Hepatotoxicity in HIV-infected children and adolescents on antiretroviral therapy.

CONTEXT AND OBJECTIVE: Adverse drug reactions are a significant problem in patients on antiretroviral therapy (ART). We determined liver enzyme elevation frequencies in HIV-infected children and adolescents receiving ART, and their association with risk factors. DESIGN AND SETTING: Cross-sectional study, at the Pediatrics Immunodeficiency Division, University Hospital, Universidade Estadual de Campinas. METHODS: Medical records of 152 children and adolescents (54.6% male; median age 7.48 years) were analyzed, with a mean of 2.6 liver enzyme determinations per patient. Clinically, patients were classified in categories N (6), A (29), B (78) and C (39). Serum levels of aspartate aminotransferase and alanine aminotransferase were evaluated. Hepatotoxicity was scored as grade 1 (1.1-4.9 times upper limit of normality, ULN), grade 2 (5.0-9.9 times ULN), grade 3 (10.0-15.0 times ULN) and grade 4 (> 15.0 times ULN). To assess hepatotoxicity risk factors, odds ratios (OR) and adjusted odds ratios (aOR) for age, gender, TCD4+ cell count, viral load and medication usage were calculated. RESULTS: We observed grade 1 hepatotoxicity in 19.7 % (30/152) patients. No cases of grade 2, 3 or 4 were detected. There was a significant association between hepatotoxicity and use of sulfonamides (OR, 3.61; 95% confidence interval (CI), 1.50-8.70; aOR, 3.58; 95% CI, 1.44-8.85) and antituberculous agents (OR, 9.23; 95% CI, 1.60-53.08; aOR, 9.05; 95% CI, 1.48-55.25). No toxicity was associated with ART. CONCLUSIONS: One fifth of patients experienced mild hepatotoxicity, attributed to antituberculous agents and sulfonamides. Our results suggest that ART was well tolerated.     

Evidence that peroxynitrite affects human osteoblast proliferation and differentiation.

Peroxynitrite (PN), a nitric oxide (NO*)-derived anion, has been associated with NO* damage in various cell types. We examined the effects of adding PN to cultured human osteoblast-like (hOB) cells obtained after hip arthroplasty. Exposure to PN (0.1-0.4 mM) decreased both hOB proliferation and differentiation, measured by [3H]thymidine uptake and alkaline phosphatase production, respectively. Incubation with 3-morpholinosydnonimine (SIN-1; 0.25-1 mM), an NO* and O2- donor that leads to PN release, also reduced both hOB proliferation and differentiation. Coincubation with both superoxide dismutase (SOD; 100 U/ml) and catalase (CAT; 50 U/ml), rendering SIN-1 a pure NO* donor, reversed its effects on hOB proliferation and differentiation. However, SIN-1-induced NO* production, measured by nitrite release to the hOB medium, was not altered by cotreatment with SOD and CAT. Expression of nitrotyrosine by hOB, a marker of PN action, was significantly increased after SIN-1 addition, as compared with untreated cells, as revealed by Western blot analysis. Interleukin-1alpha (IL-1alpha) and interferon gamma (IFN-gamma) but not tumor necrosis factor alpha (TNF-alpha) also significantly increased nitrotyrosine expression in these cells. These data show that PN is at least partially responsible for osteoblast derangement by NO* and that cytokines released during inflammatory arthropathies can induce PN production in hOB cells.     

Endocytosis of gold-labeled proteins and LDL byTrypanosoma cruzi

Endocytosis was studied at the ultrastructural level in different developmental forms ofTrypanosoma cruzi after incubation of the parasites in the presence of gold-labeled proteins (albumin-Au, peroxidase-Au and transferrin-Au) and low-density lipoprotein (LDL-Au). Epimastigote (culture) forms actively ingested LDL and proteins. Initially, gold particles were seen adhering only to the cytostome and inside the flagellar pocket. In parasites incubated at 4°C with transferrin-Au or peroxidase-Au, labeling was found only at these two sites, showing that receptor-mediated endocytosis occurs in both regions. In the cytoplasm, gold particles were seen only inside two different compartments: membrane-bound vesicles and reservosomes. Incubation of epimastigotes with acridine orange followed by fluorescence microscopy revealed intense orange staining, indicating that the reservosomes have an acidic pH. This staining was abolished after incubation of the parasites in the presence of ammonium chloride. These data confirm that this compartment is the site of accumulation of ingested lipids and proteins. Little intracellular labeling with transferrin-Au was found in in vitro — derived amastigotes and trypomastigotes (both lack reservosomes). However, although in amastigotes very few gold particles were seen bound to the cells, in trypomastigotes they were observed bound to the membrane that encloses the cell body, the flagellar pocket, and the flagellum, suggesting that the receptors are more abundant in this form.     

Cystic spinal dysraphism of the cervical and upper thoracic region

Background Cystic dysraphic lesions of the cervical and upper thoracic region are rare and only a few series have been published about the topic. These malformations can be divided into categories that include both myelocystoceles and the so-called cervical meningoceles or myelomeningoceles.Methods A retrospective study of 18 patients was conducted.Results In 17 patients a squamous or a cicatricial epithelium of variable thickness covered the dome of the lesions, while the base was covered with full-thickness skin. In one case the skin was entirely normal. Four patients displayed associated CNS malformations and three more had systemic congenital anomalies. All patients underwent surgical exploration and the length of time between birth and surgery ranged from 6 h to 9 months. The most frequent surgical finding, seen in 14 patients, was a stalk connecting the dorsal surface of the spinal cord to the cyst. In three patients the findings were consistent with myelocystocele. Only in one case was a true meningocele found. Hydrocephalus and Chiari II malformation were not as consistently associated as in myelomeningoceles. Neurological signs and symptoms were not so marked as in myelomeningoceles and were found in the follow-up of four patients. In two of them there was a non-progressive deficit, probably expressing an imperceptible involvement of the nervous system in the first year of life. The histopathological findings were of three types: neuroglial stalks, fibrovascular stalks and myelocystoceles.Conclusions Cystic dysraphisms of the cervical and upper thoracic region differ clinically and structurally from meningomyelocele and have a more favorable outcome. We believe that these malformations have not been properly labeled and propose a classification based on the structures found inside the cyst.     

p53 and skin carcinomas with skull base invasion: a case-control study.

BACKGROUND: Some skin carcinomas may be very aggressive. Increased expression of the protein p53 has been associated with tumor aggressiveness. In this study, p53 expression was evaluated in basal cell carcinomas (BCC) and squamous cell carcinomas (SCC) with skull base invasion, and was compared to tumors with good outcome. STUDY DESIGN AND SETTING: Expression of p53 was immunohistochemically analyzed and it was reported as present or absent in 24 BCC and 11 SCC with skull base invasion. Control group (good outcome) included 23 BCC and 10 SCC. RESULTS: Expression of p53 was noted in 70.83% of BCC with skull base invasion, compared to 43.48% in the control group (P = 0.058). Regarding SCC, p53 positivity was noted in only 9.09% of SCC with skull base invasion, compared to 40.00% in the control group (P = 0.149). CONCLUSIONS: In this study, p53 expression was more common among BCC with skull base invasion, compared to controls with good outcome, and the difference was considered marginally significant. This proportion was reversed in SCC, but the difference was not statistically significant. EBM rating: B-3b.