The number of clonogenic cells in a mouse jejunal crypt

A study of eight deaths involving the benzodiazepine flunitrazepam was performed to assess the contribution of this drug to the fatalities. Coronial deaths in Victoria in the 2-year period to mid-1991 were selected in which either flunitrazepam or flunitrazepam and ethanol were the principal toxicological findings. All bodies were subject to a full autopsy by forensic pathologists, and a full toxicological examination. No significant pathology was found at autopsy in any case. Very high concentrations of 7-aminoflunitrazepam, a metabolite of flunitrazepam, were present in all cases. In four cases no other significant drug was detected, whereas in the other four cases there were significant concentrations of ethanol (mean 1.6 g/L). In these two groups of cases the concentrations of 7-aminoflunitrazepam were 0.45 mg/L and 0.16 mg/L, respectively. Only moderate levels of flunitrazepam were detected, suggesting that 7-aminoflunitrazepam is produced postmortem and may be an important marker of flunitrazepam usage. The causes of death in these eight cases were probably either flunitrazepam toxicity or a combination of flunitrazepam and ethanol toxicity. Only one case appeared likely to have been a suicide. Our observations in these cases suggest that flunitrazepam may cause death in the absence of other drugs or significant disease. The presence of ethanol reduces the amount of flunitrazepam needed to cause death.     

Effect of heme and vacuole deficiency on FRE1 gene expression and ferrireductase activity in Saccharomyces cerevisiae

Doppler sonography of the fetal descending aorta, renal artery, middle cerebral artery and umbilical artery in a population of 74 fetuses with a abdominal circumference below the fifth percentile of the reference limits were done. All fetuses were free from structural and chromosomal abnormalities. The pulsatility- and the resistance indices as well as the ratios between these indices from peripheral and cerebral vessels were calculated and correlated to the fetal distress. The measurement of the pulsatility index of the middle cerebral artery provided the best results in predicting the development of fetal distress. Better results were achieved by the use of ratios of pulsatility-indices of various vessels than by the examination of the vessels alone. Our results suggest the usefulness of the examination of the middle cerebral artery and their ratios compared to the renal artery.     

Neurosteroids modulate calcium currents in hippocampal CA1 neurons via a pertussis toxin-sensitive G-protein-coupled mechanism

The inhibition of Ca2+ channel currents by endogenous brain steroids was examined in freshly dissociated pyramidal neurons from the adult guinea pig hippocampal CA1 region. The steady-state inhibition of the peak Ca2+ channel current evoked by depolarizing steps from -80 to -10 mV occurred in a concentration-dependent manner with the following IC50 values: pregnenolone sulfate (PES), 11 nM; pregnenolone (PE), 130 nM; and allotetrahydrocorticosterone (THCC), 298 nM. THCC, PE, and PES depressed a fraction of the Ca2+ channel current with a maximal inhibition of 60% of the total current. However, substitution of an acetate group for the sulfate group on PES resulted in a complete loss of activity. Progesterone had no effect (4% inhibition at 100 microM). Intracellular dialysis of PES had no effect on the Ca2+ current; concomitant extracellular perfusion of PES showed normal inhibitory activity, suggesting that the steroid binding site can only be accessed extracellularly. Analysis of tail currents at -80 mV demonstrated that THCC and PES slowed the rate of Ca2+ current activation and deactivation with no change in the voltage dependence of activation. Inhibition of the Ca2+ channel current by THCC and PES was voltage dependent. THCC primarily inhibits the omega-conotoxin (CgTX)-sensitive or N-type Ca2+ channel current. PE was nonselective in inhibiting both the CgTX- and the nifedipine (NIF)-sensitive Ca2+ channel current. These neurosteroids had no effect on the CgTX/NIF-insensitive current. In neurons isolated from pertussis toxin (PTX)-treated animals by chronic intracerebroventricular infusion (1000 ng/24 hr for 48 hr), the Ca2+ channel current inhibition by PES, PE, and THCC was significantly diminished. Intracellular dialysis with GDP-beta-S (500 microM) also significantly diminished the neurosteroid inhibition of the Ca2+ channel current. Intracellular dialysis with the general kinase inhibitors H-7 (100 microM), staurosporine (400 nM), and a 20 amino acid protein kinase inhibitor (1 microM) also significantly prevented the THCC and PES inhibition of the Ca2+ channel current. Intracellular dialysis with the more specific inhibitors of protein kinase C (PKC), the pseudosubstrate inhibitor (PKCI 19-36) (1-2 microM) and bisindolylmaleimide (1 microM) significantly diminished the THCC and PE inhibition of the Ca2+ channel current. Rp- cAMP (100 microM), a specific inhibitor of cAMP-dependent protein kinase (PKA), had no effect on the THCC and PE inhibition of the Ca2+ current.(ABSTRACT TRUNCATED AT 400 WORDS)     

Sheep pulmonary adenomatosis: a unique model of retrovirus-associated lung cancer

Sheep pulmonary adenomatosis (SPA) is a contagious bronchiolo-alveolar carcinoma of sheep associated with an exogenous type D/B retrovirus known as jaagsiekte sheep retrovirus (JSRV). SPA represents a unique model for lung cancer, and studies on its aetiopathogenesis can provide further insight into the mechanisms of epithelial neoplasms.     

Stimulatory effect of follicle-stimulating hormone on basal and luteinizing hormone-stimulated testosterone secretions by the fetal rat testis in vitro

The in vitro effect of FSH on testosterone secretion by the fetal rat testis was studied. Testes were cultured in the presence or absence of either commercial human (h) FSH (Metrodine; 200 mIU/ml) or recombinant hFSH (200 mIU/ml) for 3 days and with 100 ng/ml ovine LH during the last 4 h of culture. To avoid a stimulatory effect by the 0.4% LH that contaminates Metrodine, the cultures were performed in the presence of a monoclonal anti-hLH beta antibody and with a concentration of Metrodine that had no short term stimulatory effect on testosterone production by the fetal testes in vitro. Metrodine treatment had a positive long term effect on both basal and LH-stimulated testosterone secretion by fetal testes explanted on days 18.5, 20.5, and 22.5 postconception, which was abolished by the addition of a monoclonal anti-hFSH beta antibody. LH-free recombinant FSH also augmented basal and LH-stimulated testosterone secretion of testes explanted on days 13.5, 14.5, and 18.5 postconception. The positive effect of recombinant hFSH appeared during the second day of treatment with day 14.5 and 18.5 testes and on the third day of treatment with day 13.5 testes. As it is widely accepted that FSH receptors are exclusively localized on Sertoli cells, these results suggest that on or before day 15.5 of fetal life, 1) Sertoli cells are able to respond to FSH, 2) Sertoli cells can produce factors that are able to act on Leydig cell function, and 3) Leydig cells are sensitive to FSH-induced Sertoli cell factors. In conclusion, this study points out a potential paracrine control of fetal Leydig cell function and/or differentiation by fetal Sertoli cells as soon as fetal Leydig cells differentiate.