Association of gene expression involving innate immunity and genetic variation in interleukin 28B with antiviral response

Innate immunity plays an important role in host antiviral response to hepatitis C viral (HCV) infection. Recently, single nucleotide polymorphisms (SNPs) of IL28B and host response to peginterferon α (PEG-IFNα) and ribavirin (RBV) were shown to be strongly associated. We aimed to determine the gene expression involving innate immunity in IL28B genotypes and elucidate its relation to response to antiviral treatment. We genotyped IL28B SNPs (rs8099917 and rs12979860) in 88 chronic hepatitis C patients treated with PEG-IFNα-2b/RBV and quantified expressions of viral sensors (RIG-I, MDA5, and LGP2), adaptor molecule (IPS-1), related ubiquitin E3-ligase (RNF125), modulators (ISG15 and USP18), and IL28 (IFNλ). Both IL28B SNPs were 100% identical; 54 patients possessed rs8099917 TT/rs12979860 CC (IL28B major patients) and 34 possessed rs8099917 TG/rs12979860 CT (IL28B minor patients). Hepatic expressions of viral sensors and modulators in IL28B minor patients were significantly up-regulated compared with that in IL28B major patients (≈ 3.3-fold, P < 0.001). However, expression of IPS-1 was significantly lower in IL28B minor patients (1.2-fold, P = 0.028). Expressions of viral sensors and modulators were significantly higher in nonvirological responders (NVR) than that in others despite stratification by IL28B genotype (≈ 2.6-fold, P < 0.001). Multivariate and ROC analyses indicated that higher RIG-I and ISG15 expressions and RIG-I/IPS-1 expression ratio were independent factors for NVR. IPS-1 down-regulation in IL28B minor patients was confirmed by western blotting, and the extent of IPS-1 protein cleavage was associated with the variable treatment response. CONCLUSION: Gene expression involving innate immunity is strongly associated with IL28B genotype and response to PEG-IFNα/RBV. Both IL28B minor allele and higher RIG-I and ISG15 expressions and RIG-I/IPS-1 ratio are independent factors for NVR.     

Impact of technical modification of endoscopic papillectomy for ampullary neoplasm on the occurrence of complications

Aim: To evaluate the usefulness of a modified technique of endoscopic papillectomy (EP) for lessening the occurrence of complications. Methods: Indications for EP were adenoma or well‐differentiated adenocarcinoma confined to the papilla of Vater (T1) without tumor spread into the bile/pancreatic duct. Sixteen patients underwent the modified technique, which consists of resection with the Endocut^® mode, followed by biliary/pancreatic sphincterotomy and stenting (Group A). Twelve patients who had undergone EP, using a cutting current, followed by pancreatic duct stenting were included as control (Group B). The frequency of complications and clinical outcomes were retrospectively compared between the two groups. Results: Sixteen patients had adenoma, and 12 had adenocarcinoma. Early complications occurred in 36% of all patients (hemorrhage, 7; cholangitis, 3; perforation, 2; cholecystitis, 1). The frequency of early complications in Group A was significantly lower than that in Group B (6% vs 75%, odds ratio [OR] 0.022, 95% confidence interval [CI], 0.0020–0.25). Late complications occurred in 18% of the patients (bile duct stone, 3; hemorrhage, 1; pancreatitis, 1). There was no significant difference in the late complication rate between Group A and Group B (19% vs 17%). Local recurrences were found in 14% of the patients, without a significant difference between Group A and Group B (19% vs 8%) during a mean follow‐up period. All recurrent tumors were successfully treated with argon plasma coagulation. Conclusions: The modified technique of EP for ampullary neoplasm contributed to lessening the occurrence of early complications. However, further refinement of this technique is necessary for improving the clinical outcome.     

Increased serum soluble CD147 levels in patients with systemic sclerosis: association with scleroderma renal crisis

CD147 is a glycosylated membrane protein that belongs to the immunoglobulin superfamily. This study aimed to determine serum soluble CD147 (sCD147) levels and their clinical associations in patients with systemic sclerosis (SSc). Serum sCD147 levels were examined by enzyme-linked immunosorbent assay in 61 SSc patients and 24 healthy individuals. Serum sCD147 levels were significantly elevated in SSc patients compared with healthy individuals (P < 0.001). Among patients with SSc, there were no differences in serum sCD147 levels between limited cutaneous (n = 30) and diffuse cutaneous SSc (n = 31). Patients with SSc who had elevated sCD147 levels had renal crisis more often than those with normal sCD147 levels (13% vs 0%; P < 0.05). Serum sCD147 levels were increased in patients with SSc and associated with the presence of renal crisis. These results suggest that sCD147 may have a role in the development of renal crisis in SSc. Measurement of serum sCD147 may be useful for risk stratification for renal crisis in SSc.     

Improvement of endothelial function in parallel with the amelioration of dry cough and dyspnea due to interstitial pneumonia by intravenous cyclophosphamide pulse therapy in patients with systemic sclerosis: a preliminary report of two cases

Intravenous cyclophosphamide pulse therapy (IVCY) exerts its efficacy against interstitial lung disease (ILD) associated with systemic sclerosis (SSc) by restoring vascular injuries as well as aberrant immune activation. We recently experienced two patients with SSc-ILD in whom the values of brachial flow-mediated dilation (FMD) reflected the efficacy of IVCY. We herein report the details of these cases and discuss the potential of FMD to predict and evaluate the effect of IVCY on SSc-ILD.     

Usefulness of right ventricular tissue Doppler imaging for diagnosis of right ventricular myocardial infarction

Background

Right ventricular myocardial infarction (RVMI) is a complication of acute inferior myocardial infarction and sometimes causes severe hemodynamic disturbance. It is therefore important to promptly detect RVMI and assess the severity of right ventricular (RV) dysfunction. Tissue Doppler imaging (TDI) is a useful method to assess left ventricular function and RV function. In this study, we investigated the possibility of diagnosing RVMI using tricuspid annular velocity determined by TDI.

Methods

Thirty consecutive patients with first acute inferior myocardial infarction were studied. The diagnosis of RVMI was based on an ST-segment elevation of at least 0.1 mV in lead V4R. The patients were classified into 12 patients with RVMI (the RVMI group) and 18 patients without RVMI (non-RVMI group). All patients underwent two-dimensional echocardiography, pulsed Doppler and TDI, and coronary angiography within 48 h after onset of myocardial infarction. Tricuspid inflow velocity was recorded by pulsed Doppler and early diastolic tricuspid inflow velocity (TVE) was measured. Peak early diastolic velocity of the tricuspid annulus (TVe’) at the RV free wall was recorded using TDI. The ratio of TVE to TVe’ (TVE/TVe’) was calculated.

Results

TVe’ was significantly lower in the RVMI group compared to that in the non-RVMI group (5.9 ± 1.3 vs. 9.1 ± 3.1; p = 0.0025). On the basis of a TVe’ cutoff value of less than 8.3 cm/s, RVMI was diagnosed with 100 % sensitivity and 61 % specificity.

Conclusions

The early diastolic tricuspid annular velocity determined by TDI is a noninvasive and sensitive index for diagnosing RVMI.     

Introduction of the targeted alpha therapy (with Radium-223) into clinical practice in Japan: learnings and implementation

Annals of Nuclear Medicine - Radium-223 dichloride (Ra-223) is the first targeted alpha therapy approved for the treatment of patients with castration-resistant prostate cancer (CRPC) with bone...     

Time-dependent risk factors associated with the decline of estimated GFR in CKD patients

Background

Targeting the modifiable risk factors may help halt the progression of CKD, thus risk factor analysis is better performed using the parameters in the follow-up. This study aimed to examine the time-dependent risk factors for CKD progression using time-averaged values and to investigate the characteristics of rapid progression group.

Methods

This is a retrospective cohort study enrolling 770 patients of CKD stage 3–4. Time-dependent parameters were calculated as time-averaged values by a trapezoidal rule. % decline of estimated GFR (eGFR) per year from entry was divided to three groups: <10 % (stable), 10–25 % (moderate progression), and ≥25 % (rapid progression). Multivariate regression analyses were employed for the baseline and the time-averaged datasets.

Results

eGFR decline was 2.83 ± 4.04 mL/min/1.73 m²/year (8.8 ± 12.9 %) in male and 1.66 ± 3.23 mL/min/1.73 m²/year (5.4 ± 11.0 %) in female (p < 0.001). % decline of eGFR was associated with male, proteinuria, phosphorus, and systolic blood pressure as risk factors and with age, albumin, and hemoglobin as protective factors using either dataset. Baseline eGFR and diabetic nephropathy appeared in the baseline dataset, while uric acid appeared in the time-averaged dataset. The rapid progression group was associated with proteinuria, phosphorus, albumin, and hemoglobin in the follow-up.

Conclusion

These results suggest that time-averaged values provide insightful clinical guide in targeting the risk factors. Rapid decline of eGFR is strongly associated with hyperphosphatemia, proteinuria, and anemia indicating that these risk factors should be intervened in the follow-up of CKD.

     

Niemann-Pick C1-like 1 overexpression facilitates ezetimibe-sensitive cholesterol and beta-sitosterol uptake in CaCo-2 cells

Previous in vivo studies including those with knockout mice suggested that Niemann-Pick C1-like 1 (NPC1L1) plays an essential role in the intestinal absorption of cholesterol. To characterize the mechanism of cholesterol uptake mediated by NPC1L1, an in vitro system reflecting the function of this transporter needs to be established. In the present study, we constructed NPC1L1 overexpressing CaCo-2 cells as an in vitro model and characterized the transport properties of NPC1L1. Immunohistochemical staining revealed that CaCo-2 cells express NPC1L1 on the apical membrane. It was also demonstrated that the uptakes of both cholesterol and beta-sitosterol are increased by NPC1L1 overexpression. In addition, the uptake of cholesterol was increased in a dose-dependent manner by an increase in the content of taurocholate in micelles, whereas micellar phosphatidylcholine showed a negative correlation with cholesterol uptake. Furthermore, it was confirmed that sterol uptake increased by NPC1L1 overexpression was inhibited by ezetimibe. We could thus establish an in vitro intestinal model to study the mechanism of NPC1L1-dependent sterol uptake and to screen drug candidates whose target is NPC1L1.