Enteric-coated cysteamine for the treatment of paediatric non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a common cause of liver disease in children. Hepatic fat accumulation and oxidative stress contribute to its pathogenesis. Cysteamine bitartrate readily traverses cellular membranes and is a potent antioxidant. AIM: To evaluate the safety and efficacy of enteric-coated (EC) cysteamine in children with NAFLD. METHOD: Children, aged ≥10 y, meeting screening criteria with biopsy-proven NAFLD and serum ALT ≥60 IU/L, received twice-daily EC-cysteamine for 24 weeks. Monthly ALT, AST, body mass index (BMI) and gastrointestinal symptom scores were measured. Subjects with >50% reduction or normalisation of ALT achieved the primary endpoint. RESULTS: Of the 13 children enrolled (mean age 14.0 years), 11 completed EC-cysteamine therapy (mean dose 15.2 mg/kg/day) and were included in the final analysis. For these 11 subjects, the mean ALT levels at baseline and 24 weeks were 120.2 and 55 IU/L respectively (P = 0.002), and the AST levels were 60 and 36 IU/L respectively (P = 0.007). The primary endpoint was reached in 7 and normalisation (≤40 IU/L) of ALT in 5. After 24 week therapy, mean adiponectin levels increased (P = 0.009) and CK-18 fragment levels decreased (P = 0.013), insulin levels remained unchanged (P = 0.99). Mean leptin levels were decreased in responders (P = 0.044). Mean BMI was 34.5 at baseline and 34.2 kg/m(2) after treatment (P = 0.35). Mean symptom scores at baseline (1.1) and at 24 weeks (0.7) were similar. No major adverse events were reported. CONCLUSIONS: Enteric-coated cysteamine reduces ALT and AST levels in children with NAFLD without reduction in body mass index. Further studies will evaluate optimal cysteamine therapeutic dose and effect on liver histology in NAFLD (Clinicaltrials.gov protocol ID: 07-1699).

Hepatitis C augments cognitive deficits associated with HIV infection and methamphetamine.

OBJECTIVE: To examine the contribution of hepatitis C virus (HCV) infection to neurocognitive dysfunction in individuals with comorbid HIV infection or methamphetamine (METH) dependence. METHODS: Neurocognitive functioning was examined in 430 study participants who were either normal controls or had HCV infection, HIV infection, history of METH dependence, or combinations of these factors as risks for cognitive deficits. RESULTS: Rates of global and domain-specific neuropsychological (NP) impairment increased with the number of risk factors. HCV serostatus was a significant predictor of NP performance both globally and in the areas of learning, abstraction, and motor skills, with trends in speeded information processing and delayed recall. HCV serostatus did not predict scores in attention/working memory or verbal fluency. CONCLUSION: Hepatitis C virus infection contributes to the neuropsychological deficits observed among HIV-infected and stimulant-dependent populations.

Genetic composition of human immunodeficiency virus type 1 in cerebrospinal fluid and blood without treatment and during failing antiretroviral therapy.

Human immunodeficiency virus (HIV) infection of the central nervous system (CNS) is a significant cause of morbidity. The requirements for HIV adaptation to the CNS for neuropathogenesis and the value of CSF virus as a surrogate for virus activity in brain parenchyma are not well established. We studied 18 HIV-infected subjects, most with advanced immunodeficiency and some neurocognitive impairment but none with evidence of opportunistic infection or malignancy of the CNS. Clonal sequences of C2-V3 env and population sequences of pol from HIV RNA in cerebrospinal fluid (CSF) and plasma were correlated with clinical and virologic variables. Most (14 of 18) subjects had partitioning of C2-V3 sequences according to compartment, and 9 of 13 subjects with drug resistance exhibited discordant resistance patterns between the two compartments. Regression analyses identified three to seven positions in C2-V3 that discriminated CSF from plasma HIV. The presence of compartmental differences at one or more of the identified positions in C2-V3 was highly associated with the presence of discordant resistance (P = 0.007), reflecting the autonomous replication of HIV and the independent evolution of drug resistance in the CNS. Discordance of resistance was associated with severity of neurocognitive deficits (P = 0.07), while low nadir CD4 counts were linked both to the severity of neurocognitive deficits and to discordant resistance patterns (P = 0.05 and 0.09, respectively). These observations support the study of CSF HIV as an accessible surrogate for HIV virions in the brain, confirm the high frequency of discordant resistance in subjects with advanced disease in the absence of opportunistic infection or malignancy of the CNS, and begin to identify genetic patterns in HIV env associated with adaptation to the CNS.

Differential clearance of colloid and crystalloid solutions from the lung.

The hypothesis that alveolar fluid clearance depends on factors other than the alveolar-capillary oncotic gradient was tested by comparing lung clearance rates of three different colloid solutions and isotonic saline. The solutions (4 mL/kg) were instilled into the lower lobes of New Zealand rabbits. Colloid solutions were diluted to produce a fixed gradient of 8 mm Hg for each experiment. Fluid clearance was calculated at 3 hours, using lung gravimetrics. Surface tension, as a measure of surfactant inhibition, was measured in separate experiments using bubble surfactometry. Airway inflammatory reaction was assessed by determining leukocyte counts in bronchoalveolar lavage (BAL). Data were analyzed using ANOVA with Tukey's test for multiple comparisons. Alveolar fluid clearance rates were significantly different (p < 0.01) between groups, and varied between 2.0 +/- 0.12 mL/kg (saline), and -0.04 +/- 1.7 (plasma). Clearance rates for saline and dextran 70 were similar despite an increased plasma-alveolar osmotic gradient. Surface tension, reflecting surfactant inhibition, was greater with the plasma (3.9 +/- 3.7 mN/m) compared with the other groups (range, 0.23-0.48 mN/m) (p < 0.01). Neutrophil migration was greater with the protein group, but there were no differences in total WBC counts between groups. These data suggest that fluid clearance from the airspaces is primarily dependent on factors other than simple colloid-capillary osmotic gradient. Alveolar PMN migration was not a major determinant of fluid clearance. The association between surfactant inhibition and decreased fluid clearance rate observed with homologous plasma suggests that protein interference with the surfactant monolayer may play a role in reducing alveolar fluid clearance.(ABSTRACT TRUNCATED AT 250 WORDS)