related to good sanitation and excellent PD training programs. Peritoneal membrane failure continues to be the major challenge for long-term technique survival on PD in Japan.     

Types of human leukocyte antigen and decrease in HCV core antigen in serum for predicting efficacy of interferon-Α in patients with chronic hepatitis C: analysis by a prospective study

Background A prospective study was conducted to evaluate the influence of host factors, including human leukocyte antigen (HLA), and viral factors, including hepatitis C virus (HCV) core antigen, on the response to interferon (IFN)-.Methods Natural IFN- was given to 66 patients with chronic hepatitis C at a dose of 9 million units per day for 2 weeks, followed by 9 million units three times a week for 22 weeks.Results Sustained virological response without detectable HCV RNA in serum 24 weeks after the end of IFN therapy was achieved in 21 patients, while it was not in 32 patients; the remaining 13 patients were not evaluated. HCV core antigen and HCV RNA started to decrease 1 and 4 weeks, respectively, after the commencement of IFN in responders (P = 0.02 and P = 0.05, respectively). On univariate analysis, age of 50 years or less (P < 0.001); lack of HLA DR6 (P = 0.018) or DR52 (P < 0.041); platelets more than 14 × 10⁴/mm³ (P = 0.031); HCV core antigen 500fmol/l or less (P = 0.001); and HCV RNA 100KIU/ml or less were predictive of response. On multivariate analysis, age 50 years or less (odds ratio [OR], 4.009; P = 0.039); lack of HLA DR6 (OR, 8.130; P = 0.027); IFN-naive (OR, 11.63; P = 0.016); HCV core antigen 500fmol/l or less (OR, 10.61; P = 0.007); and genotypes other than 1b (OR, 8.929; P = 0.010) were predictive of response.Conclusions Lack of HLA DR6 determined the response to IFN. HCV core antigen was useful in predicting and monitoring the response to IFN.     

Lung tumorigenesis promoted by anti-apoptotic effects of cotinine, a nicotine metabolite through activation of PI3K/Akt pathway

We previously found that genetic polymorphism in cytochrome P450 2A6 (CYP2A6) is one of the potential determinants of tobacco-related lung cancer risk. It has been reported that the plasma concentration of cotinine, a major metabolite of nicotine, in carriers of wild-type alleles of CYP2A6 is considerably higher than that in carriers of null or reduced-function alleles of CYP2A6, raising the possibility that cotinine plays an important role in the development of lung cancer. As a novel mechanism of lung tumorigenesis mediated by CYP2A6, we investigated the effects of cotinine on the suppression of apoptosis and promotion of lung tumor growth. In human lung adenocarcinoma A549 cells, cotinine inhibited doxorubicin-induced cell death by suppressing caspase-mediated apoptosis. Enhanced phosphorylation of Akt, a key factor responsible for cell survival and inhibition of apoptosis, was detected after cotinine treatment. These data suggest that cotinine suppresses caspase-mediated apoptosis induced by doxorubicin through activation of the PI3K/Akt pathway. Furthermore, we clarified that cotinine significantly facilitated tumor growth in the Lewis lung cancer model and accelerated development of lung adenomas induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in A/J mice. We herein propose that cotinine induces tumor promotion by inhibiting apoptosis and enhancing cellular proliferation, thus underlining the importance of CYP2A6 in tobacco-related lung tumorigenesis.     

Focused DNA microarray analysis for sex-dependent gene expression of drug metabolizing enzymes, transporters and nuclear receptors in rat livers and kidneys

Cytochrome P450(CYP)s are known to show a sexual dimorphic expression in rat livers. However, the comprehensive analysis for the sex-dependent gene expressions of drug metabolizing enzymes except for CYPs, transporters and nuclear receptors in rat livers and kidneys has not been investigated yet. The purpose of the present study was to identify the novel drug metabolizing and pharmacokinetics (DMPK)-related gene(s) which show the sex difference in the mRNA expressions in rat livers and kidneys. Total RNAs were prepared from livers and kidneys in both male and female rats (Crl:CD(SD) and Crlj:WI). A DNA microarray analysis using a "GeneSQUARE Multiple Assay DNA Microarray Drug Metabolism Gene Expression for Rat" was performed. DMPK-related genes which showed sex differences in the mRNA expression were identified in rat livers or kidneys. Especially, the female dominant expressions of UDP glucuronosyltransferase (UGT) s were seen in rat livers and kidneys. The sex difference of UGT expressions in rats might be one of the causal factors of the sex difference of the biological response to UGT substrates.     

Crossover study of amlodipine versus nifedipine CR with home blood pressure monitoring via cellular phone: internet-mediated open-label crossover trial of calcium channel blockers for hypertension (i-TECHO trial)

OBJECTIVE: We developed a new data collection system named i-converter that could transmit data to a website via cellular phone. Using the system, we compared the effects of two calcium channel blockers on the home blood pressure. METHODS: Amlodipine and nifedipine CR were administered to 41 patients with essential hypertension for more than 6 weeks each in a randomized open-label crossover study. The dose of each drug was increased until the home blood pressure reached the target level of under 135/85 mmHg. RESULTS: The morning home systolic and diastolic blood pressures were significantly lower during nifedipine CR treatment: 133 +/- 10/81 +/- 8 mmHg with amlodipine versus 131 +/- 8/80 +/- 8 mmHg with nifedipine CR, P < 0.05. The morning pulse rate was significantly higher during nifedipine CR treatment (69 +/- 9 beats/min with amlodipine versus 70 +/- 9 beats/min with nifedipine CR, P < 0.05). The evening home blood pressure and pulse rate, however, showed no significant differences between the two drugs (128 +/- 11/74 +/- 7 mmHg and 74 +/- 10 beats/min with amlodipine versus 128 +/- 10/75 +/- 7 mmHg and 74 +/- 9 beats/min with nifedipine CR, all not significant). CONCLUSIONS: Nifedipine CR had a stronger antihypertensive effect than amlodipine during the critical morning period, but the morning pulse rate was higher. Our new data transmission system was effective for collecting precise data on the blood pressure and pulse rate via the internet.     

Usefulness of dynamic computed tomography for the diagnosis of mediastinal hemangioma

An asymptomatic 59-year-old female was admitted with an abnormal shadow on her chest radiography. Chest computed tomography (CT) revealed a mass measuring 20 mm in the anterior mediastinum. At the arterial phase on dynamic contrast-enhanced CT (dynamic CT), the pattern of "peripheral puddles", defined as discrete well-defined peripheral enhancing globles, was found in the mass. The tumor was completely resected via a median sternotomy, and was histopathologicaly diagnosed as hemangioma. In this case, dynamic CT was very useful for the preoperative diagnosis, and then the enhancement pattern of "peripheral puddles" on dynamic CT may be a conclusive finding for the diagnosis of mediastinal hemangiomas.     

Human cytochrome P450 1A1 is a novel target gene of liver X receptor α

Cytochrome P450 (CYP) 1A1 is involved in the metabolic activation of polycyclic aromatic hydrocarbons (PAHs) and is induced by several compounds, including PAHs. The induction of CYP1A1 mediated by the aryl hydrocarbon receptor (AhR) has been well investigated; however, little has been reported on the mechanisms of CYP1A1 induction mediated by factors other than AhR. In this study, we investigated the involvement of liver X receptor alpha (LXRα) in the induction of CYP1A1. TO-901317, an LXRα ligand, induced CYP1A1 mRNA in a dose-dependent fashion. Luciferase reporter assays using HepG2 cells showed that TO-901317 was capable of activating the promoter of the CYP1A1 gene and that a direct repeat 4 (DR4) motif located in a region from -452 to -467 was required for the induction of CYP1A1 through LXRα. Specific binding of LXRα to this DR4 motif was confirmed by gel shift and chromatin immunoprecipitation assays. Co-treatment of HepG2 cells with TO-901317 and 2,3,7,8-tetrachlorodibenzo-p-dioxin, a typical AhR ligand, caused the synergistic induction of CYP1A1 mRNA. Thus, we propose that the expression of CYP1A1 is regulated by LXRα as well as by AhR, suggesting that exposure to both LXRα and AhR ligands can result in the alteration of individual susceptibility to environmental carcinogens metabolically activated by CYP1A1.