Antibodies to tumor necrosis factor alpha prevent increases in cell replication in liver due to the potent peroxisome proliferator, WY- 14,643

Several structurally dissimilar hypolipidemic drugs, plasticizers and halogenated hydrocarbons induce peroxisomes in hepatocytes, and cause hepatocellular adenoma and carcinoma in rats and mice. The mechanism by which these agents act is unknown, although recent studies have suggested a link between increased cell proliferation and hepatic cancer caused by peroxisome proliferators. Here, we demonstrate that neutralizing antibodies to tumor necrosis factor alpha (TNF alpha) block increases in protein kinase C and cell proliferation due to [4- chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (WY-14,643), a hypolipidemic drug and potent peroxisome proliferator that causes tumors. WY-14,643 moderately elevated the level of TNF alpha mRNA in the liver. TNF alpha was detected immunohistochemically exclusively in Kupffer cells. These results demonstrate that WY-14,643 acts as an indirect mitogen on hepatocytes via TNF alpha. We propose that the Kupffer cell, a major source of TNF alpha in the liver, is involved in the mechanism of the mitogenic effect of WY-14,643.      

Antiretroviral therapy in HIV-infected individuals in clinical practice: Are the criteria for initiating and choosing the type of drug regimen based only on immunologic and virologic values?

Objectives: To determine factors associated with beginning antiretroviral therapy and with the number of drugs used. Methods: Longitudinal study of 3169 HIV-infected individuals naïve from anti-retroviral drugs at enrolment in 65 infectious disease clinics in Italy. Initiation of antiretroviral therapy and number of drugs used (i.e., <3 vs. 3 drugs) were the main outcome measures. Adjusted odds ratios were calculated by logistic models to establish cofactors of these two measures. Results: From January 1997 to December 1998, 1288 (40.6%) individuals started therapy, 58.0% of whom were given a triple combination regimen. This regimen became more frequent over time. By multivariate analysis, high levels of HIV-RNA and low CD4 counts were the most important independent predictors of starting any type of therapy. A significant association was also found with HIV exposure category, reason for being antiretroviral-naïve, presence/absence of liver disease, presence/absence of a new AIDS-defining disease, and clinical centre. High levels of HIV-RNA and low CD4 counts were also the most important predictors of starting with 3 drugs, compared to < 3 drugs, and men had an independent higher probability of starting with 3 drugs, compared to women. The probability of starting with 3 drugs significantly increased with calendar time. Conclusions: CD4 and HIV-RNA were the main cofactors of initiating both any type of therapy and therapy with 3 drugs. The large variability among clinical centres suggests that clinicians are uncertain as to the exact timing of beginning therapy and the specific regimen, especially among women.     

Evaluation of attempted prevention of unexpected infant death in very high-risk infants by planned health care

Three hundred and ninety-six babies born in Sheffield between 1982 and 1990 identified as being at "very high risk" of unexpected infant death by means of a scoring system, received an intensive programme of health care including a case discussion between a paediatrician, the GP and the health visitor held in the family doctor's surgery, weekly visits from the health visitor and informal hospital admission. Significantly fewer sudden unexpected infant deaths occurred in this group than were expected by logistic regression anlysis or occurred in the best available control group with comparable scores ( p = 0.024). Problems in evaluation include identification of an adequate control population, ethical difficulties in introducing a controlled study when the programme is already perceived as effective, and the calculation of "expected death rates". The results of this study indicate that very energetic programmes of intervention may prevent some deaths in vulnerable infants.     

Serum profiles of insulin-like growth factors and their binding proteins in adults with growth hormone receptor deficiency treated with insulin like growth factor I

Six adult patients with growth hormone receptor deficiency (GHRD) (2 men, 4 women) with an identical defect in the growth hormone receptor (GHR) gene, were treated with recombinant human insulin-like growth factor I (IGF-I), 40 μgikg S.C. twice daily, for 7 days. Serum concentrations of IGF peptide and IGF binding protein-3 (IGFBP-3) were measured by specific radioimmunoassays; serum IGFBPs were also measured by Western ligand blotting. The size distribution of both IGF-I and IGF-II was measured in serum following size-exclusion fast-performance liquid chromatography. IGF-I treatment resulted in a normalization of serum IGF-I levels on days 1–7 of treatment and a decrease in serum IGF-II levels. The fall in IGF-II levels and the simultaneous rise in IGF-I levels, however, resulted in an unchanged total serum IGF level. The low IGFBP-3 values did not significantly change during treatment, whereas there was a slight increase in IGFBP-2 levels. Preliminary analysis of size-fractionated sera suggested an increase in IGF-I levels in the 40 and 150 kDa regions at the expense of IGF-II levels. The results suggest that despite the failure of IGF-I treatment to increase IGFBPs significantly, serum IGFBP concentrations were sufficient to maintain normal levels of IGF-I. 0 Laron syndrome, growth hormone receptor deficiency, insulin-like growth factors, insulin-like growth factor binding protein     

The diagnostic role of "in utero" magnetic resonance imaging

OBJECTIVE: To assess the diagnostic potential of Magnetic Resonance Imaging (MRI) in the management of ultrasonically diagnosed congenital anomalies. PATIENTS AND METHODS: Ninety-two patients were included into the study after the ultrasonic diagnosis of an abnormality. Sixty-three of these patients were affected by an abnormality of the central nervous system (CNS) and 29 by abnormalities in other apparatuses. The GRE technique was used to obtain T1 and T2 star-weighted images. RESULTS AND DISCUSSION: Satisfactory imaging was obtained in all but one case. In order to define the "reliability" of MRI for a given condition, a diagnostic score was designed and separately given by the obstetrician and the radiologist involved in the case. MRI scored less than ultrasonography for abnormalities of the fetal contour and for large and complex distortion of the CNS as holoprosencephaly. For subtle midbrain anomalies, as well as for neuronal migration disorders, MRI definitely was superior to sonography. For other anomalies, as for example congenital diaphragmatic hernia, MRI was better than conventional techniques in assessing prognosis and outcome, but less reliable in assessing associated anomalies. MRI seems to be a valuable adjunct to us for prenatal diagnosis of only selected fetal anomalies and requires precise guidelines in a multidisciplinary approach to prenatal pathology.