Growth modulation of hepatocytes and rat liver epithelial cells (WB-F344) by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)

Modulation of DNA synthesis by 2,3,7,8-tetrachlorodi-benzo-p-dioxin(TCDD) was studied in primary cultures of hepatocytes and inrat liver epithelial cells (WB-F344) to develop models for studieson the interactions between the activated Ah receptor and cellulargrowth control. In hepatocytes TCDD either positively or negativelymodulated EGF-stimulated DNA synthesis. In the presence of ethlnylestradiol10^–12 M TCDD moderately increased EGF-stimulated DNA synthyesis(     

Excellent uricosuric efficacy of benzbromarone in cyclosporin-A-treated renal transplant patients: a prospective study

Patients on cyclosporin A (CsA) often develop hyperuricaemiaand gout. In transplant patients the use of uricosuric drugsfor treating hyperuricaemia may be preferable to allopurinolbecause of the known interaction of the latter with azathioprine.We therefore prospectively studied the uricosuric efficacy of100 mg benzbromarone (Bbr;Desuric®) daily in 25 CsA-treatedrenal transplant patients with stable graft function and hyperuricaemia(>359 µmol/l for females, >491 µmol/l formales). Benzbromarone decreased plasma uric acid from 579±18µmol/l to 313±24 µmol/l (mean±SEM;P<0.001) and thereby normalized plasma uric acid in 21 of25 patients. The remaining four patients had creatininc clearancesbetween 21 and 25 ml/min, the lowest of the entire study group.Mean fractional clearance of uric acid increased from 5.4±0.4%to 17.2±1.0% (P<0.001). The relative decrease of plasmauric acid closely correlated with baseline creatinine clearance(r=0.67; P<0.001). CsA trough values were not influenced.None of the patients experienced any significant side-effects.As an unexpected find-ing, urinary uric acid excretion increasedfrom 2082 ± 175 µmol7sol;24 h to 3233 ±232µmol/24 h after 4 weeks' treatment with benzbromarone. In conclusion, benzbromarone normalized plasma uric acid inall CsA-treated renal transplant recipients with a creatinineclearance >25 ml/min. Due to its excellent efficacy and lackof significant side-effects, benzbromarone appears to be preferableto allopurinol in CsA-treated renal transplant recipients witha creati nine clearance over 25 ml/min.     

Synthesis and transport of GAP-43 in entorhinal cortex neurons and perforant pathway during lesion-induced sprouting and reactive synaptogenesis.

Metabolic labeling and quantitative 2D gel autoradiography were used to assess changes in the synthesis and transport of GAP-43 in entorhinal cortex (EC) neurons and perforant pathway during lesion-induced sprouting and reactive synaptogenesis. In normal adult rats, there is a high constitutive level of GAP-43 synthesis and transport in EC neurons projecting to the hippocampus. Following unilateral EC lesions, there is a 2-fold (100%) increase in the transport of newly synthesized GAP-43 to the contralateral or 'sprouting' hippocampus. The timing of this upregulation (between 6 and 15 days) suggests that changes in GAP-43 expression occur in response to the growth of presynaptic terminals during sprouting.     

Current issues in maternal serum alpha-fetoprotein screening.

Measurement of maternal serum alpha-fetoprotein originated in the early 1970s as a means to screen for fetal neural tube defects, a relatively common and devastating class of malformations. Since that time, assay methods have improved, interpretation has been refined, follow-up testing for neural tube defects has advanced, and many other disease associations have been uncovered. It is a unique test, both in its clinical application and its laboratory implementation. The present review outlines current procedures for maternal serum alpha-fetoprotein screening and summarizes recent developments.     

Experimental vaccination of young chickens with a live, non-pathogenic strain of Escherichia coli

A non-pathogenic, piliated strain of Escherichia coli (BT-7; Frommer et al., 1990), isolated from a meat-type chicken flock, was studied as a candidate for a live vaccine to protect chickens from E. coli infection. Active immunization provided substantial protection of chicks vaccinated at 14 or 21 days of age, resulting in better resistance to challenge than in those vaccinated at 1 or 7 days. Chicks vaccinated at 21 days of age and challenged 1 week later with pathogenic E. coli strains 01-.K1, 02:K1 or 078:K80, exhibited good protection for at least 2 weeks against all strains. Three vaccination routes were found to give the highest resistance to challenge with pathogenic E. coli strain 078:K80. Intramuscular (i.m.) at 7 and 21 days of age, i.m. at 21 days of age and spray at 7, followed by per os at 21 days of age. Vaccination per os once at 7 or twice at 7 and 21 days resulted in good protection. Chicks exhibiting high antibody titres by ELISA were well-protected against challenge.     

Akromegalie und generalisierte Lipodystrophie

The rare autosomal-recessive Berardinelli-Seip congenital lipodystrophy syndrome (BSCL) is characterized by general lipodystrophy, acromegalic appearance, hypertriglyceridemia, insulin resistance and hepatomegaly. Here, we present the case of an 11 month old female infant of consanguineous parents from Libya, who was brought to us for diagnosis because of her unusual appearance since birth. Additionally to the above mentioned symptoms, we found an accelerated bone age, myopathy without muscle weakness, but no signs of mental retardation or cardiomyopathy. This constellation of symptoms is typical for the BSCL1 mutation phenotype, which was confirmed by molecular genetics. The girl will undergo frequent clinical and laboratory controls and follow a fibre- and medium chain fatty acid rich diet. This case demonstrates a genetic extreme of“metabolic syndrome X” and thus could provide new knowledge about diabetes mellitus type 2 and its prophylaxis.     

Development of a novel class of cyclic hexapeptide oxytocin antagonists based on a natural product.

A new structural class of cyclic hexapeptide oxytocin antagonists derived from Streptomyces silvensis and typified by L-365,209 (cyclo-[L-prolyl1-D-phenylalanyl2-L- isoleucyl3-D-dehydropiperazyl4-L-dehydroperazyl5-D-(N- methyl)phenylalanyl6]) was recently reported. In this paper we further delineate the structure-activity profile for this new class by systematic study of L-365,209 analogs obtained by total synthesis. The optimal combination of cyclic amino acid ring sizes at positions 1, 4, and 5 and the role of the N-alkyl substituent at position 6 was elucidated. The lipophilic amino acids at positions 2 and 3 and the unusual amino acid D-dehydropiperazic acid at position 4 were found to be the most critical residues for obtaining good oxytocin receptor affinity. Analogs containing a basic side chain at the less critical 5- and 6-positions maintained good receptor affinity and also had useful levels of water solubility for intravenous formulation. By combining potency- and solubility-enhancing substitutions, several analogs were identified that have the desired combination of properties in vitro (22, cyclo-[L-prolyl-D-tryptophanyl-L-isoleucyl-D-pipecolyl-L-pipeco lyl-D- histidyl]; 25, cyclo-[L-prolyl-D-2-naphthylalanyl-L-isoleucyl-D-pipecolyl-L -pipecolyl-D- histidyl]; 26, cyclo-[L-prolyl-D-tryptophanyl-L-isoleucyl-D-dehydropiperazyl-L-++ pipecolyl-D-histidyl]; 33, cyclo-[L-prolyl-D-tryptophanyl-L-isoleucyl-D-pipecolyl-L- piperazinylcarboxy-D-(N-methyl)phenylalanyl]; 34, cyclo-[L-prolyl-D-phenylalanyl-L-isoleucyl-D-dehydropiperazyl-L-or nithyl- D-(N-methyl)phenylalanyl]). In general, this class exhibited good selectivity for binding to the oxytocin receptor versus the arginine vasopressin V1a and V2 receptor subtypes, although increased V2 receptor affinity was observed in one case (32, cyclo[L-prolyl-D-2-naphthylalanyl-L-isoleucyl-D-pipecolyl-L- lysyl-D-(N- methyl)phenylalanyl]). Unexpectedly, compound 33 was found to stimulate contractions of the isolated rat uterus via activation of the uterine bradykinin receptor. Compounds 22, 25, 26, 33, and 34 were found to be potent antagonists of oxytocin-stimulated contraction of the rat uterus in vitro and in vivo. Compounds 22 and 25 were additionally characterized as potent antagonists of oxytocin-stimulated uterine contractions in the near-term pregnant rhesus monkey. These studies thus demonstrate the selectivity and efficacy of certain members of this novel class of antagonists and suggest their use as pharmacological tools in further defining the role of oxytocin in both term and preterm labor.     

Renin-producing renal cell carcinomas—clinical and experimental investigations on a special form of renal hypertension

Summary The pathogenetic relationship between tumour and hypertension was investigated in 129 patients with renal cell carcinoma, of whom 41 (31.8%) were hypertensive. Of these 41 patients with renal tumours and hypertension, 6 (14.6%) were found to have primary reninism. In these patients the plasma renin activity in blood from the renal veins showed a tumour kidney to contralateral kidney ratio of between 4 and 7, and 2 patients also had secondary hyperaldosteronism. In the same 6 cases the renin content in the renal tumour tissue was significantly higher than that in tissue from the adjacent tumour-free renal cortex of the ipsilateral kidney. Immunohistochemical demonstration of renin in the tumour was only possible in these 6 cases. In 5 of these patients blood pressure returned to normal following nephrectomy; in the 6th case there was a drop in blood pressure after nephrectomy. In 3 renin-positive tumours examined, autonomous renin production was demonstrated in cell culture. Renin-producing renal cell carcinomas are an uncommon cause of renal hypertension. The differential diagnosis of hypertension should therefore also include renal tumour.     

The Significance of Histology and Morphometry in Predicting Lymph Node Metastases in Patients with Squamous Cell Carcinoma of the Vulva

The material consists of a series of 73 patients with squamous cell carcinoma of the vulva. The site and the size of the primary tumor and the histological status of the lymph nodes of the groin were known. Two pathologists evaluated nuclear hyperchromatism, nuclear polymorphism, histological differentiation, number of mitoses, inflammatory response, and vascular invasion and graded these parameters from one to three. The reliability of the histopathological grades evaluated by the κ coefficient showed considerable interobserver variation. Despite this a model which included the subjective parameter nuclear hyperchromatism could predict patients without lymph node metastases. The model consisted of patients with tumors which were not situated on the clitoris, were less than 40 mm in diameter, and exhibited only slight hyperchromatism. The model fitted 19 (26%) and 14 (19%) of the patients with two different pathologists evaluating the nuclear hyperchromatism and none of these patients had lymph node metastases. The quantitative parameter—mean nuclear volume—determined by morphometry was of no diagnostic value for the prediction of patients without groin node metastases at the time of operation.