Peptide products of the neurotrophin-inducible gene vgf are produced in human neuroendocrine cells from early development and increase in hyperplasia and neoplasia.

BACKGROUND: Although the neurotrophin-inducible gene vgf is expressed in mammalian neurons and endocrine cells, limited data is available in man. AIM: The objective of the study was to map proVGF peptides in human endocrine cells during development, adulthood, hyperplasia, and tumors. METHODS: Antisera were generated against peptides related to internal cleavage or cleavage-amidation sites (rat proVGF(422-430) and human proVGF(298-306)-NH2) and the proVGF C-terminal ending (human proVGF(607-615)). Developing and normal adult endocrine cells, hyperplastic endocrine lesions (thyroid, parathyroid, lung, and stomach), and 120 tumors (102 endocrine) were studied. Immunogold electron microscopy was performed on normal adult pancreas and gut, and Western blotting was performed on extracts of control tissues and endocrine tumors. RESULTS: proVGF fragments were revealed in developing pituitary, gut, pancreas, and adrenal medulla from 10 gestational weeks, in normal adult pituitary and adrenal medulla, pancreatic glucagon, and insulin cells and gut serotonin cells, in hyperplastic thyroid calcitonin cells, lung P cells, gastric enterochromaffin-like cells, and gastrin cells, and in 88 of 102 endocrine tumors. At electron microscopy proVGF immunoreactivity was restricted to electron-dense granules. Western blotting revealed large molecular weight forms and cleavage fragments in both control tissues and tumor extracts. CONCLUSIONS: proVGF-related peptides are present in endocrine cells early during development and adulthood and increase in hyperplasia and tumors, and proVGF fragments could be novel diagnostic tools for endocrine cells and related lesions, including tumors.

A randomised, open label, controlled trial on the effect of interferon plus amantadine compared with interferon alone for treatment of chronic hepatitis C.

BACKGROUND: Combination of the antiviral drug amantadine with interferon (IFN) may be more effective than IFN monotherapy for treatment of chronic hepatitis C. METHODS: We randomised 93 patients with chronic hepatitis C to IFNIFN 6 MU 3 times/week for 24 weeks, followed by IFN 3 MU 3 times/week for further 24 weeks given in combination with amantadine 100 mg t.i.d. (regimen A, n=48) or as monotherapy (regimen B, n=45). Control liver biopsies were obtained 6 months post treatment. RESULTS: At the end of the trial a similar proportion of patients had normal serum ALT levels (35% for regimen A, and 44% for regimen B) as measured by intention to treat criteria. Sustained biochemical response at 6 months post treatment was 15 and 20%, and sustained virological response was 10 and 20% for regimen A and B, respectively. The effect on liver histology was also similar: the inflammatory components of the Knodell score decreased by 1.3+/-0.6 points for regimen A and by 1.6+/-0.6 for regimen B, and score for fibrosis remained unchanged with both regimens. CONCLUSIONS: Combination of IFN therapy with amantadine does not enhance the effect of IFN as shown by biochemical, virological and histological criteria.

Severe hepatotoxicity during combination antiretroviral treatment: incidence, liver histology, and outcome.

OBJECTIVES: To assess incidence, risk factors, histology, and outcome of severe hepatotoxicity (SH) during antiretroviral treatment (ART). METHODS: Seven hundred fifty-five HIV-seropositive patients consecutively prescribed new ART were selected. Liver function tests were assessed at baseline, after 1 month, and every 4 months thereafter. Liver biopsy was recommended in case of SH (i.e., increase in liver enzymes >/=10 times the upper limit of normal or 5 times baseline if markedly abnormal). RESULTS: Twenty-six cases of SH were observed with an incidence of 4.2% person-years. Liver failure (LF) was rarely seen (1.1 per 100 person-years). Liver damage was invariably observed in patients with chronic viral hepatitis. Liver histology showed exacerbation of viral hepatitis in all 16 patients for whom a liver biopsy was available at the time of SH. A direct correlation was found between alanine aminotransferase increase and increase in CD4 T-cell count in patients with SH (r = 0.53, p <.001). Death occurred during follow-up in 7 of 26 (27%) patients, all of whom showed LF and baseline CD4+ count less than 200 cells/mm(3) (7/7 patients = 100% vs. 8/19 patients without LF; p <.01). Relapse of SH was observed after ART was recommenced in 7 of 17 (41%) patients. Five of these 7 patients did not show further SH relapse after treatment with interferon. CONCLUSIONS: This study provides estimates of SH and LF in a large population-based setting where hepatitis C virus coinfection is highly prevalent and provides indications that liver damage may be caused by immune reconstitution and related exacerbation of viral hepatitis. A strict follow-up for hepatotoxicity is mandatory when ART is initiated in patients with <200 CD4+ T cells/mm(3). Antihepatitis pre- or comedication could be an effective preventive or curative measure.