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- Comparative Salivary Proteome of Hepatitis B- and C-Infected Patients. [JOURNAL ARTICLE]
- PLoS One 2014; 9(11):e113683.
Hepatitis B and C virus (HBV and HCV) infections are an important cause of cirrhosis and hepatocellular carcinoma. The natural history has a prominent latent phase, and infected patients may remain undiagnosed; this situation may lead to the continuing spread of these infections in the community. Compelling reasons exist for using saliva as a diagnostic fluid because it meets the demands of being an inexpensive, noninvasive and easy-to-use diagnostic method. Indeed, comparative analysis of the salivary proteome using mass spectrometry is a promising new strategy for identifying biomarkers. Our goal is to apply an Orbitrap-based quantitative approach to explore the salivary proteome profile in HBV- and HCV-infected patients. In the present study, whole saliva was obtained from 20 healthy, (control) 20 HBV-infected and 20 HCV-infected subjects. Two distinct pools containing saliva from 10 subjects of each group were obtained. The samples were ultracentrifuged and fractionated, and all fractions were hydrolyzed (trypsin) and injected into an LTQ-VELOS ORBITRAP. The identification and analyses of peptides were performed using Proteome Discoverer1.3 and ScaffoldQ + v.3.3.1. From a total of 362 distinct proteins identified, 344 proteins were identified in the HBV, 326 in the HCV and 303 in the control groups. Some blood proteins, such as flavin reductase (which converts biliverdin to bilirubin), were detected only in the HCV group. The data showed a reduced presence of complement C3, ceruloplasmin, alpha(1)-acid glycoprotein and alpha(2)-acid glycoprotein in the hepatitis-infected patients. Peptides of serotransferrin and haptoglobin were less detected in the HCV group. This study provides an integrated perspective of the salivary proteome, which should be further explored in future studies targeting specific disease markers for HBV and HCV infection.
- Internal-external percutaneous transhepatic biliary drainage for patients with malignant obstructive jaundice. [Journal Article]
- Asian Pac J Cancer Prev 2014; 15(21):9391-4.
To evaluate the effect of internal-external percutaneous transhepatic biliary drainage (IEPTBD) for patients with malignant obstructive jaundice.During the period of January 2008 and July 2013, internal-external drainage was performed in 42 patients with malignant obstructive jaundice. During the procedure, if the guide wire could pass through the occlusion and into the duodenum, IEPTBD was performed. External drainage biliary catheter was placed if the occlusion was not crossed. Newly onset of infection, degree of bilirubin decrease and the survival time of patients were selected as parameters to evaluate the effect of IEPTBD.Twenty newly onset of infection were recorded after procedure and new infectious rate was 47.6%. Sixteen patients with infection (3 before, 13 after drainage) were uncontrolled after procedure, 12 of them (3 before, 9 after drainage) died within 1 month. The mean TBIL levels declined from 299.53 umol/L before drainage to 257.62 umol/L after drainage, while uninfected group decline from 274.86 umol/L to 132.34 umol/Lp (P < 0.5). The median survival time for uninfected group was 107 days, and for infection group was 43 days (P < 0.05).The IEPTBD drainage may increase the chance of biliary infection, reduce bile drainage efficiency and decrease the long-term prognosis, and the external drainage is a better choice for patients with malignant obstructive jaundice need to biliary drainage.
- Population Pharmacokinetics of Micafungin and its Metabolites M1 and M5 in Children and Adolescents: Towards Further Certainty in Dosing. [JOURNAL ARTICLE]
- Antimicrob Agents Chemother 2014 Nov 24.
The aim of this analysis was to identify therapeutic micafungin regimens for children that produce the same micafungin exposures known to be effective for the prevention and treatment of Candida infections in adults. Pediatric pharmacokinetic data from 229 patients between the ages of 4 months and <17 years were obtained from four Phase I and two Phase III clinical trials. Population pharmacokinetic models were used to simulate the proportion of children who had a steady-state area under the concentration-time curve (AUC24) of micafungin within the 10(th) to 90(th) percentile range observed in a population of adults receiving a dose of micafungin with established efficacy for invasive candidiasis (100 mg/day), i.e., 75 to 139 μg⋅h/ml. Simulated pediatric dosages of 0.5 to 5 mg/kg/day were explored. A two-compartment model was used that incorporated body weight as a predefined covariate for allometric scaling of the pharmacokinetic parameters. During construction of the model, aspartate aminotransferase and total bilirubin were also identified as covariates that had a significant effect on micafungin clearance. A dose of 2 mg/kg resulted in the highest proportion of children within the predefined micafungin AUC target range for invasive candidiasis. Cut-offs of either 40 kg or 50 kg for weight-based dosing resulted in heavier children being appropriately dosed. Thus, dose regimens of 1, 2, and 3 mg/kg/day micafungin are appropriate for prevention and treatment of invasive candidiasis, and treatment of esophageal candidiasis, respectively, in children aged 4 months to <17 years.
- Surgical rehabilitation of short and dysmotile intestine in children and adults. [JOURNAL ARTICLE]
- Scand J Gastroenterol 2014 Nov 25.:1-9.
Abstract Aims. This is a descriptive study aiming to compare outcomes of intestinal rehabilitation surgery among pediatric and adult intestinal failure (IF) patients with either primary intestinal motility disorders or short bowel syndrome (SBS) treated by our nationwide program. Methods. Medical records of IF patients (n = 31, 71% children) having undergone autologous intestinal reconstructions (AIR) (n = 25), intestinal transplantation (ITx) (n = 5), or being listed for ITx (n = 2) between 1994 and 2014 were reviewed. Results. At surgery, median age was 3.4 (interquartile range, 1.0-22.1) in SBS (n = 22) and 16.5 (3.2-26.7) years in dysmotility patients (n = 9) who received median 60% and 83% of energy requirement parenterally, respectively. Median small bowel length was shorter in SBS than dysmotility patients (34 versus 157 cm, p < 0.001). Following AIR, none of the dysmotility patients achieved permanent intestinal autonomy, whereas 68% of SBS patients weaned off parenteral nutrition (PN) (p = 0.022) and none required listing for ITx. Five dysmotility patients who underwent ITx achieved intestinal autonomy. Regarding both AIR and ITx procedures, no significant difference in PN weaning was observed between the two subgroups. At last follow-up, 3.3 (0.6-8.0) years postoperatively, median plasma bilirubin was 6 (4-16) µmol/l, while liver biopsy showed fibrosis (Metavir stage 1-2) in 50% and cholestasis in 8%. Proportion of PN energy requirement had reduced significantly (p = 0.043) among PN-dependent SBS (n = 7) but not among dysmotility patients (n = 5). Overall survival was 90%. Conclusion. AIR surgery was beneficial among selected SBS patients, whereas in intestinal dysmotility disorders, permanent PN weaning was only achieved by ITx.
- Effect of Yin-Zhi-Huang on up-regulation of Oatp2, Ntcp, and Mrp2 proteins in estrogen-induced rat cholestasis. [JOURNAL ARTICLE]
- Pharm Biol 2014 Nov 25.:1-7.
Abstract Context: Yin-Zhi-Huang (YZH), a prescription of traditional Chinese medicine, is widely used to treat neonatal jaundice or cholestasis. Objective: This study investigates the regulatory effect of YZH on the localization and expression of organic anion transporting polypeptides 2 (Oatp2), Na(+)-taurocholate co-transporting polypeptide (Ntcp), multidrug-resistance-associated protein 2 (Mrp2), and bile salt export pump (Bsep) in estrogen-induced cholestasis rats. Material and methods: Cholestasis model rats were induced via subcutaneous injection of estradiol benzoate (EB, 5 mg/kg/d) for 5 d. Other EB-induced rats were treated with saline (2 ml) or YZH (1.5 g/kg, two times a day) for 7, 14, and 21 d. The biochemical and pathologic examinations were performed. Moreover, the localization and expression of Oatp2, Ntcp, Mrp2, and Bsep were determined by immunohistochemisty and Western blotting, respectively. Results: YZH treatment could significantly decrease the serum total bile acids (TBA) (4.9 ± 0.6-2.8 ± 0.8) and direct bilirubin (DBIL) (2.6 ± 0.7-1.0 ± 0.1) levels, improve the histological disorganization, and, respectively, increase the expression of Oatp2 and Ntcp by 46% and 28% compared with saline-treated (p < 0.05) rats at 14 d. The expression of Mrp2 increased by 45% was observed in YZH treated compared with saline-treated (p < 0.05) rats at 7 d. However, there was a little change in the expression of Bsep (p > 0.05) after YZH treatment for 7, 14, and 21 d. Discussion and conclusion: In conclusion, the therapeutic effect of YZH to cholestasis could be attributed to the regulation of Oatp2, Ntcp, Mrp2, and Bsep.
- Neonatal bilirubin binding capacity discerns risk of neurological dysfunction. [JOURNAL ARTICLE]
- Pediatr Res 2014 Nov 24.
BACKGROUNDBilirubin binding capacity (BBC) defines the dynamic relationship between an infant's level of unbound or "free" bilirubin and his/her ability to "tolerate" increasing bilirubin loads. BBC is not synonymous with albumin levels because albumin binding of bilirubin is confounded by a variety of molecular, biologic, and metabolic factors.METHODSWe utilized a novel modification of a previously-developed hematofluorometric method to directly assay BBC in whole blood from preterm and term neonates and then combined these data with an archived database. Total bilirubin (TB) was also measured, and multiple regression modeling was used to determine whether BBC in combination with TB measurements can assess an infant's risk for developing bilirubin-induced neurotoxicity.RESULTSTB and BBC levels ranged from 0.7-22.8 and 6.3-47.5mg/dL, respectively. GA correlated with BBC (r=0.54, P <0.0002) with a slope of 0.93mg/dL/wk by logistic regression. Our calculations demonstrate that recently recommended GA-modulated TB thresholds for phototherapy and exchange transfusion correspond to 45% and 67% saturation of our observed regression line, respectively.CONCLUSIONWe speculate that the spread of BBC levels around the regression line (±5.8mg/dL) suggests that individualized BBC assays would provide a robust approach to gauge risk of bilirubin neurotoxicity compared to TB and GA.Pediatric Research (2014); doi:10.1038/pr.2014.191.
- Total Serum Bilirubin Predicts Fat-Soluble Vitamin Deficiency Better Than Serum Bile Acids in Infants With Biliary Atresia. [JOURNAL ARTICLE]
- J Pediatr Gastroenterol Nutr 2014 Dec; 59(6):702-707.
Fat-soluble vitamin (FSV) deficiency is a well-recognized consequence of cholestatic liver disease and reduced intestinal intraluminal bile acid. We hypothesized that serum bile acid (SBA) would predict biochemical FSV deficiency better than serum total bilirubin (TB) level in infants with biliary atresia.Infants enrolled in the Trial of Corticosteroid Therapy in Infants with Biliary Atresia after hepatoportoenterostomy were the subjects of this investigation. Infants received standardized FSV supplementation and monitoring of TB, SBA, and vitamin levels at 1, 3, and 6 months. A logistic regression model was used with the binary indicator variable insufficient/sufficient as the outcome variable. Linear and nonparametric correlations were made between specific vitamin measurement levels and either TB or SBA.The degree of correlation for any particular vitamin at a specific time point was higher with TB than with SBA (higher for TB in 31 circumstances vs 3 circumstances for SBA). Receiver operating characteristic curve shows that TB performed better than SBA (area under the curve 0.998 vs 0.821). Including both TB and SBA did not perform better than TB alone (area under the curve 0.998).We found that TB was a better predictor of FSV deficiency than SBA in infants with biliary atresia. The role of SBA as a surrogate marker of FSV deficiency in other cholestatic liver diseases, such as progressive familial intrahepatic cholestasis, α-1-antitrypsin deficiency, and Alagille syndrome in which the pathophysiology is dominated by intrahepatic cholestasis, warrants further study.
- Cellular-mediated immune responses in the liver tissue of patients with severe Plasmodium falciparum malaria. [Journal Article, Research Support, Non-U.S. Gov't]
- Southeast Asian J Trop Med Public Health 2014 Sep; 45(5):973-83.
The immune responses against Plasmodiumfalciparum malaria infections are complex and poorly understood. No published studies have yet reported the lymphocyte subsets involved in the human liver tissue of P. falciparum malaria patients. To understand the cellular-mediated immune responses in the liver during malaria infection, we determined the numbers of the various lymphocyte subsets in tissue samples obtained at autopsy from patients who died with P. falciparum malaria infection. All the liver tissue specimens had been stored at the Department of Tropical Pathology, Faculty of Tropical Medicine, Mahidol University, Thailand. On the basis of total bilirubin (TB) levels prior to death, patients were divided into 2 groups: those with hyperbilirubinemia [total bilirubin (TB) > or =51.3 micromol/l) (n = 9)] and those without hyperbilirubinemia (TB < 51.3 micromol/l) (n = 12). Normal liver specimens (n = 10) were used as controls. An immunohistochemistry method was used to analyze the types and numbers of lymphocytes (T and B lymphocytes), and Kupffer cells, using specific antibodies against CD3+, CD4+, CD8+, CD20+, and CD68+. Our findings reveal the numbers of T lymphocytes (CD3+ T-cells) and their subsets (CD4+ and CD8+ T-cells) were significantly greater in the portal tracts and sinusoids of liver tissue obtained from P. falciparum malaria cases with hyperbilirubinemia than those without hyperbilirubinemia or controls. CD8+ T-cells were the major lymphocyte subset in the liver tissue of patients with severe falciparum malaria. A significant positive correlation was seen between the numbers of CD4+ and CD8+ T-cells and the liver enzyme levels among P. falciparum malaria patients. The number of CD68+ cells (Kupffer cells) was significantly greater in the liver sinusoids of P. falciparum malaria cases with hyperbilirubinemia than those without hyperbilirubinemia. These findings suggest T-cells, especially CD8+ T-cells and Kupffer cells are an important part of the cellular immune response in the liver tissue of P. falciparum infected patients.
- Effects on Pharmacokinetics of Propranolol and Other Factors in Rats After Acute Exposure to High Altitude at 4,010 m. [JOURNAL ARTICLE]
- Cell Biochem Biophys 2014 Nov 23.
A series of pathological, physiological, and biochemical changes, even anatomical histological changes happen while humans arrive at the high plateau region from plain area. There is a certain relationship between the body's compensatory or decompensated adjustments to the environment and the changes of absorption, distribution, metabolism, and excretion of drugs. The objective of the study is to observe the effects of acute exposure to high altitude at 4,010 m on pharmacokinetics of propranolol in rats, and to provide basis and new ideas to adjust drug dosage and administration, so as to promote rational drug use in high altitude. 28 healthy male wistar rats were randomly divided into four groups, group A and B which were in plain area; group C and D which were acutely exposed to high altitude by aviation; group A and C were used for pharmacokinetics determination of propranolol, while group B and D had no drug administration for physiological and pathological changes research at high altitude. The pharmacokinetics of propranolol significantly changed; area under curve, C max (the peak concentration), mean residence time, and t 1/2 (the biological half-life) increased significantly by 481.72, 398.94, 44.87, and 58.77 %, respectively; clearance and V (apparent volume of distribution) decreased by 81.50 and 70.56 %, respectively, after acute exposure to high altitude at 4,010 m; Analytic results show that pH, buffer base, base excess, ctCO2 (content of total carbon dioxide), sO2 (oxygen saturation of arterial blood), pO2 (oxygen tension of arterial blood), and cNa(+) severely decreased by 2.43, 630.00, 311.00, 11.48, 91.38, 76.22, and 2.82 %, respectively, while pCO2 (carbon dioxide tension of arterial blood) and cCl(-) significantly increased by 47.40 and 6.76 %. Lactate dehydrogenase and total protein significantly decreased by 58.44 and 26.82 %, while total bilirubin and alkaline phosphatase severely increased by 338 and 24.94 % after acute exposure to high altitude at 4,010 m. Pathological research shows that alveolar wall is hyperemic, edematous, and incrassate; alveolus epithelium becomes hyperplastic while neutrophilic granulocytes infiltrate; brain neurons are edematous and perivascular space occurred; neurons of seahorse are metamorphic and karyopyknotic; mesangial cells are hyperplastic in kidney glomerulus tissue. We should reduce the dosage or extend the dosing interval in high altitude to maintain the drug concentration in therapeutic window since velocity of metabolism and excretion are reduced.
- Characterization of Liver Function Parameter Alterations After Transjugular Intrahepatic Portosystemic Shunt Creation and Association With Early Mortality. [JOURNAL ARTICLE]
- AJR Am J Roentgenol 2014 Dec; 203(6):1363-1370.
OBJECTIVE. The purpose of this article is to characterize the temporal evolution and clinical impact of laboratory liver function parameters after transjugular intrahepatic portosystemic shunt (TIPS) creation. MATERIALS AND METHODS. In this single-institution retrospective study, 157 patients (98 men and 59 women; median age, 55 years) underwent TIPS between 2000 and 2012 and had 1-month hepatobiliary laboratory follow-up. Medical record review was used to compare baseline, peak, and low bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, and international normalized ratio (INR) levels within 30 days after TIPS in surviving and dying patients to assess laboratory responses to shunt creation. RESULTS. TIPSs were created with a hemodynamic success rate of 98%, with median pressure gradient reduction of 13 mm Hg. Ninety-day mortality was 21%. Hepatobiliary laboratory values showed significant increases in the days after TIPS compared with baseline levels (bilirubin, 1.6 vs 3.5 mg/dL; AST, 49 vs 149 U/L; ALT, 26 vs 90 U/L; alkaline phosphatase, 97 vs 177 U/L; and INR, 1.5 vs 2.0; p < 0.05 in all cases). Patients surviving to 90 days experienced statistically significant but transient laboratory value elevations-up to twofold over baseline-within days of TIPS, whereas patients dying within 90 days experienced three-to fourfold increases over a longer period that did not return to baseline. Differences in laboratory evolution were statistically significant in surviving versus dying patients. CONCLUSION. TIPS results in acute transient elevation of hepatobiliary enzymes, which may be more pronounced in patients with early mortality. An exaggerated laboratory elevation in excess of threefold greater than baseline or a prolonged increase exceeding 1 week may herald poorer clinical outcome.