Prospective epidemiologic studies aid in identifying genetic variants associated with diseases, health risks, and physiologic traits. These genetic variants may eventually be measured clinically for purposes of diagnosis, prognosis, and treatment. As evidence of the potential clinical value of such information accrues, research studies face growing pressure to report these results to study participants or their physicians, even before sufficient evidence is available to support widespread screening of asymptomatic persons. There is thus a need to begin to develop consensus on whether and when genetic findings should be reported to participants in research studies. The National Heart, Lung, and Blood Institute (NHLBI) convened a Working Group on Reporting Genetic Results in Research Studies to discuss if, when, and how genetic information should be reported to study participants. The Working Group concluded that genetic test results should be reported to study participants when the associated risk for the disease is significant; the disease has important health implications such as premature death or substantial morbidity or has significant reproductive implications; and proven therapeutic or preventive interventions are available. Finally, the Working Group recommended procedures for reporting genetic research results and encouraged increased efforts to create uniform guidelines for this activity.

Sleep-promoting factor (factor S) was extracted, partially purified, and concentrated from cerebrospinal fluid and from acid-acetone extracts of brain stem anc cortex of sleep-deprived goats and sheep. 2. Solutes greater than 500 daltons were largely removed by serial ultrafiltrations through molecular sieves (Amicon membranes UM10 and UM05); solutes less than 350 daltons were largely eliminated by gel filtration through Sephadex G10 columns. Sleep-promoting activity was found in a fraction eluted prior to [14C] sucrose marker. 3. Concentrated fraction were infused intraventricularly in rats (0.1 ml in 30 min just prior to 12-h dark cycle) and in rabbits (0.3 ml in 90 min in morning). Sleep-promoting activity was assayed by decrease in nocturnal locomotor activity of rats and by duration and amplitude of slow-wave cortical EEG in rabbits.

Specific, GTP hydrolysis catalyzed by membranes prepared from neuroblastoma-glioma (NG108-15) hybrid cells can be measured in the presence of adenosine-5'- [13,v-imido] triphosphate (p[NH]ppA), ATP, and a nucleoside triphosphateregenerating system. Opiates and opioid peptides stimulate low K. GTP hydrolysis when measured in the presence of Na' and Mg2+. Opiate stimulation is rapid, stereospecific, and reversed by the antagonist naloxone. Potencies of opiates as stimulators of GTP hydrolysis and as inhibitors of adenylate cyclase are closely correlated. Agents that stimulate adenylate cyclase, including prostaglandin E1, 2-Cl-adenosine, secretin, and NaF, have little or no effect upon the rate of GTP hydrolysis. Opiates have no effect upon either adenylate cyclase or GTPase activity in membranes prepared from C6-BU1 glioma cells, which lack opiate receptors. In view ofthe pivotal role ofGTP in the activation ofadenylate cyclase, we conclude that receptor-mediated stimulation of GTP hydrolysis is the mechanism by which opiates and other inhibitory hormones lower adenylate cyclase activity in NG1O8-15 cell membranes.

Receptors that reversibly bind opiates and opioid peptides have been solubilized from brain and neuroblastoma-glioma hybrid cell NG108-15 membranes. Active receptors are specifically solubilized with a new type of detergent 3-[(3-cholamidopropyl)dimethylammonio}1-propanesulfonate, which is a zwitterionic derivative of cholic acid. The solubilized receptor complexes behave as large molecules with a Stokes radius of 70 A and contain protein as an essential constituent.A necessary first step in the study of the structure and mechanism of action of opiate receptors is their separation, in an active form, from membranes. was from Calbiochem; f3-endorphin (camel) was from Boehringer Mannheim; etorphine-HCI was a gift from Robert Willette (National Institute of Drug Abuse) and naloxone-HCI was donated by Endo Laboratories (New York). Other opiates were gifts from Arthur Jacobson (National Institute of Arthritis, Metabolism, and Digestive Diseases). Sodium cholate and Zwittergent were from Calbiochem; CHAPS was synthesized as described (7). Dithiothreitol and sucrose (ultra-pure reagent) were from Bethesda Research Laboratories (Rockville, MD).Cell Growth. Neuroblastoma-glioma hybrid NG108-15 cells were grown as described (3), except that 850-cm2 tissue culture roller bottles (Corning) were used. The bottles were gassed at the time of planting with 5% C02/95% air, but not upon subsequent feeding.Brain Membrane Preparation. Crude mitochondrial fractions (P2) from rat brain were prepared as described (8) and stored at -800C. Bovine brain membranes were prepared from whole brain, without the cerebellum and medulla, and homogenized in 10 vol of 50 mM Tris-HCl (pH 7.5). After filtration through cheesecloth, the pellet from i centrifugation at 40,000 X g for 30 min was resuspended in a total of 2 vol of 50 mM Tris-HCl (pH 7.5) and frozen at -80'C until use.Solubilization. NG108-15 cell homogenate was centrifuged at 50,000 rpm (160,000 X g) for 30 min at 40C. The pellet was resuspended in 50 mM Tris-HCl (pH 7.5) to a protein concentration of 8-15 mg/ml. The suspension was homogenized on ice in the presence of 10 mM CHAPS with 25 strokes of a ground-glass homogenizer, then centrifuged for 60 min at 160,000 X g in cellulose nitrate tubes. The clear supernatant was separated from a floating cloudy layer and the pellet by puncturing the tube with a 23-gauge needle at a point 1 cm above the pellet and gently withdrawing the liquid into a 10-ml syringe.Aliquots of brain membrane suspensions were diluted with 2 vol of 50 mM Tris-HCl (pH 7.5), 50 ,g of pancreatic trypsin inhibitor per ml (Worthington), 0.1 mM phenylmethylsulfonyl fluoride (Calbiochem), and 0.01% dimethyl sulfoxide (Eastman). The suspension was centrifuged at 165,000 X g for 15 min, and the pellet was resuspended in 2 vol of the above buffer with 10 mM CHAPS to a protein concentration of approximately 12 mg/ml. This suspension was agitated at 40C for 1 hr, then centrifuged at 105,000 X g for 60 min. The clear, slightly yellow supernatant fraction was carefully...

Abstract.Multicenter clinical trials require approval by multiple local institutional review boards (IRBs). The Multicenter Airway Research Collaboration mailed a clinical trial protocol to its U.S. investigators and 44 IRBs ultimately reviewed it. Objective: To describe IRB responses to one standard protocol and thereby gain insight into the advantages and disadvantages of local IRB review. Methods: Two surveys were mailed to participants, with telephone follow-up of nonrespondents. Survey 1 was mailed to 82 investigators across North America. Survey 2 was mailed to investigators from 44 medical centers in 17 U.S. states. Survey 1 asked about each investigator's local IRB (e.g., frequency of meetings, membership), whereas survey 2 asked about IRB queries and concerns related to the submitted clinical trial. Results: Both surveys had 100% response rate. Investigators submitted applications a median of 58 days (interquartile range [IQR], 40-83) after receipt of the pro-