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- Cadmium-Induced Toxicity and the Hepatoprotective Potentials of Aqueous Extract of Jessiaea Nervosa Leaf. [JOURNAL ARTICLE]
- Adv Pharm Bull 2013; 3(2):309-313.
Purpose: Hepatoprotective potentials of Jussiaea nervosa leaf extract against Cadmium-induced hepatotoxicity were investigated. Methods: Forty albino rats were randomly assigned into groups A-G with 4 rats in each of the groups A-F. Group A served as control and were given feed only while rats in groups B-F were orally exposed to varying concentrations of cadmium for six weeks. Effects of cadmium were most significant at 12 mg/Kg body weight (BW), and this dose was used for subsequent test involving oral administration of Jussiaea nervosa leaf extracts. In this segment, group G (n= 16) was sub-divided into four: G1-G4, with each sub-group containing four rats. Rats in sub-group G1 were given cadmium and feed only and served as positive control. Rats in sub-groups G2, G3, and G4 were given cadmium and 20, 50 and 100g/kg BW of Jussiaea nervosa extract, respectively, for six weeks. Blood and liver were analysed using standard laboratory techniques and methods. Results: Liver function parameters (ALT, AST, ALP, bilirubin) were significantly (p<0.05) elevated in exposed rats in comparison to the controls, except for total protein and albumin, which were significantly decreased. Histopathological assessment reveals renal pathology in exposed rats in sharp contrast with the controls. Jussiaea nervosa extract however lowered the values of liver function parameters with 100mg/Kg BW dose producing the highest ameliorative effects. Similarly, the serum albumin and total protein significantly (p<0.05) improved with normal liver architecture. Conclusion: The results show the hepatoprotective potentials of Jussiaea nervosa extract against Cd toxicity.
- Leptospirosis and dengue fever: a predictive model for early differentiation based on clinical and biochemical parameters. [JOURNAL ARTICLE]
- Trop Doct 2013 Dec 5.
Leptospirosis and dengue fever are increasingly seen as causes of tropical febrile illness and often are clinically indistinguishable. This two-year prospective study from a tertiary care centre comprised 200 patients including 68 men (mean 34.8 years) with dengue and 73 (mean 46.19 years) with leptospirosis. Oliguria, icterus, muscle tenderness, anaemia, leukocytopenia, thrombocytopenia, elevated erythrocyte sedimentation rate (ESR), acute renal failure (ARF) and hypoalbuminaemia appeared more commonly in leptospirosis in comparison to dengue. Eighteen per cent mortality was observed in leptospirosis compared to one per cent in dengue. ARF, hyperbilirubinaemia, acute respiratory distress syndrome (ARDS), creatine kinase (CK) elevation and thrombocytopenia were predictors of death in leptospirosis and thrombocytopenia, ARDS and ARF predictors of death in dengue. On receiver operating characteristics (ROC) analysis, leucocytosis >11000/mm(3), ESR >40 mm, serum creatinine >2 mg/dL, total serum bilirubin >2 mg/dL, CK >500 U/L and serum albumin <3 mg/dL were more likely to be an indication of leptospirosis at presentation compared to dengue.
- Brainstem auditory electrophysiology is supressed in term neonates with hyperbilirubinemia. [JOURNAL ARTICLE]
- Eur J Paediatr Neurol 2013 Nov 18.
Whether hyperbilirubinemia suppresses electrophysiological activity of the neonatal auditory brainstem remains to be investigated.To determine whether hyperbilirubinemia suppresses the brainstem auditory electrophysiology in term neonates.Maximum length sequence brainstem auditory evoked response (MLS BAER) was recorded shortly after confirming hyperbilirubinemia in 58 term neonates. Wave amplitudes of the response were analyzed in detail.Compared with age-matched term controls, the neonates with hyperbilirubinemia showed a significant reduction in the amplitudes of MLS BAER waves III and particularly V at all click rates 91-910/s. The reduction tended to be more significant at higher than lower rates. Wave I amplitude was reduced at 910/s. V/I amplitude ratio was decreased at all click rates. Therefore, the amplitudes of MLS BAER, particularly later, waves were all reduced. The amplitudes of all MLS BAER waves tended to be reduced with the increase in total serum bilirubin level. All wave amplitudes were correlated with the level of total serum bilirubin at some or most click rates.Brainstem auditory electrophysiology is suppressed in neonates with hyperbilirubinemia, which related to the severity of hyperbilirubinemia. Wave amplitudes are valuable BAER variables to detect functional impairment of the brainstem and auditory pathway in neonatal hyperbilirubinemia, and are recommended to be used in assessing bilirubin neurotoxicity to the neonatal brain.
- Bilirubin mediated oxidative stress involves antioxidant response activation via Nrf2 pathway. [JOURNAL ARTICLE]
- Cell Signal 2013 Dec 2.
Unconjugated bilirubin (UCB) is responsible for neonatal jaundice and high level of free bilirubin (Bf) can lead to kernicterus. Previous studies suggest that oxidative stress is a critical component of UCB-induced neurotoxicity. The Nrf2 pathway is a powerful sensor for cellular redox state and is activated directly by oxidative stress and/or indirectly by stress response protein kinases. Activated Nrf2 translocates to nucleus, binds to Antioxidant Response Element (ARE), and enhances the up-regulation of cytoprotective genes that mediate cell survival. The aim of the present study was to investigate the role of Nrf2 pathway in cell response to bilirubin mediated oxidative stress in the neuroblastoma SH-SY5Y cell line. Cells exposed to a toxic concentration of UCB (140 nM Bf) showed an increased intracellular ROS levels and enhanced nuclear accumulation of Nrf2 protein. UCB stimulated transcriptional induction of ARE-GFP reporter gene and induced mRNA expression of multiple antioxidant response genes as: xCT, Gly1, γGCL-m, γGCL-c, HO-1, NQO1, FTH, ME1, and ATF3. Nrf2 siRNA decreased UCB induced mRNA expression of HO1 (75%), NQO1 (54%), and FTH (40%). The Nrf2-related HO-1 induction was reduced to 60% in cells pre-treated with antioxidant (NAC) or specific signalling pathway inhibitors for PKC, P38α and MEK1/2 (80, 40 and 25%, respectively). In conclusion, we demonstrated that SH-SY5Y cells undergo an adaptive response against UCB-mediated oxidative stress by activation of multiple antioxidant response, in part through Nrf2 pathway.
- Serum Levels of Interleukin-22 and Hepatitis B Core-related Antigen Are Associated with Treatment Response to Entecavir Therapy in Chronic Hepatitis B. [JOURNAL ARTICLE]
- Hepatol Res 2013 Dec 6.
We sought to clarify the associations between serum cytokines and chemokines, hepatitis B surface antigen (HBsAg), HB core-related antigen (HBcrAg), and hepatitis B virus (HBV) DNA and response to entecavir therapy in chronic hepatitis B.We analyzed 6 cytokines (IL-2, IL-6, IL-10, IL-12p70, IL-21, and IL-22) and 5 chemokines (CCL2, CCL3, CXCL9, CXCL10, and CXCL11) before and at 6, 12, and 24 months during entecavir therapy in 48 chronic hepatitis B patients. Quantitative measurement of HBsAg, HBcrAg, and HBV DNA was performed. A virological response (VR) was defined as serum HBV DNA < 2.1 log copies/mL by treatment month 24.Thirty-nine patients (81%) achieved a VR. Serum IL-6 (P =0.031), CXCL-9 (P = 0.002), and CXCL-10 (P = 0.001) were high in chronic HBV and correlated positively with transaminases and bilirubin. Before treatment, elevated IL-22 (P = 0.031) and lower HBsAg (P = 0.001) and HBcrAg (P < 0.001), but not HBV DNA, were associated with a favorable treatment outcome. In multivariate analysis, high IL-22 (hazard ratio = 13.67, P = 0.046) and low HBcrAg (hazard ratio = 10.88, P = 0.048) were independently associated with a VR. The levels of IL-22 (P < 0.001), HBsAg (P < 0.001), and HBcrAg (P < 0.001) all decreased from baseline to 24 months of treatment in virological responders.Serum IL-22 and HBcrAg are predictive markers of a VR to entecavir therapy in patients with chronic hepatitis B.
- Urinary tract infection (UTI) in newborns: risk factors, identification and prevention of consequences. [Journal Article]
- Coll Antropol 2013 Sep; 37(3):871-6.
The aim of the study is identification of urinary tract infections (UTI) and urinary tract anomalies (UTA) already in the perinatal period. The authors attempted to prevent serious consequences of the above conditions in the examined children. Family history data, certain conditions in pregnancy and appertaining symptoms in children were elaborated to specify selective distinctive criteria for children at risk. Newborns (1200) were selected for potential existence of a UTI. All the examined newborns underwent a urinalysis. Those with significant bacteriuria were taken urine specimens, C-reactive protein (RVP), Complete Blood Count (CBC) and bilirubin. The newborns with a UTI and a suspected UTA were sent to ultrasound examination, direct radio nuclide cystography and Tc99m MAG3 dynamic scanning. The frequency of a UTI in the perinatal period amounted to 4.5%. A UTA was found in 29.6% of the examinees. The infection was more likely to appear among newborns with a UTA in their families, a UTI, pre-eclampsia and a febrile infection in mother, intrauterine growth retardation, premature rupture of membranes (RVP), umbilical cord strangulation, jaundice, cyanosis, breathing difficulties, seizures and asphyxia.
- Pooled Population Pharmacokinetic Analysis of Phase I, II and III Studies of Linifanib in Cancer Patients. [JOURNAL ARTICLE]
- Clin Pharmacokinet 2013 Dec 4.
Linifanib is a multi-targeted receptor tyrosine kinase inhibitor, which can inhibit members of the vascular endothelial growth factor and platelet-derived growth factor receptor families. The objective of this analysis was to characterize the population pharmacokinetics of linifanib in cancer patients.We pooled 7,351 linifanib plasma concentrations from 1,010 cancer patients enrolled in 13 clinical studies. Population pharmacokinetic modelling was performed using NONMEM version 7.2. The covariates that were screened included the cancer type, co-medications, creatinine clearance, formulation, fed status, liver function markers (bilirubin, blood urea nitrogen [BUN], aspartate aminotransferase [AST], alanine aminotransferase [ALT]), albumin, age, sex, race, body weight, surface area and body mass index.A two-compartment model with first-order absorption and disposition best described linifanib pharmacokinetics. An increase in body weight was associated with less than proportional increases in volumes of distribution. Subjects with hepatocellular carcinoma and renal cell carcinoma were estimated to have 63 and 86 % larger volumes of distribution, respectively, than subjects with the other cancer types. Females had 25 % slower oral clearance (CL/F) than males, while subjects with colorectal cancer had 41 % faster CL/F than other subjects. For linifanib bioavailability, subjects with refractory acute myeloid leukaemia or myelodysplastic syndrome had 43 % lower bioavailability, evening doses were associated with 27 % lower bioavailability than morning doses, and administration of linifanib under fed conditions decreased the bioavailability by 14 %. Finally, the oral solution formulation showed two-fold faster absorption than the tablet formulations.The use of mixed-effects modelling allowed robust assessment of the impact of the concomitant effects of body size, different cancer types, formulation, diurnal variation, sex and food on linifanib pharmacokinetics. The developed population pharmacokinetic model describes linifanib concentrations adequately and can be used to conduct simulations or to evaluate the linifanib exposure-response relationship.
- Physiological concentrations of unconjugated bilirubin prevent oxidative stress-induced hepatocanalicular dysfunction and cholestasis. [JOURNAL ARTICLE]
- Arch Toxicol 2013 Dec 4.
Bilirubin is an endogenous antioxidant with cytoprotective properties, and several studies highlight its potential in the treatment of pro-oxidant diseases. We demonstrated that oxidative stress (OS), a key feature in most hepatopathies, induces cholestasis by actin cytoskeleton disarrangement and further endocytic internalization of key canalicular transporters, such as the bile salt export pump (Bsep) and the multidrug resistance-associated protein 2 (Mrp2) . Here, we evaluated the capability of physiological concentrations of unconjugated bilirubin (UB) to limit OS and the impairment in biliary secretory function induced by the model pro-oxidant agent, tert-butylhydroperoxide (tBuOOH). UB fully prevented the formation of reactive oxygen species and membrane lipid peroxidation induced by tBuOOH in isolated rat hepatocytes. In the isolated rat hepatocyte couplet model, UB (17.1 μM) prevented the endocytic internalization of Bsep and Mrp2 and the impairment in their secretory function induced by tBuOOH. UB also prevented actin disarrangement, as evaluated by both plasma membrane bleb formation and actin fluorescent staining. Finally, UB prevented tBuOOH-induced cPKC activation. Experiments in isolated perfused rat livers showed that UB prevents the increase in oxidized glutathione biliary excretion and the drop in bile flow and the biliary excretion of specific Bsep and Mrp2 substrates. We conclude that physiological concentrations of UB are sufficient to prevent the biliary secretory failure induced by OS, by counteracting actin disarrangement and the consequent internalization of canalicular transporters relevant to normal bile formation. This reveals an important role for UB in preserving biliary secretory function under OS conditions.
- Intestinal response to myeloablative chemotherapy in piglets. [JOURNAL ARTICLE]
- Exp Biol Med (Maywood) 2013 Dec 5.
Chemotherapy-induced myeloablation prior to allogeneic hematopoietic stem cell transplantation (HSCT) may be associated with severe toxicity. The current understanding of the pathophysiology of oral and gastrointestinal (GI) toxicity is largely derived from studies in rodents and very little is known from humans, especially children. We hypothesized that milk-fed piglets can be used as a clinically relevant model of GI-toxicity related to a standard conditioning chemotherapy (intravenous busulfan, Bu plus cyclophosphamide, Cy) used prior to HSCT. In study 1, dose-response relationships were investigated in three-day-old pigs (Landrace × Yorkshire × Duroc, n = 6). Pigs were given one of three different dose combinations of Bu and Cy (A: 4 days Bu, 2 × 1.6 mg/kg plus 2 days Cy, 60 mg/kg; B: 4 days Bu, 2 × 0.8 mg/kg plus 2 days Cy, 30 mg/kg; C: 2 days Bu at 2 × 1.6 mg/kg plus 1 day Cy, 60 mg/kg) and bone marrow was collected on day 11. Histology of bone marrow samples showed total aplasia after treatment A. Using this treatment in study 2, Bu-Cy pigs showed lowered spleen and intestinal weights and variable clinical signs of dehydration, sepsis, and pneumonia at tissue collection. Oral mucositis was evident as ulcers in the soft palate in 4/9 Bu-Cy pigs and villus height and brush-border enzyme activities were reduced, especially in the proximal intestine. There were no consistent effects on tissue cytokine levels (IL-8, IL-6, IL-1β, TNF-α) or blood chemistry values (electrolytes, liver transaminases, bilirubin, alkaline phosphatase), except that blood iron levels were higher in Bu-Cy pigs. We conclude that a myeloablative Bu-Cy regimen to piglets results in clinical signs comparable to those seen in pediatric patients subjected to myeloablative treatment prior to HSCT. Piglets may be used as a model for investigating chemotherapy-induced toxicity and dietary and medical interventions.
- The Relationship between the Behavioral Hearing Thresholds and Maximum Bilirubin Levels at Birth in Children with a History of Neonatal Hyperbilirubinemia. [JOURNAL ARTICLE]
- Iran J Otorhinolaryngol 2013 Jun; 25(72):127-134.
Neonatal hyperbilirubinemia is one of the most important factors affecting the auditory system and can cause sensorineural hearing loss. This study investigated the relationship between behavioral hearing thresholds in children with a history of jaundice and the maximum level of bilirubin concentration in the blood.This study was performed on 18 children with a mean age of 5.6 years and with a history of neonatal hyperbilirubinemia. Behavioral hearing thresholds, transient evoked emissions and brainstem evoked responses were evaluated in all children.Six children (33.3%) had normal hearing thresholds and the remaining (66.7%) had some degree of hearing loss. There was no significant relationship (r=-0.28, P=0.09) between the mean total bilirubin levels and behavioral hearing thresholds in all samples. A transient evoked emission was seen only in children with normal hearing thresholds however in eight cases brainstem evoked responses had not detected.Increased blood levels of bilirubin at the neonatal period were potentially one of the causes of hearing loss. There was a lack of a direct relationship between neonatal bilirubin levels and the average hearing thresholds which emphasizes on the necessity of monitoring the various amounts of bilirubin levels.