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Biomedical subjects

A Dhawan

Publications and source records attributed to A Dhawan.

At least 19 recordsLinked to original sources
PubMed2006

Segmental liver transplantation from non-heart beating donors--an early experience with implications for the future.

We report our experience of pediatric liver transplantation with partial grafts from non-heart beating donors (NHBD). Controlled donors less than 40 years of age with a warm ischemia time (WI) of less than 30 min were considered for pediatric recipients. Death was declared 5 min after asystole. A super-rapid recovery technique with aortic and portal perfusion was utilized. Mean donor age was 29 years and WI 14.6 min (range 11-18). Seven children, mean age 4.9 years (0.7-11), median weight 20 kg (8.4-53) received NHBD segmental liver grafts. Diagnoses included seronegative hepatitis, neonatal sclerosing cholangitis, familial intrahepatic cholestasis, hepatoblastoma, primary hyperoxaluria and factor VII deficiency (n=2). The grafts included four reduced and one split left lateral segments, one left lobe and one right auxiliary graft. Mean cold ischemia was 7.3 h (6.2-8.8). Complications included one pleural effusion and one biliary collection drained percutaneously. At 20 months (10-36) follow-up all children are alive and well with functioning grafts. Donation after cardiac death is a significant source of liver grafts for adults and children with careful donor selection and short cold ischemic times.

Adolescent↗
PubMed2005

Effects of serum from patients with acute liver failure due to paracetamol overdose on human hepatocytes in vitro.

OBJECTIVE: Our goal was to investigate the effects of serum from patients with acute liver failure due to paracetamol (acetaminophen) overdose on the function of human hepatocytes in vitro. METHODS: Freshly isolated human hepatocytes plated on collagen-coated culture plates were, incubated (24 hours 37 degrees C) in medium containing pooled human sera (0%-80%) obtained from normal individuals or from patients with acute liver failure due to paracetamol overdose. The effects of the sera on cell function were assessed using MTT, [14C]-leucine incorporation, and cytochrome P450 (CYP1A1/2) activity assays. RESULTS: The overall cellular metabolic activity was significantly greater at all concentrations after exposure to acute liver failure serum compared to normal serum. There were no significant differences in the decreases produced by pooled acute liver failure and normal sera at concentrations up to 80% on the [14C]-leucine incorporation or CYP1A1/2 activity. CONCLUSION: The overall cell function/activity of human hepatocytes was not impaired in vitro on exposure to serum from patients with acute liver failure due to paracetamol overdose.

Acetaminophen↗
PubMed2004

Fatty liver disease in children.

NAFLD/NASH is now recognised as an increasing clinical problem in children and adolescents. Risk factors include obesity, insulin resistance, and hypertriglyceridaemia. Drug hepatoxicity and genetic or metabolic diseases that can cause hepatic steatosis must be excluded. Affected children are usually asymptomatic although a few may complain of malaise, fatigue, or vague recurrent abdominal pain. Liver biopsy is the gold standard for diagnosis, and is important in determining disease severity and prognosis. The natural history of childhood NASH may be progressive liver disease for a significant minority. Long term follow up studies in this population are still lacking. The mainstay of treatment is weight reduction. The use of pharmacological therapy, though promising, ideally needs further evaluation in well designed randomised controlled studies in children.

Adolescent↗
PubMed2003

Basiliximab (Simulect) for the treatment of steroid-resistant rejection in pediatric liver transpland recipients: a preliminary experience.

BACKGROUND: The role of interleukin-2 receptor antibodies as rescue therapy in steroid-resistant rejection (SRR) has not been studied. We evaluated the safety and efficacy of an interleukin-2 receptor antibody, basiliximab (Simulect, Novartis, East Hanover, NJ), in treating SRR in pediatric liver transplant recipients. METHODS: This was a prospective study of seven pediatric liver transplant recipients with biopsy-proven SRR who would have otherwise received OKT3 or antithymocyte globulin. The primary immunosuppression consisted of cyclosporine (Neoral, Novartis), azathioprine, and prednisolone in four patients and tacrolimus and prednisolone in three patients who had undergone retransplantation for chronic rejection (n=2) and hyperacute rejection (n=1). Four patients had received two cycles of high-dose steroids, and three patients had received a single cycle; all had been converted to tacrolimus, followed by the addition of mycophenolate mofetil. RESULTS: The median time from transplant to SRR was 30 days (range, 8 days-23 months). Five children received two doses of basiliximab (10 mg, 3-7 days apart), and two children received a single dose. Aspartate aminotransferase levels normalized in three children 12, 21, and 30 days after basiliximab treatment. Aspartate aminotransferase levels decreased without normalizing in two children, but there was no further evidence of cellular rejection on repeat biopsies. All five children are rejection-free with a median follow-up of 22 months (range, 5-32 months). Biochemical abnormalities persisted in the remaining two children, and both developed chronic rejection. There were no immediate side effects associated with basiliximab. Two patients were treated empirically for possible cytomegalovirus infection 21 and 57 days after basiliximab treatment, with no evidence of cytomegalovirus disease. CONCLUSION: Five of seven pediatric liver transplant recipients with SRR experienced successful outcomes with basiliximab treatment without major side effects, indicating that it is a safe alternative to OKT3 and other antilymphocyte antibodies.

Antibodies, Monoclonal↗
PubMed2003

Effect of pretreatment of cytochrome P450 (P450) modifiers on neurobehavioral toxicity induced by deltamethrin.

To investigate the involvement of cytochrome P450 (P450) enzyme induction and the effect of different P450 modifiers in the neurobehavioral toxicity of deltamethrin, deltamethrin (10 mg/kg; orally for 1 day) was administered to young male albino Wistar rats, or in rats pretreated with phenobarbital (PB; 80 mg/kg, ip for 5 days), an inducer of P450 2B1/2B2 or 3-methylcholanthrene (MC; 30 mg/kg, ip for 5 days), an inducer of P450 1A1/1A2 or cobalt chloride (CoCl(2); sc for 2 days), a depletor of P450s. The administration of PB or MC or CoCl(2) alone did not produced any symptoms of neurobehavioral toxicity. While a single oral administration of deltamethrin produced tremors in two out of 10 rats and decreased the spontaneous locomotor activity, pretreatment with MC or PB potentiated the deltamethrin induced neurobehavioral toxicity with 50% of the treated rats exhibiting tremors. Half of the animals pretreated with MC prior to exposure to deltamethrin also exhibited choreoathetosis. The decrease in the spontaneous locomotor activity was found to be much more significant in PB- or MC-pretreated animals exposed to deltamethrin. In contrast to the pretreatment with inducers, rats pretreated with CoCl(2) exhibited no symptoms of tremors or choreoathetosis, indicating that a reactive metabolite of deltamethrin is formed by P450 catalysed reactions which is involved in the neurobehavioral toxicity of deltamethrin.

Animals↗
PubMed2003

Effect of lindane on hepatic and brain cytochrome P450s and influence of P450 modulation in lindane induced neurotoxicity.

Oral administration of lindane (2.5, 5, 10 and 15 mg/kg, body weight) for 5 days was found to produce a dose-dependent increase in the activity of P450 dependent 7-ethoxyresorufin-O-deethylase (EROD), 7-pentoxyresorufin-O-dealkylase (PROD) and N-nitrosodimethylamine demethylase (NDMA-d) in rat brain and liver. A significant increase in the hepatic and brain P450 monooxygenases was also observed when the duration of exposure of low dose (2.5 mg/kg) of lindane was increased from 5 days to 15 or 21 days. As observed with different doses, the magnitude of induction in the activity of P450 monooxygenases was several fold higher in liver microsomes when compared with the brain. Western blotting studies have indicated that the increase in the P450 enzymes could be due to the increase in the expression of P450 1A1/1A2, 2B1/2B2 and 2E1 isoenzymes. In vitro studies using organic inhibitors specific for individual P450 isoenzymes and antibody inhibition experiments have further demonstrated that the increase in the activity of PROD, EROD and NDMA-d are due to the increase in the levels of P450 2B1/2B2, 1A1/1A2 and 2E1 isoenzymes, respectively. Induction studies have further shown that while pretreatment of 3-methylcholanthrene (MC), an inducer of P4501A1/1A2, did not produce any significant effect in the incidence of lindane induced convulsions, pretreatment with phenobarbital (PB), an inducer of P450 2B1/2B2 or ethanol, an inducer of P450 2E1 catalysed reactions, significantly increased the incidence of lindane induced convulsions. Similarly, when the P450-mediated metabolism of lindane was blocked by cobalt chloride incidence of convulsions was increased in animals treated with lindane indicating that lindane per se or its metabolites formed by PB or ethanol inducible P450 isoenzymes are involved in its neurobehavioral toxicity.

Administration, Oral↗
PubMed2003

Evaluation of members of the TGFbeta superfamily as candidates for the oocyte factors that control mouse cumulus expansion and steroidogenesis.

Oocytes secrete factors that control cumulus and granulosa functions, including cumulus expansion and steroid hormone production. Some members of the transforming growth factor beta (TGFbeta) superfamily influence these activities, yet it is still not determined conclusively whether any of these superfamily members are the previously reported oocyte-secreted factors. The aim of this study was to examine the effects of TGFbeta1 and growth differentiation factor 9 (GDF-9) on cumulus expansion and progesterone production by mouse oocytectomized (OOX) complexes in culture. TGFbeta1 mimics the effects of oocytes by both enabling cumulus expansion and inhibiting progesterone production; however, neutralizing antibodies to TGFbeta1 in cultures of cumulus-oocyte complexes (COCs) or in co-cultures of OOX complexes failed to inhibit the ability of oocytes to enable cumulus expansion or inhibit progesterone production. Activin A had no effect on progesterone production by OOX complexes. In experiments using oocytes obtained from mice with deficient expression of GDF-9, OOX complexes cultured in the presence of heterozygous oocytes were capable of full expansion, whereas OOX complexes cultured with oocytes from GDF-9 null mice did not expand. Similarly, GDF-9 null oocytes failed to suppress FSH-induced progesterone production by OOX complexes. These results support the hypothesis that GDF-9 is the cumulus expansion enabling factor produced by mouse oocytes and that GDF-9 also inhibits cumulus progesterone production; however, the possibility remains that loss of GDF-9 may indirectly affect the ability of oocytes to produce the factors that regulate cumulus cell activity.

Activins↗
PubMed2002

Cytochrome P450 2E1 dependent catalytic activity and lipid peroxidation in rat blood lymphocytes.

To investigate the similarities in the catalytic activity of blood lymphocyte P450 2E1 in blood lymphocyte with the liver isoenzyme, NADPH dependent lipid peroxidation and activity of N-nitrosodimethyamine demethylase (NDMA-d) was studied in rat blood lymphocytes. Blood lymphocytes were found to catalyse NADPH dependent (basal) lipid peroxidation and demethylation of N-nitrosodimethylamine (NDMA). Pretreatment with ethanol or pyrazole or acetone resulted in significant increase in the NADPH dependent lipid peroxidation and the activity of NDMA-d in blood lymphocytes and liver microsomes. In vitro addition of CCl(4) to the blood lymphocytes isolated from control or ethanol pretreated rats resulted in an increase in the NADPH dependent lipid peroxidation. Significant inhibition of the basal and CCl(4) supported NADPH dependent lipid peroxidation and NDMA-d activity in blood lymphocytes isolated from control or ethanol pretreated rats by dimethyl formamide or dimethyl sulfoxide or hexane, solvents known to inhibit P450 2E1 catalysed reactions in liver and anti- P450 2E1, have indicated the role of P450 2E1 in the NADPH dependent lipid peroxidation in rat blood lymphocytes. The data indicating similarities in the NADPH dependent lipid peroxidation and NDMA-d activity in blood lymphocyte with the liver microsome have provided evidence that blood lymphocyte P450 2E1 could be used as a surrogate to monitor and predict hepatic levels of the enzyme.

Acetone↗
PubMed2002

Serum hyaluronic acid concentrations are increased in cystic fibrosis patients with liver disease.

AIM: To determine whether serum hyaluronic acid (HA) concentrations are abnormal in patients with cystic fibrosis (CF) liver disease, and if so, whether the abnormality is associated with disease severity. METHODS: A total of 74 patients with CF were assessed for evidence of liver involvement as indicated by clinical, ultrasound, and biochemical findings. Serum hyaluronic acid concentrations were measured and compared with concentrations in 293 normal controls. Lung function in the CF patients was also recorded. RESULTS: Thirty four CF patients had no evidence of liver disease; in these, serum HA concentrations were similar to those in healthy controls (median (range): 16.1 (9.4-75.1) v 15 (1-77) microg/l). Nineteen CF patients had established liver disease detected by clinical and ultrasound examination, with significantly increased HA concentrations (56.1 (26-355) microg/l). Serum HA concentrations were also significantly increased, although to a lesser extent, in 21 CF patients with an abnormal liver ultrasound scan alone (22.4 (9.5-43.4) microg/l). There was no correlation between serum HA concentration and lung function. CONCLUSION: Serum HA concentrations were significantly increased in children with clinical or ultrasound evidence of liver disease, being higher in those with more advanced hepatic damage. Despite the inflammation and fibrosis present in CF lungs there was no correlation between HA concentration and lung function, suggesting that high concentrations were a failure of hepatic clearance rather than overproduction in the lung. Longitudinal measurement of HA concentrations may prove a useful marker for the development of significant liver damage in CF patients.

Biomarkers↗
PubMed2002

Intestinal permeability and absorptive capacity in children with portal hypertension.

BACKGROUND: Portal hypertension may affect intestinal function leading to malnutrition in children with liver disease. The aim was to determine whether children with portal hypertension with or without liver disease had impaired absorptive capacity and intestinal barrier function (intestinal permeability) and to ascertain whether these abnormalities related to changes in body composition. METHODS: Twenty-six children with portal hypertension were divided according to aetiology into: Group 1 intrahepatic (n = 15) and Group 2 prehepatic (n = 11). Thirty-five children acted as controls. Carbohydrate absorption and intestinal permeability were assessed using a sugar absorption/permeability test and a variety of anthropometric measurements were obtained. RESULTS: 3-O-methyl-D-glucose, D-xylose and L-rhamnose excretion were significantly reduced in both patient groups compared to controls (P < or = 0.008) and the differential urinary excretion of melibiose/rhamnose (intestinal permeability) was significantly increased in Group 1 only (P < 0.05). Anthropometric measurements showed low Z scores in both groups, but there was no significant (P > 0.05) difference between them. There was no significant correlation between urinary excretion of sugars. anthropometric measurements and energy intake. CONCLUSIONS: Increased portal pressure reduces the absorptive capacity of the small intestine, while liver disease itself leads to increased intestinal permeability.

Adolescent↗
PubMed2002

Social support in treatment-seeking heroin-dependent and alcohol dependent patients.

Social support is being recognized as a positive influence on health. It may influence motivation, treatment compliance and outcome in drug dependent patients. On the basis of clinical impression, it was hypothesized that social support in heroin (illicit drug) dependent patients is poorer than in alcohol dependent patients. The current study was undertaken to assess and compare the social support amongst treatment seeking alcohol dependent patients and heroin dependent patients. Despite lesser proportion of patients with any legal source of income in the heroin dependent subject group, the mean social support score across the two study groups was comparable. Overall, the mean social support scores were low in both the groups. The study provides some undestanding about the perceived social support amongst treatment seeking drug dependent individuals from India and also indicates the need to address the issue of social support in substance users.

Adolescent↗
PubMed2001

In vivo accuracy of thoracic pedicle screws.

STUDY DESIGN: A retrospective observational study of 279 transpedicular thoracic screws using postoperative computed tomography (CT). OBJECTIVE: To determine the accuracy of transpedicular thoracic screws. SUMMARY OF BACKGROUND DATA: Previous studies have reported the importance of properly placed transpedicular thoracic screws. To our knowledge, the in vivo accuracy of pedicle screw placement throughout the entire thoracic spine by CT is unknown. METHODS: The accuracy of thoracic screw placement within the pedicle and vertebral body and the resultant transverse screw angle (TSA) were assessed by postoperative CT. Cortical perforations of the pedicle were graded in 2-mm increments. Screws were regionally grouped for analysis. RESULTS: Forty consecutive patients underwent instrumented posterior spinal fusion using 279 titanium thoracic pedicle screws of various diameters (4.5-6.5 mm). The regional distribution of the screws was 39 screws at T1-T4, 77 screws at T5-T8, and 163 screws at T9-T12. Fifty-seven percent of screws were totally confined within the pedicle. Although medial perforation of the pedicle wall occurred in 14% of screws, in <1% there was >2 mm of canal intrusion. Lateral pedicular perforation occurred in 68% of perforating screws and was significantly more common than medial perforation (P < 0.0005). Seventeen screws penetrated the anterior vertebral cortex by an average of 1.7 mm. Screws inserted between T1 and T4 had a decreased incidence of full containment within the pedicle (P < 0.0005) and vertebral body (P = 0.039) compared with T9-T12. The mean TSA for screws localized within the pedicle was 14.6 degrees and was significantly different from screws with either medial (mean 18.0 degrees ) or lateral (mean 11.5 degrees ) pedicle perforation (P < 0.0005). Anterior vertebral penetration was associated with a smaller mean TSA of 10.1 degrees (P = 0.01) and with lateral pedicle perforation (P < 0.0005). There were no neurologic or vascular complications. CONCLUSIONS: Ninety-nine percent of screws were fully contained or were inserted with either < or =2 mm of medial cortical perforation or an acceptable lateral breech using the "in-out-in" technique. Anterior cortical penetration occurred significantly more often with lateral pedicle perforation and with a smaller mean TSA. The incidence of fully contained screws was directly correlated with the region of instrumented thoracic spine.

Adolescent↗
PubMed2001

Calcineurin-inhibitor related nephrotoxicity- reversibility in paediatric liver transplant recipients.

AIM: To study the efficacy of mycophenolate mofetil (MMF) as renal rescue in paediatric liver transplant recipients with calcineurin-inhibitor- (CI) related nephrotoxicity. METHODS: Pediatric liver transplant recipients with stable graft function and a glomerular filtration rate (GFR) <80 ml/min/1.73 m2 were enrolled. MMF was introduced at 20 mg/kg/day and increased to 40 mg/kg/day after 1 week. CI dose was then reduced 6 weeks to achieve blood levels 25% of baseline. GFR was reassessed after 6 and 12 months. RESULTS: Fourteen children with a median (range) interval from transplant of 57 (4-111) months were studied. Their median (range) GFR in ml/min/1.73 m2 increased from a baseline of 52 (31-71), to 69 (38-111) and 73 (35-98) at 6 and 12 months, respectively (P=0.00014). Side effects of MMF include leucopaenia in two and backache in one, two of whom discontinued MMF. Acute allograft rejection occurred in three children. All 14 are well with a median (range) follow-up of 24 (14-38) months from MMF introduction. CONCLUSION: MMF allows the recovery of renal function from CI related nephrotoxicity in more than 70% of paediatric liver transplant recipients with renal impairment.

Adolescent↗
PubMed2001

Cytochrome P450 1A1 (CYP1A1) in blood lymphocytes evidence for catalytic activity and mRNA expression.

Studies initiated to characterise the catalytic activity and expression of CYP1A1 in rat blood lymphocytes revealed significant activity of 7-ethoxyresorufin-O-deethylase (EROD) in rat blood lymphocytes. Pretreatment with 3-methylcholanthrene (MC) and beta-naphthoflavone (NF) resulted in significant induction in the activity of lymphocyte EROD suggesting that like the liver enzyme, EROD activity in lymphocytes is inducible and is mediated by the MC inducible isoenzymes of P450. The increase in the activity of EROD was associated with a significant increase in the apparent Vmax and affinity of the substrate towards EROD. That this increase in the activity of EROD could be primarily due to the increase in the expression of CYP1A1 isoenzymes was demonstrated by RT-PCR and western immunoblotting studies indicating an increase in the expression of CYP1A1 in blood lymphocytes after MC pretreatment. Significant inhibition in the EROD activity of MC induced lymphocyte by anti-CYP1A1/1A2 and alpha-naphthoflavone further provided evidence that the CYP1A1/1A2 isoenzymes are involved in the activity of EROD in blood lymphocytes. The data indicating similarities in the regulation of CYP1A1 in blood lymphocytes with the liver isoenzyme suggests that factors which may affect expression of CYP1A1 in liver may also affect expression in blood lymphocytes and that blood lymphocytes could be used as a surrogates for studying hepatic expression of the xenobiotic metabolising enzymes.

Animals↗
PubMed2001

The effect of smoking and eating habits on DNA damage in Indian population as measured in the Comet assay.

This study was undertaken with the aim of assessing the status of DNA damage in a normal healthy Indian population. The 62 male volunteers in this study belonged to the smoking, non-smoking, vegetarian and non-vegetarian categories, were well educated and aged between 23 and 57 years. The data revealed significant differences in the extent of DNA damage in the smokers versus non-smokers as well as between the vegetarians and non-vegetarians. A significant difference was also observed amongst the different groups of smokers depending on the extent of smoking. An age-dependent effect in DNA damage was also observed. This preliminary study has, for the first time, revealed differences in the extent of DNA damage in the normal Indian population depending on their eating and smoking habits as well as age.

Adult↗