Anthropometric, biochemical and clinical assessment of malnutrition among Egyptian children with chronic liver diseases: a single institutional cross-sectional study.

BACKGROUND: Malnutrition is a common problem among children with chronic liver diseases (CLD). We aimed to assess the nutritional status of children with CLD and to correlate the anthropometric indices with the severity of liver disease, liver function tests, insulin growth factor-1 (IGF-1) and 25-hydroxy vitamin D (25- OH D). METHODS: A total of 69 patients with CLD and 50 healthy controls (6 months - 6 years) were included in the study. Nutritional status was assessed by anthropometric indices expressed in standard deviation score (Z score), biochemical, hematological and clinical parameters. RESULTS: We found 52.2% of CLD patients underweight by weight for age (W/A); 50.2% were stunted by height for age/ length for age (HAZ or LAZ); and 39% exhibited wasting by weight/height or (length) for age (W/HZ or W/LZ) z scores analysis. The mean values of z scores for all anthropometric parameters were significantly correlated with unconjugated and conjugated bilirubin and INR (p < 0.05), except HAZ or LAZ. Also, a significant correlation to albumin was found, except for W/HZ or (W/LZ) (p = 0.157). The z scores < - 2 SD based on W/ H versus arm indicators showed significant differences in MUAC, UAA and AMA (p < 0.001). We found no correlation between anthropometric z-scores and the mean IGF-1 and (25- OH D) values (p > 0.05). Malnutrition was directly correlated with the severity of hepatic dysfunction, particularly, Child-Pugh C cases. The mean IGF-1 and (25- OH D) values were significantly correlated with the severity of liver disease (p < 0.001). CONCLUSIONS: Our results identified anthropometric arm indicators and MUAC/A measurements as an effective applied methods for assessing nutritional status in CLD children. Moreover, Integrating comprehensive clinical assessment, anthropometric measurements and objective biochemical analyses is essential for evaluation, follow-up and management of CLD children with variable degree of malnutrition.

Urinary abnormalities in children and adolescents with Wilson disease before and during treatment with d-penicillamine.

BACKGROUND AND AIM: Renal abnormalities can occur at any time point during the course of Wilson disease (WD). We aimed to fill a literature gap in this respect by studying urinary abnormalities in children and adolescents with WD. METHODS: This study included 60 children with WD presenting to the Pediatric Hepatology Unit, Cairo University. The following data were retrieved from the patients' files including age, sex, liver function tests, serum ceruloplasmin, 24-h urinary copper, serum creatinine, blood urea nitrogen, urinalysis, urinary albumin/creatinine ratio, urinary calcium/creatinine ratio, urinary ß2-microglobulin, liver and renal biopsy results when available. RESULTS: All studied cases had no symptoms related to renal involvement. Microscopic hematuria was detected in 11% and 12% at baseline and within 5 years of therapy, respectively. Moderate microalbuminuria was detected in 34%, 50%, and 33% at baseline, within 5 years and > 5 years after therapy, respectively. Hypercalciuria was detected in 23% at baseline, 34% in those patients treated for up to 5 years and 37.5% > 5 years of therapy. Age and international normalized ratio were significantly higher in patients with high calcium/creatinine ratio compared with those with normal values at initial evaluation. Frequency of elevated urinary ß2-microglobulin was 36%, 36%, and 37% in patients at baseline, up to 5 years and > 5 years of therapy, respectively. CONCLUSION: Asymptomatic urinary abnormalities are present in patients with WD at any time point of the disease and during treatment with d-penicillamine. They have to be searched for, as early intervention may prevent progression to renal insufficiency.

Copper concentrations in Egyptian infants with cholestasis: A single center study.

BACKGROUND AND STUDY AIMS: Hepatobiliary cholestatic disorders produce excess copper (Cu) retention in the liver, which is toxic and may cause hepatitis, fulminant hepatic failure, cirrhosis and death. In this study, we measured hepatic Cu and tested its correlation with serum Cu (S. Cu) and serum ceruloplasmin (S. ceruloplasmin) in cholestatic infants. PATIENTS AND METHODS: 41 cholestatic infants were enrolled as cases and 11 healthy infants as control subjects. S. Cu and S. ceruloplasmin were done for all infants and hepatic Cu was measured in the liver specimen in cases. RESULTS: Cases were 63.5% males with their age ranging between 1 and 7 months, while control subjects were 45.5% males with an age range between 3 and 18 months. Among cases, 41.5% had biliary atresia and 58.5% had intrahepatic cholestasis. Cholestatic infants had significantly higher levels of S. Cu and S. ceruloplasmin than control subjects and their hepatic Cu concentration was significantly higher than literature control. Infants with biliary atresia showed higher levels of Cu indices, with no statistical significance. Serum and hepatic Cu levels positively correlated with each other and with S. ceruloplasmin. Results of ROC curve showed that S. Cu was highly sensitive and specific for predicting hepatic Cu concentration at cut-off 181 µg/dl. CONCLUSION: Serum and hepatic Cu concentrations were markedly elevated in patients with cholestasis and positively correlated with each other and with S. ceruloplasmin. S. Cu level can predict hepatic Cu concentration.

Novel antimicrobial superporous cross-linked chitosan/pyromellitimide benzoyl thiourea hydrogels.

In this work, chitosan (CS) was cross-linked with different amounts of pyromellitimide benzoyl thiourea moieties. The structure of the cross-linked CS was confirmed by elemental analyses, FTIR and (1)H- NMR spectroscopy. The cross-linking process proceeds via reacting of the amino groups of CS with the isothiocyanate groups of the N,N'-bis [4-(isothiocyanate carbonyl)phenyl] pyromellitimide cross-linker. The amount of the cross-linker was varied with respect to CS to produce four new pyromellitimide benzoyl thiourea cross-linked CS (PIBTU-CS) hydrogels designated as PIBTU-CS-1, PIBTU-CS-2, PIBTU-CS-3, and PIBTU-CS-4 of increasing cross-linking degree percent of 11, 22, 44 and 88%, respectively. The scanning electron microscopy observation indicates the extremely porous structure of the hydrogels. XRD results showed that the crystallinity of CS was decreased upon cross-linking. The four hydrogels exhibit a higher antibacterial activity on Bacillus subtilis and Streptococcus pneumoniae as Gram positive bacteria and against Escherichia coli as Gram negative bacteria and higher antifungal activity on Aspergillus fumigatus, Syncephalastrum racemosum and Geotricum candidum than that of the parent CS as shown from their higher inhibition zone diameters and their lower MIC values. The swell ability of the hydrogel as well as their antimicrobial activity increased with increasing cross-linking density.

Fibrin adhesive in conjunction with epithelial ingrowth removal after laser in situ keratomileusis: long-term results.

PURPOSE: To describe the long-term results of fibrin adhesive use in the management of epithelial ingrowth after laser in situ keratomileusis (LASIK). SETTING: Private practice, Minneapolis, Minnesota, and an academic medical center, Durham, North Carolina, USA. DESIGN: Retrospective case series. METHODS: Patients with a history of LASIK had epithelial ingrowth removal with mechanical debridement and fibrin glue application. Visual outcomes and the presence or absence of epithelial ingrowth were evaluated again after 3 months and at the last follow-up. The main outcome measures were recurrence of epithelial ingrowth and visual acuity. RESULTS: Thirty-nine eyes of 38 patients were evaluated. After epithelial ingrowth removal and application of fibrin glue, 31 eyes (79.5%) had no recurrence of ingrowth at the final follow-up and 5 eyes (12.8%) had mild epithelial ingrowth not requiring removal. Three eyes (7.7%) had significant epithelial ingrowth at the 3-month follow-up that required subsequent removal and fibrin application. At the 3-month follow-up visit, 76.9% of eyes achieved 20/25 or better corrected distance visual acuity (CDVA) and 69.2% of eyes achieved 20/40 or better uncorrected distance visual acuity (UDVA). At the last follow-up visit (mean 26.6 ± 17.0 months [SD]), 84.6% of eyes had 20/25 or better CDVA and 74.4% of eyes had 20/40 or better UDVA. CONCLUSIONS: Fibrin adhesive in conjunction with manual epithelial removal prevented a clinically significant recurrence of epithelial ingrowth in the majority of eyes. Larger randomized studies are needed to compare the success of this technique with that of others. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned.

Relevance of the mammalian target of rapamycin pathway in the prognosis of patients with high-risk non-muscle invasive bladder cancer.

High-risk non-muscle invasive bladder cancer (NMIBC) is associated with higher rates of recurrence and progression. Molecular markers within aberrant signaling pathways in cancer need further evaluation of their role as prognostic indicators and potential future targets for prevention of recurrence. Our objective was to investigate the role of the mammalian target of rapamycin (mTOR) signaling pathway on the stage and outcome of patients with high-risk NMIBC. Tissue microarrays were built from archival bladder tumor specimens (n = 142). Various clinicopathologic variables were collected retrospectively from patients treated with transurethral resection. Immunohistochemical staining was performed for phosphatase and tensin homolog, phosphorylated Akt, phosphorylated mTOR, phosphorylated S6 (p-S6), eukaryotic translation initiation factor 4E-binding protein-1, and p27. Multivariate analysis using Cox regression models addressed recurrence-free survival (RFS), progression-free survival, and worsening-free survival. In multivariate analysis, p-S6 was an independent predictor of shorter RFS (hazard ratio, 3.55; 95% CI, 1.31-9.64). Expression of p27 was inversely correlated with RFS (hazard ratio, 0.27; 95% CI, 0.10-0.74). Low levels of phosphatase and tensin homolog expression were associated with worsening-free survival (P < .03). None of the markers showed correlation with progression-free survival. Our results demonstrate that activation of the mTOR pathway, as assessed by p-S6 and expression of p27, might be used to provide prognostic information, particularly as a predictor of recurrence among patients with high-risk NMIBC.

Assessment of coagulation and fibrinolysis in children with chronic liver disease.

We aimed at assessing the coagulation profile and detecting early evidence of fibrinolysis in pediatric patients with chronic liver disease. Seventy-six patients (40 boys) with a mean age of 9.8 ±â€Š3.4 years suffering from chronic liver disease were enrolled in this study. They were followed up in the Pediatric Hepatology Unit, Cairo University Children's Hospital. Thirty healthy children were included as controls. Patients were classified etiologically into four groups: chronic viral hepatitis, autoimmune hepatitis, miscellaneous and cryptogenic groups. Investigations to detect coagulopathy were done for all patients and controls: prothrombin time (PT), activated partial thromboplastin time, fibrinogen, fibrinogen degradation products, and D-dimer and complete blood count. Liver functions were done for all patient groups. A significantly lower platelet count, prolonged prothrombin time, with prolonged aPTT time was detected in all patients compared with controls (P < 0.001). The fibrinogen level showed no significant difference between patients and controls. D-dimer level was significantly higher in the miscellaneous and cryptogenic groups when compared to other patient groups and control group (P < 0.001). Significantly higher D-dimer levels were detected in patients with liver cirrhosis of child class A and B compared with noncirrhotic and control groups (P < 0.001). D-dimer correlated positively with PT (r = 0.290, P = 0.003), and negatively with platelet count (r = -0.324, P = 0.001) and prothrombin concentration (r = -0.270, P = 0.018). Fibrinolytic activity, as evidenced by high D-dimer, was detected in pediatric patients with chronic liver disease particularly if cirrhotic.

Synthesis and antimicrobial activity of some novel cross-linked chitosan hydrogels.

Four novel hydrogels based on chitosan were synthesized via a cross-linking reaction of chitosan with different concentrations of oxalyl bis 4-(2,5-dioxo-2H-pyrrol- 1(5H)-yl)benzamide. Their structures were confirmed by fourier transform infrared X-ray (FTIR), scanning electron microscopy (SEM) and X-ray diffraction. The antimicrobial activities of the hydrogels against two crop-threatening pathogenic fungi namely: Aspergillus fumigatus (A. fumigatus, RCMBA 06002), and Aspergillus niger (A. niger, RCMBA 06106), and five bacterial species namely: Bacillis subtilis (B. subtilis, RCMBA 6005), Staphylococcus aureus (S. aureus, RCMBA 2004), Streptococcus pneumoniae (S. pneumonia, RCMB 000101) as Gram positive bacteria, and Salmonella typhimurium (S. typhimurium, RCMB 000104), and Escherichia coli (E. coli, RCMBA 5003) as Gram negative bacteria have been investigated. The prepared hydrogels showed much higher antimicrobial activities than that of the parent chitosan. The hydrogels were more potent in case of Gram-positive bacteria than Gram-negative bacteria. Increasing the degree of cross-linking in the hydrogels resulted in a weaker antimicrobial activity.

Novel antimicrobial organic thermal stabilizer and co-stabilizer for rigid PVC.

Biologically active N-benzoyl-4-(N-maleimido)-phenylhydrazide (BMPH) was synthesized and its structure was confirmed by elemental analysis and various spectral tools. It was examined as a thermal stabilizer and co-stabilizer for rigid poly (vinyl chloride) at 180 °C in air. Blending BMPH with reference samples in different ratios greatly lengthens the thermal stability value and improves the extent of discoloration of PVC. TGA confirmed the improved stability of PVC in presence of the investigated organic stabilizer. GPC measurements were done to investigate the changes occurred in the molecular masses of the degraded samples of blank PVC and PVC in presence of the novel stabilizer. BMPH showed good antimicrobial activity towards two kinds of bacteria and two kinds of fungi.

Patterns of hepatitis B infection in Egyptian children in the era of obligatory hepatitis B vaccination.

BACKGROUND AND STUDY AIMS: Mass compulsory HBV vaccination was applied in Egypt in 1992. The first dose of vaccine is administered at 2 months of age and routine screening of pregnant women for HBsAg is not applied. We aimed to evaluate the pattern of HBV infections after the implementation of HBV vaccination in Egyptian children. PATIENTS AND METHODS: Fifty-six children with HBV infection presented to the Paediatric Hepatology Unit, Cairo University Children's Hospital, over the period from 1992 to 2006. Their data were reviewed for risk factors, clinical, serological and histopathological profiles. These cases were followed-up for 6.3 ± 3.4 years. The data of those born before 1993 (did not receive HBV vaccine) (group I) was compared to those who received the vaccine (group II). RESULTS: Sixty percent of HBV infected cases were born before 1993. Comparison of data of both groups revealed: (1) A significant younger age of onset in group II (3.34 ± 3.31 years vs. 9.84 + 2.95 years; p ≤ 0.01). (2) Vertical transmission was a significant risk factor in group II. (3) Chronic hepatitis developed in almost half of cases in both groups but cirrhosis was diagnosed only in 4 cases (all from group I) (p=0.04). CONCLUSION: Vertically transmitted HBV infection is becoming an important risk factor for acquisition of HBV among children born after the era of mass vaccination in Egypt. Mass screening for HBsAg of pregnant Egyptian women and/or giving a birth dose of HBV vaccine is becoming mandatory with the increased incidence of vertical transmission.

Measuring of gastric emptying in Egyptian pediatric patients with portal hypertension by using real-time ultrasound.

BACKGROUND/AIM: Among the various methods for evaluating gastric emptying, the real-time ultrasound is safe, does not require intubation, or rely on either radiologic or radionuclide technique. The aim of our work was to measure the gastric emptying in pediatric patients with portal hypertension by using the real-time ultrasound. PATIENTS AND METHODS: Forty patients with portal hypertension with mean age 7 ± 2.8 years and 20 healthy children as a control group underwent gastric emptying study by using real-time ultrasound. The cross-sectional area of the gastric antrum was measured in the fasting state and then each subject was allowed to drink tap water then calculated by using formula area (π longitudinal Χ anteroposterior diameter/4). The intragastric volume was assumed to be directly proportional to the cross-sectional area of the antrum. RESULTS: The mean gastric emptying half-time volume was significantly delayed in portal hypertension patients (40 ± 6.8 min) compared with the control subjects (27.1 ± 3.6) min (P<0.05). Patients with extrahepatic portal vein obstruction had significant delayed gastric emptying in comparison to patients with portal hypertension due to other etiologies (36.14 ± 4.9 vs 44.41 ± 6.04 min; P<0.01). CONCLUSION: Ultrasound is a noninvasive and a reliable method for measuring gastric emptying in pediatric patients. Gastric emptying was significantly delayed in patients with portal hypertension. Etiology of portal hypertension may influence gastric emptying time in patients with chronic liver disease.

A clinical study of Wilson's disease: The experience of a single Egyptian Paediatric Hepatology Unit.

BACKGROUND AND STUDY AIMS: Most paediatric patients with Wilson's disease (WD) present with hepatic manifestations, but some may have neurologic or psychiatric features. Our aim was to define the clinical, biochemical features and the outcome of therapy of a group of Egyptian children diagnosed with WD. PATIENTS AND METHODS: The study was carried out at the Paediatric Hepatology Unit at Cairo University Children's Hospital, Egypt; 54 patients were diagnosed with WD from 1996 to 2009. The diagnosis was based on low serum ceruloplasmin levels, increased urinary copper concentrations before or after D-penicillamine challenge and/or the presence of Kayser-Fleischer (K-F) rings. RESULTS: The clinical presentation was as follows: hepatic presentation in 33 patients (61%), hepato-neurologic 3 (5.5%), neurologic 5 (9.3%) and presymptomatic 13 (24%). Twelve couples had more than one affected sib. Increased urinary copper concentrations before or after D-penicillamine challenge was found in all patients, low serum ceruloplasmin in 97% and K-F rings in 31.5%. All patients were treated with penicillamine and zinc sulphate except one presymptomatic case who was treated with zinc sulphate only. Three patients underwent liver transplantation and eight patients died after a median duration of treatment of 6 months (1-36). The hepatic symptoms improved with treatment but the neurological symptoms remained stationary. CONCLUSIONS: Clinical and biochemical assays remain the standard for diagnosis of WD. Penicillamine and zinc therapy can effectively treat WD with hepatic symptoms. Liver transplantation remains life saving for those with fulminant and end stage WD. Screening for presymptomatic sibs is of utmost importance.

Hereditary tyrosinemia type 1 from a single center in Egypt: clinical study of 22 cases.

BACKGROUND: Hereditary tyrosinemia type 1 (HT1) is an increasingly recognized inborn error of metabolism among Egyptian children. This study was undertaken to define the presenting clinical, biochemical and imaging features and outcome of 2-(2-motrp-4-trifluoromethylbenzoyl)-1, 3-cyclohexanedione (NTBC) therapy and liver transplantation in a cohort of Egyptian children diagnosed with HT1. METHODS: The study was carried out at the Pediatric Hepatology Unit at Cairo University Children's Hospital. HT1 was diagnosed by quantification of succinylacetone (SA) in dry blood spots. RESULTS: Twenty-two patients were diagnosed with HT1 in a period of 3 years from August 2006 to July 2009. Infants with focal hepatic lesions and hepatomegaly (n=13) were younger at diagnosis than those with rickets (n=5) (median age: 3.25 vs. 10 months; P=0.05). Alpha fetoprotein was highly elevated in all children. Seven children died within a few weeks of diagnosis before therapy was initiated. Ten children were treated with NTBC. The response to NTBC treatment was apparent by a steep drop in serum alpha fetoprotein (AFP) and undetectable SA in urine within 2 months. Three children underwent living donor liver transplantation after treatment with NTBC for 10, 18 and 22 months respectively, despite adequate response to therapy because of financial issues. The explanted livers were all cirrhotic with no dysplasia or malignant transformation. CONCLUSIONS: Focal hepatic lesions are the commonest presentation of HT1 patients and they present at an earlier age than rickets. NTBC is effective but very expensive. Liver transplantation is still considered in HT1 patients.

Predictors of non-alcoholic fatty liver disease in obese and overweight Egyptian children: single center study.

BACKGROUND/AIM: Pediatric non-alcoholic fatty liver disease (NAFLD) is a global problem which has been increasingly recognized with the dramatic rise in pediatric obesity. The aim of the present study was to identify the clinical, sonographic, and biochemical predictors for NAFLD in obese children. MATERIALS AND METHODS: Seventy-six children (2-15 years) were included after an informed consent. All were subjected to full anthropometric assessment (including height, weight, body mass index, subscapular skin fold thickness, waist and hip circumference and calculation of waist: hip ratio), biochemical assessment of liver function tests, lipid profile and insulin resistance and sonographic assessment of hepatic echogenicity. Liver biopsy when indicated, was done in 33 patients. RESULTS: Sixteen patients (21%) had elevated ALT and 6 (7.9%) had elevated AST. Significant dyslipidemia (low HDL-c, high total cholesterol, high LDL-c and triglycerides) and higher insulin resistance were found in obese patients (P<0.01). The main sonographic findings were hepatomegaly in 20 patients (26.3%) and echogenic liver in 41 patients (53.9%). Liver biopsy showed simple steatosis in eight cases (24.2%) and non-alcoholic steatohepatitis (NASH) in seven cases (21.2%). Anthropometric measurements, increased hepatic echogenicty by ultrasound, insulin resistance and lipid profile were good predictors of NAFLD in obese children if assessed together. However, LDL-c was the only sensitive predictor (independent variable) for NAFLD in both uni- and multivariate logistic regression analyses. CONCLUSION: Dyslipidemia per se is a strong predictor of NAFLD among obese Egyptian children.

The mammalian target of rapamycin pathway is widely activated without PTEN deletion in renal cell carcinoma metastases.

BACKGROUND: Inhibitors of the mammalian target of rapamycin (mTOR) are emerging as promising therapies for metastatic renal cell carcinoma (RCC). Because rational treatment strategies require understanding the activation status of the underlying signaling pathway being targeted at the desired stage of disease, the authors examined the activation status of different components of the mTOR pathway in RCC metastases and matched primary tumors. METHODS: The authors immunostained metastatic RCC samples from 132 patients and a subset of 25 matched primary RCCs with antibodies against phosphatidylinositol 3'-kinase, PTEN, phospho-Akt, phospho-mTOR, and p70S6. PTEN genomic status was assessed by fluorescent in situ hybridization. Marker expression was correlated to clinicopathologic variables and to survival. RESULTS: The mTOR pathway showed widespread activation in RCC metastases of various sites with strong correlation between different components of this signaling cascade (P<.0001), but without significant PTEN genomic deletion. Only cytoplasmic phospho-mTOR showed independent prognostic significance (P = .029) and fidelity between primary RCCs and their matched metastases (P = .004). CONCLUSIONS: Activation of various components of the mTOR signaling pathway in metastatic RCC lesions across various tumor histologies, nuclear grades, and metastatic sites suggests the potential for vertical blockade of multiple steps of this pathway. Patient selection may be improved by mTOR immunostaining of primary RCC.

Study of predictive value of pediatric risk of mortality (PRISM) score in children with end stage liver disease and fulminant hepatic failure.

OBJECTIVE: To evaluate the use of the PRISM score as a predictor of outcome in patients with end stage liver disease (ESLD) and fulminant hepatic failure (FHF). METHODS: The present study included 30 patients with ESLD and FHF, with ages ranging from 2 to 108 months, who were admitted to the Emergency room (ER) and the Pediatric Hepatology Unit at Cairo University Children's Hospital (tertiary referral hospital) over a six-month-period from May through October 2008. Survivors were followed up for 6 months. Two other scores were also calculated, the PELD score and the Child-Pugh score. The outcome was defined as survivors and deceased. RESULTS: Deceased patients as compared with survivors were significantly younger (median age 7 vs. 24 months, p=0.003). A ROC curve was constructed for the PRISM score, the predicted death rate (PDR) and the PELD score in the 30 patients. PRISM score was significantly associated with mortality (p=0.04). The best cut off value was 9.5 (70.6% sensitive and 61% specific). PDR was also significantly associated with mortality (p=0.011). The best cut off value for PDR was 5.95 (70.6% sensitive, 85% specific). On the other hand, the PELD score was not associated with mortality (p=0.202). CONCLUSIONS: PRISM score can be applied with an adequate degree of accuracy for severity assessment and mortality prediction to pediatric patients with ESLD or FHF.

Can aspartate aminotransferase to platelet ratio index replace liver biopsy in chronic hepatitis C?

BACKGROUND AND AIM: We aimed to evaluate the accuracy of readily available laboratory tests (ALT, AST, platelet count, AST to platelet ratio index: APRI) in predicting liver fibrosis in chronic hepatitis C, in comparison to the predictive accuracy obtained by liver biopsy. Pediatrics, METHODS: One hundred and thirteen patients suffering from chronic hepatitis C (CHC) were included in this study. They included 76 children enrolled from the Pediatric Hepatology Unit and 37 adults enrolled from the Hepatology Unit of Tropical Medicine Department, Cairo University, Egypt. Fibrosis results obtained from liver biopsy were assigned a score from 0 to 4 score as per Metavir scoring. Results of serum ALT and AST levels were expressed as ratio of the upper limit of normal (ULN). RESULTS: Of the pediatric patients, 28 (36.8%) showed no evidence of fibrosis on liver biopsy, 26 (34.2%) showed grade 1 fibrosis, and 22 (29%) had grade 2 fibrosis. Among the adult patients, 12 (32.4%) had grade 2 fibrosis and 25 patients (67.6%) had grades 3 to 4 fibrosis. There was a lack of correlation between the degree of fibrosis and AST levels, AST/ALT ratio, platelet count and APRI. The AUROC curve for predicting significant fibrosis was 0.5 for AST levels, 0.37 for AST/ALT ratio and 0.49 for APRI, in pediatric patients (p > 0.05). In adult patients the AUROC curve for predicting significant fibrosis was 0.59 for AST levels, 0.76 for AST/ALT ratio and 0.63 for APRI (p > 0.05). CONCLUSION: Liver biopsy remains the gold standard to assess the extent of hepatic fibrosis in patients with CHC.

Alagille syndrome: clinical and ocular pathognomonic features.

PURPOSE: This study was carried out to determine the frequency of clinical diagnostic criteria in patients with Alagille syndrome (AGS) in comparison to a group of children with cholestasis and histologically proven neonatal hepatitis (NH). The type and frequency of ocular manifestations are highlighted. METHODS: According to histologic findings on liver biopsy, the 32 patients included in the study were classified into 2 groups: group 1 had paucity of interlobular bile ducts (PILBD) (n=13) and at least 3 of 5 characteristics of AGS and group 2 had NH on liver biopsy (n=19). RESULTS: The mean age of patients with AGS was higher than in group 2 (3.9 vs 1.6 years) (p<0.05). Pruritus was a significant symptom in the AGS group (p<0.05). Characteristic facies was detected in 61.5% of the AGS group. None of our patients with AGS had vertebral anomalies. Although cardiac murmurs were heard in 5 patients with AGS, cardiac anomalies were detected in only 3 by echocardiography: pulmonary stenosis in 2 patients and patent foramen ovale in 1. Posterior embryotoxon (PE) was detected in 69.2% of patients with AGS as compared to 10.5% of the NH group. Optic nerve drusen was detected in 91% of patients with AGS as compared to 5.3% of patients with NH. CONCLUSIONS: Optic nerve drusen was the most common finding in AGS, followed by PE and facial features. Ocular ultrasound needs to be performed in all cholestatic infants with PILBD.

Androgen-regulated expression of arginase 1, arginase 2 and interleukin-8 in human prostate cancer.

BACKGROUND: Prostate cancer (PCa) is the most frequently diagnosed cancer in North American men. Androgen-deprivation therapy (ADT) accentuates the infiltration of immune cells within the prostate. However, the immunosuppressive pathways regulated by androgens in PCa are not well characterized. Arginase 2 (ARG2) expression by PCa cells leads to a reduced activation of tumor-specific T cells. Our hypothesis was that androgens could regulate the expression of ARG2 by PCa cells. METHODOLOGY/PRINCIPAL FINDINGS: In this report, we demonstrate that both ARG1 and ARG2 are expressed by hormone-sensitive (HS) and hormone-refractory (HR) PCa cell lines, with the LNCaP cells having the highest arginase activity. In prostate tissue samples, ARG2 was more expressed in normal and non-malignant prostatic tissues compared to tumor tissues. Following androgen stimulation of LNCaP cells with 10 nM R1881, both ARG1 and ARG2 were overexpressed. The regulation of arginase expression following androgen stimulation was dependent on the androgen receptor (AR), as a siRNA treatment targeting the AR inhibited both ARG1 and ARG2 overexpression. This observation was correlated in vivo in patients by immunohistochemistry. Patients treated by ADT prior to surgery had lower ARG2 expression in both non-malignant and malignant tissues. Furthermore, ARG1 and ARG2 were enzymatically active and their decreased expression by siRNA resulted in reduced overall arginase activity and l-arginine metabolism. The decreased ARG1 and ARG2 expression also translated with diminished LNCaP cells cell growth and increased PBMC activation following exposure to LNCaP cells conditioned media. Finally, we found that interleukin-8 (IL-8) was also upregulated following androgen stimulation and that it directly increased the expression of ARG1 and ARG2 in the absence of androgens. CONCLUSION/SIGNIFICANCE: Our data provides the first detailed in vitro and in vivo account of an androgen-regulated immunosuppressive pathway in human PCa through the expression of ARG1, ARG2 and IL-8.

Co-assessment of cytoplasmic and nuclear androgen receptor location in prostate specimens: potential implications for prostate cancer development and prognosis.

OBJECTIVE: To address, by co-assessing cytoplasmic and nuclear androgen receptor (AR) expression in prostate tissues, the contribution of the AR throughout the stages of prostate cancer (PC) and its value as a marker for predicting biochemical recurrence (BCR) after radical prostatectomy (RP). PATIENTS AND METHODS: Archival prostate specimens from patients who were cancer-free (43), with hormone-sensitive prostate cancer (HSPC, 62), and with androgen-independent prostate cancer (AIPC, 30) were used to construct tissue microarrays (total 135). Prostatic intraepithelial neoplasia (PIN) and non-neoplastic tissues (NA) found adjacent to HSPC were also included. Nuclear and cytoplasmic AR expression was scored by two observers using a composite scale, after immunohistochemical detection of the AR. The nuclear/cytoplasmic AR expression ratio was also calculated. Univariate Kaplan-Meier plots, and multivariate Cox and survival-tree analyses, were then used to assess the ability of the AR to predict BCR in the patients with HSPC. RESULTS: There was markedly greater nuclear AR staining intensity in NA than in normal prostate tissues from cancer-free patients. Cytoplasmic AR expression was highest in AIPC and markedly more than in HSPC. The nuclear/cytoplasmic AR expression ratio was highest in NA and PIN. In univariate analyses, a low nuclear AR, low cytoplasmic AR, and a high nuclear/cytoplasmic AR expression ratio were associated with BCR. Although cytoplasmic AR was an independent predictor of BCR in a Cox multivariate model (hazard ratio 2.736, 95% confidence interval 1.228-6.091, P = 0.014), survival-tree analyses suggested a complex relationship between AR expression and clinicopathological features. CONCLUSION: We propose that increased nuclear AR expression might be a precursor to PC and that cytoplasmic AR could contribute to the AIPC phenotype. The predictive ability of the AR might be closely linked to clinicopathological features.