Substantial pharmacokinetic interaction between digoxin and ritonavir in healthy volunteers

BACKGROUND: Ritonavir is a potent in vitro inhibitor of several cytochrome P450 isozymes and ABC transporters including the efflux pump P-glycoprotein (P-gp). This study assessed the effect of repetitive ritonavir administration on digoxin distribution and total and renal digoxin clearance as a marker for P-gp activity in vivo. METHODS: In a randomized, placebo-controlled crossover study, 12 healthy male participants received oral ritonavir (300 mg twice daily) for 11 days. With the assumption that ritonavir steady state had been reached, 0.5 mg digoxin was given intravenously on day 3. Digoxin concentrations were determined in plasma and urine by radioimmunoassay, and plasma ritonavir concentrations were determined by liquid chromatography-tandem mass spectrometry. Digoxin kinetics was estimated by compartmental and noncompartmental analyses, by use of the area under the plasma concentration-time curve, and the corresponding digoxin amount excreted into urine was used for digoxin clearance calculations. RESULTS: Ritonavir significantly (P <.01) increased digoxin area under the plasma concentration-time curve from time 0 to infinity by 86% and its volume of distribution by 77% and decreased nonrenal and renal digoxin clearance by 48% and 35%, respectively. Digoxin terminal half-life in plasma increased by 156% (P <.01). CONCLUSION: This inhibition of renal digoxin clearance is likely caused by ritonavir inhibition of P-gp. Its extent is considerable and similar to the effect of other potent P-gp inhibitors on digoxin disposition such as quinidine. These findings may, therefore, indicate that the pharmacokinetics of P-gp substrates sharing the renal tubular elimination pathway will be affected when combined with therapeutic doses of ritonavir in antiretroviral treatment regimens. In addition and contrarily to quinidine, these data indicate that ritonavir promotes digoxin distribution in the body.     

An improved quantitative measurement for thyroid cancer detection based on elastography

Objective

To evaluate color thyroid elastograms quantitatively and objectively.

Materials and methods

125 cases (56 malignant and 69 benign) were collected with the HITACHI Vision 900 system (Hitachi Medical System, Tokyo, Japan) and a liner-array-transducer of 6–13 MHz. Standard of reference was cytology (FNA—fine needle aspiration) or histology (core biopsy). The original color thyroid elastograms were transferred from red, green, blue (RGB) color space to hue, saturation, value (HSV) color space. Then, hard area ratio was defined. Finally, a SVM classifier was used to classify thyroid nodules into benign and malignant. The relation between the performance and hard threshold was fully investigated and studied.

Results

The classification accuracy changed with the hard threshold, and reached maximum (95.2%) at some values (from 144 to 152). It was higher than strain ratio (87.2%) and color score (83.2%). It was also higher than the one of our previous study (93.6%).

Conclusion

The hard area ratio is an important feature of elastogram, and appropriately selected hard threshold can improve classification accuracy.     

压敏胶片法在记忆生物力学实验中的新应用

目的:寻求记忆生物力学实验的新途径,探讨压敏胶片的生物力学特性及其在记忆生物力学实验中的应用。方法:利用生物力学实验装置,对待测试压敏胶片施加不同压力,得到不同颜色,分析比较颜色的灰度值,找出应力与颜色灰度值之间的关系。结果:对所得20组实验结果进行分析得到应力与颜色灰度值之间的关系,同时采用曲线拟和及最小二乘法得出应力与灰度值的对应关系式:yi=83.38816xi2-39244.89748xi+5199277.493。结论:压敏胶片法能够将动态的压力转化成静态的颜色灰度,在记忆生物力学实验中,选择合适的压敏胶片及工作环境,压敏胶片法将不失为一种较为理想的新方法。     

Optimized Fluoroscopy Setting and Appropriate Project Position Can Reduce X-ray Radiation Doses Rates during Electrophysiology Procedures

Background:

Nonfluoroscopic three-dimensional electroanatomical system is widely used nowadays, but X-ray remains indispensable for complex electrophysiology procedures. This study aimed to evaluate the value of optimized parameter setting and different projection position to reduce X-ray radiation dose rates.

Methods:

From June 2013 to October 2013, 105 consecutive patients who underwent complex ablation were enrolled in the study. After the ablation, the radiation dose rates were measured by two different settings (default setting and optimized setting) with three projection positions (posteroanterior [PA] projection; left anterior oblique [LAO] 30° projection; and LAO 45° projection). The parameter of preset voltage, pulse width, critical voltage, peak voltage, noise reduction, edge enhancement, pulse rate, and dose per frame was modified in the optimized setting.

Results:

The optimized setting reduced radiation dose rates by 87.5% (1.7 Gy/min vs. 13.6 Gy/min, P < 0.001) in PA, 87.3% (2.5 Gy/min vs. 19.7 Gy/min, P < 0.001) in LAO 30°, 85.9% (3.1 Gy/min vs. 22.1 Gy/min, P < 0.001) in LAO 45°. Increase the angle of projection position will increase the radiation dose rate.

Conclusions:

We can reduce X-ray radiation dose rates by adjusting the parameter setting of X-ray system. Avoiding oblique projection of large angle is another way to reduce X-ray radiation dose rates.     

Differences in Liver Injury and Trophoblastic Mitochondrial Damage in Different Preeclampsia-like Mouse Models

Background:

Preeclampsia is a multifactorial disease during pregnancy. Dysregulated lipid metabolism may be related to some preeclampsia. We investigated the relationship between triglycerides (TGs) and liver injury in different preeclampsia-like mouse models and their potential common pathways.

Methods:

Preeclampsia-like models (Nw-nitro-L-arginine-methyl ester [L-NAME], lipopolysaccharide [LPS], apolipoprotein C-III [Apo] transgnic mice + L-NAME, β2 glycoprotein I [βGPI]) were used in four experimental groups: L-NAME (LN), LPS, Apo-LN and βGPI, respectively, and controls received saline (LN-C, LPS-C, Apo-C, βGPI-C). The first three models were established in preimplantation (PI), early-, mid- and late-gestation (EG, MG and LG). βGPI and controls were injected before implantation. Mean arterial pressure (MAP), 24-hour urine protein, placental and fetal weight, serum TGs, total cholesterol (TC) and pathologic liver and trophocyte changes were assessed.

Results:

MAP and proteinuria were significantly increased in the experimental groups. Placenta and fetal weight in PI, EP and MP subgroups were significantly lower than LP. Serum TGs significantly increased in most groups but controls. TC was not different between experimental and control groups. Spotty hepatic cell necrosis was observed in PI, EG, MG in LN, Apo-LN and βGPI, but no morphologic changes were observed in the LPS group. Similar trophoblastic mitochondrial damage was observed in every experimental group.

Conclusions:

Earlier preeclampsia onset causes a higher MAP and urine protein level, and more severe placental and fetal damage. Preeclampsia-like models generated by varied means lead to different changes in lipid metabolism and associated with liver injury. Trophoblastic mitochondrial damage may be the common terminal pathway in different preeclampsia-like models.     

Evaluation of the relationship between T663A polymorphism in the alpha-epithelial sodium channel gene and essential hypertension

Objectives:

To evaluate the relationship between alpha epithelial sodium channel (alpha-ENaC) T663A polymorphism and the risk of essential hypertension.

Methods:

This meta-analysis was conducted between November 2014 and February 2015 in Shanghai Medical Instrumentation College, Shanghai, China. We collected all published available case-control data (N=12) identified through PubMed, Web of Science, Scopus, and Chinese National Knowledge Infrastructure (CNKI) up to December 2014. The pooled odds ratio (OR) with 95% confidence interval (CI) was calculated using the fixed- or random-effect model.

Results:

Although subgroup analysis showed that alpha-ENaC T663A polymorphism was associated with essential hypertension in North American individuals (OR=1.55, 95% CI=1.22-1.98, p=0.0003), our meta-analysis results did not confirm such association overall (OR=1.03, 95% CI=0.92-1.15, p=0.62). The lack of association was further confirmed by the non-superiority test (p<0.0001).

Conclusion:

Alpha-ENaC T663A polymorphism might not be a risk factor for essential hypertension.Hypertension is one of the most important risk factor for cardiovascular disease.1-3 However, its etiology in the vast majority of cases (~90%) is unknown, and thus the essential hypertension term is employed to describe such situations.4 Nowadays, essential hypertension is considered as a multifactorial disease resulting from the interplay of many genetic, environmental, and behavioral factors.5 Among them, sodium has long been deemed as one of the pivotal environmental factors due to its direct regulatory effect on blood pressure.5,6 The amiloride-sensitive epithelial sodium channel (ENaC) lies in the collecting duct of the kidney, and regulates sodium reabsorption. This channel is composed of 3 homologous subunits: alpha, beta, and gamma. Several studies have reported that mutations in beta-ENaC or gamma-ENaC can result in constitutive sodium reabsorption, thus leading to the development of an autosomal-dominant Mendelian hypertensive disorder, Liddle syndrome.7-11 Therefore, some “milder” mutations or functional polymorphisms were assumed to play some etiological roles in essential hypertension. Following this hypothesis, recent studies have reported some potential associated variants.12 Among them, T663A polymorphism in the alpha-ENaC gene has attracted some attention due to its reported ability to influence the channel activity.13,14 The A allele of T663A polymorphism could reduce the surface expression of ENaC, and the T allele of T663A polymorphism could increase ENaC activity.13,14 Accordingly, Ambrosius et al15 observed that the A allele of T663A polymorphism was associated with being normotensive in Blacks and Caucasians. However, a similar study performed in a Japanese population indicated that the A allele of T663A polymorphism was enriched in essential hypertensive patients,16 and Wang et al17 found that there was a lack of association between the T663A polymorphism and essential hypertension in 2 ethnic groups in China. Therefore, there is still a controversy over the association between T663A polymorphism in the alpha-ENaC gene and essential hypertension. Therefore, we performed a meta-analysis to investigate the relationship between alpha-ENaC T663A polymorphism and essential hypertension.     

LOXL4 is downregulated in hepatocellular carcinoma with a favorable prognosis

Lysyl oxidase like 4 (LOXL4), a member of the secreted copper-dependent amine oxidases that contribute to the assemble and maintenance of the extracellular matrix (ECM), was found to be up-regulated or down-regulated in different cancer types, suggesting its paradoxical roles in cancer. The specific role of LOXL4 in hepatocellular carcinoma (HCC), however, is still yet to be defined. Twenty-eight pairs of HCC specimens were used for LOXL4 mRNA expression analysis. The mRNA expression in HCC cell lines was examined, and HepG2 was selected for LOXL4 small interfering RNA (siRNA) interference to investigate the biological function of LOXL4, LOXL4 immunohistochemical staining was performed using a tissue microarray containing 298 HCC patients. The prognostic and diagnostic value of LOXL4 was evaluated using Cox regression and Kaplan-Meier analysis. LOXL4 mRNA or protein expression was significantly lower in HCC tissues than peritumoral tissues (LOXL4 mRNA expression, P = 0.018; LOXL4 protein expression, P < 0.001). Low LOXL4 expression was associated with lower overall survival (OS) rates and higher cumulative recurrence rates. Multivariate analysis indicated that LOXL4 was an independent prognostic indicator for OS and time to recurrence (TTR). Our results revealed that LOXL4 was down-regulated in HCC and correlated with aggressive tumors and a worse clinical outcome. LOXL4 may be a potential biomarker to identify the HCC patients with a higher risk of recurrence.     

Changes of mesenchymal stromal cells mobilization and bone turnover in an experimental bone fracture model in ovariectomized mice

Objective: The aim of this study was to characterize the mesenchymal stromal cells (MSCs) and endothelial progenitor cells (EPCs) mobilization, and bone turnover in osteoporotic fracture healing in ovariectomized mice. Methods: In total, 112 female C57/BL mice were divided into two groups. The first group was sham-operated (SO), and the other group was ovariectomized (OVX). After three weeks, the right femora of the mice were fractured under anesthesia and internally fixed with steel pin. Peripheral blood and bone marrow were was collected for flow cytometry analysis, at 0 hours (h), 12 h, 24 h, 72 h and 168 h after fracture. MSCs and EPCs levels were assessed using cell surface antigens in different combinations (CD44+ CD34-CD45-, and CD34+ KDR+CD45-) by flow cytometry. At 0, 14, 28 and 42 days after fracture, sera were assayed for circulating levels of procollagen type I-N-terminal propeptide (P1NP) and C-terminal telopeptide of type I-collagen (CTX) by ELISA. Femurs were harvested at 2 weeks and 6 weeks after fracture for X-ray radiography, micro-computed tomography (micro-CT) and histology. Results: Our results showed that bone marrow and peripheral blood MSCs numbers of the OVX mice were significantly lower than the SO mice, at 12 h, 24 h and 72 h after fracture. In addition, circulating P1NP and CTX levels of the OVX mice were significantly higher than the SO mice, at 2 and 4 weeks. Conclusion: Results of the present study revealed disorders of bone marrow MSCs mobilization and bone turnover may partially account for the delay of osteoporotic fracture healing.     

Immunolocalization of membrane-type 1 MMP in human rheumatoid synovium tissues

Membrane-type 1 matrix metalloproteinase (MT1-MMP, also known as MMP14), the best characterized membrane-anchored MMP, is an important matrix-degrading proteinase that could digest a broad spectrum of extracellular matrix proteins and accelerate angiogenesis. We have previously reported that some MMPs involved in the angiogenesis and the pannus formation within the joint, leading to the erosion of articular cartilage and bone in the pathological process of rheumatoid arthritis (RA). In the present study, we used immunohistochemistry assay and con-focal scanning technique to study the detailed immunolocalization of MT1-MMP in human RA synovium tissues as well as the infiltrating immune cell subsets. Our results showed that the positive MT1-MMP immunostaining could be found in synoviocytes, vascular endothelial cells, infiltrating macrophages and monocytes in RA synovium tissues, while weak or negative immunostaining could be found in infiltrating T cells, B cells and NK cells, respectively. Moreover, the Ki-67⁺ highly proliferating synoviocytes also showed higher MT1-MMP expression in RA synoviocytes. Thus, the aberrant expression of MT1-MMP in RA synoviocytes as well as infiltrating immune cells may contribute to the proliferation of the synoviocytes, and the angiogenesis and the pannus formation in RA pathological progression.