A pharmacogenetic investigation of intravenous furosemide in decompensated heart failure: a meta-analysis of three clinical trials.

We conducted a meta-analysis of pharmacogenomic substudies of three randomized trials conducted in patients with decompensated heart failure (HF) that were led by National Heart Lung and Blood Institute (NHLBI)-funded HF Network to test the hypothesis that candidate genes modulate net fluid loss and weight change in patients with decompensated HF treated with a furosemide-based diuretic regimen. Although none of the genetic variants previously shown to modulate the effects of loop diuretics in healthy individuals were associated with net fluid loss after 72 h of treatment, a set of rare variants in the APOL1 gene, which codes for apolipoprotein L1 (P=0.0005 in the random effects model), was associated with this end point. Moreover, a common variant in the multidrug resistance protein-4 coding gene (ABCC4, rs17268282) was associated with weight loss with furosemide use (P=0.0001). Our results suggest that both common and rare genetic variants modulate the response to a furosemide-based diuretic regimen in patients with decompensated HF.

The MDM2 oncoprotein is overexpressed in rhabdomyosarcoma cell lines and stabilizes wild-type p53 protein.

MDM2 gene overexpression has been implicated in the pathogenesis of human neoplasia via inhibition of the p53 tumor-suppressor function. To investigate the potential involvement of the MDM2 oncogene in the pathogenesis of childhood rhabdomyosarcoma (RMS) we studied MDM2 abnormalities in six RMS cell lines in correlation with the p53 status. Three showed overexpression of MDM2 mRNA and protein, one with concomitant MDM2 gene amplification. All three lacked p53 mutation and expressed low levels of p53 mRNA but exhibited elevated p53 proteins. Double immunostaining revealed that the overexpressed MDM2 and p53 proteins were co-localized to the same cell nuclei. Furthermore, the two proteins were physically associated, as shown by co-immunoprecipitation and Western blot analysis. The half-life of the p53 protein was prolonged in the MDM2-expressing RMS cells. The extended half-life wildtype p53 protein and its complex formation with the elevated MDM2 suggest that the underlying mechanism for p53 protein accumulation in these cell lines is p53 stabilization by an overabundant MDM2 protein. The overexpressed MDM2 protein had a short half-life. The three remaining RMS cell lines exhibited low MDM2 mRNA and protein levels and carried p53 mutations. This study suggest that MDM2 overexpression represents an alternative mechanism for p53 inactivation in a subset of childhood RMS without p53 mutations. The results further indicate that the elevated MDM2 protein is responsible for wildtype p53 protein accumulation via stabilization.

Possible regulation of hypothalamus and lung histidine decarboxylase activity by cAMP-dependent protein kinase.

Activity of crude histidine decarboxylases (HisDC) from the hypothalamus and the lungs, was markedly reduced by incubating with ATP.Mg, cAMP and cAMP-dependent protein kinase A, whereas activity of the crude glandular stomach enzyme changed only slightly under equal condition. The omission of one of these components failed to reduce HisDC activity by as much as the complete system. Addition of bovine heart (type II) or rat cerebellum protein kinase A (types I and II) inhibitor to the assay prevented enzyme inactivation; moreover, protein kinase A inhibitors permitted moderate activation under phosphorylating and control conditions. Cytosolic hypothalamus HisDC activity was elevated 2-2.2-fold by incubating the cytosol for 15 min in the presence of MnCl2, a known stimulator of phosphoprotein phosphatase; this was prevented when 20 mM NaF, a common inhibitor of phosphoprotein phosphatase, was added to the cytosol. The apparent Km of ATP.Mg-treated hypothalamus HisDC for histidine was elevated 5-10-fold compared to controls, whereas the Vmax was approximately the same. Under this condition, the Km was calculated as high as 0.5-2.2 mM (depending on phosphorylating conditions), while controls had a Km of 0.1-0.3 mM (depending on the initial phosphorylating states). Addition of rabbit muscle (type I), bovine heart (type II) or rat cerebellum (types I and II) inhibitor of protein kinase A, to the phosphorylating mixture, abolished the difference in Km between control and ATP.Mg-treated HisDC. Moreover, rat cerebellum protein kinase A inhibitors increased Vmax to above the control level; while 20 mM NaF (inhibitor of phosphoprotein phosphatase) decreased Vmax to approximately one half of that of the controls. These data indicate that HisDC activity in the hypothalamus and the lungs, but not in the stomach, is affected in oppositely by protein kinase A and phosphoprotein phosphatases.

Childhood rhabdomyosarcoma in Hungary.

56 children with rhabdomyosarcoma were treated in Hungary between 1975 and 1984. Tumor localization, age and sex distribution was similar to reported figures. Survival analysis demonstrated a better prognosis for orbital and urogenital rhabdomyosarcoma. Except for Stage I patients the more advanced cases had an inferior survival to other reported series. Intensification of therapy did not seem to clarify this point. Improving survival necessitates a uniform therapeutic approach that takes prognostic factors into consideration.

Prognostic factors in acute lymphoid leukaemia of childhood. II. Cell surface markers.

Monoclonal sera have been used to determine the surface phaenotype of leukaemic cells during the last three years. Bone-marrow specimens of 57 children with recently diagnosed acute lymphoid leukaemia were examined; four cases were classified as T-cell leukaemia, 2 cases as B-cell leukaemia, in 37 cases cALLa was positive and fourteen children were classified as O-cell type, based on the absence of markers. Analysis of symptom-free survival revealed a very poor prognosis in B-cell leukaemia; there was no significant difference between the remaining groups. Within the cALLa positive cases L1 exhibited a markedly more favourable prognosis than L2.

[Pituitary function and growth in children under treatment for leukemia (author's transl)]. / Hypophysenfunktion und Wachstum bei Kindern unter Leukämiebehandlung.

The effect of cranial irradiation with doses of 2,400 and 4,800 rad on the pituitary function of children with acute lymphoblastic leukaemia was studied. The plasma growth hormone level after arginine simulations was normal in 13 out of 15 children. The rise of TSH after TRH stimulation and the metyrapone test were also normal. The growth of 40 children during an observation period of 3 or more years was also normal.