Electron transfer to cytochrome P-450scc limits cholesterol-side-chain-cleavage activity in the human placenta

The aim of this study was to determine whether electron transfer from adrenodoxin reductase and adrenodoxin limits the activity of cytochrome P-450scc in mitochondria from the human placenta. Mitochondria were disrupted by sonication to enable exogenous adrenodoxin and adrenodoxin reductase to deliver electrons to cytochrome P-450scc. After sonication, the rate of pregnenolone synthesis was greatly decreased relative to that by intact mitochondria, due to dilution of endogenous adrenodoxin and adrenodoxin reductase into the incubation medium. The addition of saturating concentrations of bovine or human adrenodoxin and bovine adrenodoxin reductase to the disrupted mitochondria gave an initial rate of pregnenolone synthesis that was 6.3-fold higher than that for intact mitochondria. Similar results were observed when 20alpha-hydroxycholesterol was used as substrate rather than endogenous cholesterol. The turnover number of cytochrome P-450scc in sonicated placental mitochondria supplemented with adrenodoxin and adrenodoxin reductase was comparable to that for the purified enzyme assayed under conditions where electron transfer was not limiting. Addition of exogenous adrenodoxin and adrenodoxin reductase to sonicated mitochondria from the pig corpus luteum and rat adrenal had a much smaller effect on pregnenolone synthesis compared with intact mitochondria, than observed for the placenta. We conclude that in the human placenta, electron transfer to cytochrome P-450scc is limiting, permitting pregnenolone synthesis to proceed at only 16% maximum velocity.     

Determination of plasma concentrations of propofol associated with 50% reduction in postoperative nausea

BACKGROUND: Subhypnotic doses of propofol possess direct antiemetic properties. The authors sought to determine the plasma concentration of propofol needed to effectively manage postoperative nausea and vomiting. METHODS: Patients aged 18-70 yr who were classified as American Society of Anesthesiologists physical status 1 or 2 and had surgery during general anesthesia were approached for the study. Only patients who had nausea (verbal rating score > 5 on a 0- to 10-point scale), retching, or vomiting in the postanesthetic care unit participated. Propofol was administered to these patients to achieve target plasma concentrations of 100, 200, 400, and 800 ng/ml using a computer-assisted continuous infusion device. Target concentrations were increased every 15 min until patients described at least a 50% reduction in symptoms on the verbal rating score. An arterial blood sample was obtained at each step. The measured plasma propofol concentrations were used to analyze data. Blood pressure, heart and respiratory rates, arterial blood saturation, sedation score, and overall satisfaction with treatment were recorded. RESULTS: Of the 89 patients who consented to the study, 15 patients met entry criteria and were enrolled. Five of these patients also had retching or vomiting when they entered the study. Fourteen patients responded successfully to treatment. One patient did not achieve the required response at plasma concentrations of 830 ng/ml. Hence the success rate for the treatment of postoperative nausea and vomiting was 93%. Among patients who responded, the median plasma concentration associated with an antiemetic response was 343 ng/ml. There was no difference in sedation scores from baseline and no episodes of desaturation. Hemodynamic parameters were stable during the study. CONCLUSIONS: Propofol is generally efficacious in treating postoperative nausea and vomiting at plasma concentrations that do not produce increased sedation. Simulations indicate that to achieve antiemetic plasma propofol concentrations of 343 ng/ml, a bolus dose of 10 mg followed by an infusion of approximately 10 microg x kg(-1) x min(-1) are necessary.     

Tissue specific expression of FMR-1 provides evidence for a functional role in fragile X syndrome

Prostaglandin E2 levels in isolated rat islets were increased from 64 +/- 11 pg/30 islets when incubated in medium containing 2 mM glucose to 115 +/- 9 pg/30 islets in medium containing 20 mM glucose. In contrast, glyceraldehyde (10 mM) reduced prostaglandin E2 levels to 29 +/- 6 pg/30 islets. Inhibition of glucose metabolism by mannoheptulose (10 mM) abolished the stimulatory effect of glucose on prostaglandin E2 levels and inhibited glucose-induced insulin release. The cyclooxygenase inhibitor, flurbiprofen (20 microM), did not affect insulin release caused by glucose or glyceraldehyde. In the presence of 1 mg/ml bovine serum albumin, insulin secretion induced by 20 mM glucose (6.9 +/- 1.1% of islet insulin content) was reduced by the lipoxygenase inhibitor BW755 C (20 microM) to 3.1 +/- 0.6%, and by the phospholipase A2 inhibitor, p-bromophenacyl bromide (10 microM), to 2.1 +/- 0.8%. In the absence of bovine serum albumin the inhibitory action of BW755 C and p-bromophenacyl bromide on glucose-induced insulin release was significantly more pronounced. These drugs whether in the presence or absence of bovine serum albumin, did not affect glyceraldehyde-stimulated insulin secretion. Glyceraldehyde (10 mM), potentiated glucose-induced insulin release in the presence of 2-8 mM glucose, but not for 10-20 mM glucose. Although the phospholipase A2 activator, melittin, initiated insulin release in the presence of 2 mM glucose and enhanced 10 mM glyceraldehyde-stimulated insulin secretion it had no effect on 20 mM glucose-induced insulin release. These two stimulatory effects of melittin on insulin release were totally abolished by p-bromophenacyl bromide.(ABSTRACT TRUNCATED AT 250 WORDS)     

A carbocyclic nucleoside analogue is a TNF-alpha inhibitor with immunosuppressive action: role of prostaglandin E2 and protein kinase C and comparison with pentoxifylline

PURPOSE: To compare the activity of topical 0.05% and 0.01% mequitazine versus vehicle in the prevention of allergic conjunctivitis induced by a conjunctival provocation test with allergens. METHODS: Forty subjects with a history of grass pollen allergic conjunctivitis were enrolled in this comparative, randomized, double-masked study. Fifteen minutes before the conjunctival provocation test, subjects received one instillation alone of 0.05% mequitazine eyedrops in one eye and in the fellow eye either one drop of 0.01% dose or vehicle, at the same dosage. Then a specific conjunctival provocation test (CPT) was performed with the allergen threshold concentration previously defined. The therapeutic efficacy was assessed by the decrease in a symptomatic composite score representing the allergic reaction. RESULTS: Topical mequitazine at the dose of 0.05% significantly decreases the intensity of the allergic reaction compared to vehicle. Moreover, the group treated with this dose needed a higher allergen concentration to trigger ocular signs. The 0.01% dose appears efficient only on itching, compared to vehicle. CONCLUSION: The results of this study support the efficacy and the onset of action of 0.05% mequitazine eyedrops versus 0.01% or vehicle in the prevention of allergic conjunctivitis induced by a conjunctival provocation test.     

Exposure to nitrogen dioxide (NO2) and respiratory disease risk

Epidemiological evidence suggests that exposure to nitrogen dioxide (NO2) through the use of unvented gas cookers in homes is associated with respiratory symptoms. Toxicological evidence, mainly in animal models, suggests that NO2 may increase the susceptibility to infection by viruses and bacteria. This review examines the evidence and proposes mechanisms whereby such exposure may occur, in particular how NO2 may aggravate respiratory symptoms in the presence of coexistent infection.     

Soluble adhesion molecules in CSF are increased in children with severe head injury

Leukocyte-endothelial adhesion molecules, critical to the development of acute inflammation, are expressed in brain as part of the acute inflammatory response to traumatic brain injury (TBI). We measured the concentrations of the adhesion molecules P-selectin, ICAM-1, E-selectin, L-selectin, and VCAM-1 in ventricular cerebrospinal fluid (CSF) from children with severe TBI (Glasgow coma score < 8) and compared these findings with those from children with bacterial meningitis. P-selectin, an adhesion molecule associated with ischemia/reperfusion, was increased in children with TBI versus meningitis and control. Univariate and multivariate regression analyses demonstrated associations between CSF P-selectin and child abuse and age of < 4 years, and a significant, independent association between CSF intercellular adhesion molecule-1 (ICAM-1) and child abuse. These results are consistent with a specific acute inflammatory component to TBI in children. Future studies of secondary injury mechanisms and therapy after TBI should assess on the roles of P-selectin and ICAM-1 in injury and repair processes in brain after TBI.