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Biomedical subjects

G W Williams

Publications and source records attributed to G W Williams.

At least 19 recordsLinked to original sources
PubMed1996

Inhibition of male sex behavior by androgen receptor blockade in preoptic area or hypothalamus, but not amygdala or septum.

Inhibition of masculine copulatory behavior was previously demonstrated following systemic injections of hydroxyflutamide (OHF). In the present study, we examined the localization of the effects of this androgen receptor blocker by direct intracranial implantation of OHF into the medial preoptic area (MPOA), ventromedial nucleus of hypothalamus (VMN), medial amygdala (AME), and lateral septum (SEPT). Animals were implanted intracranially with crystalline OHF or cholesterol, and at the same time received two 10-mm testosterone-filled Silastic capsules SC. Tests for restoration of copulatory behavior were initiated 3 days later, and conducted twice weekly for 2 weeks. Implants of OHF into the MPOA were effective in preventing restoration of male sexual behavior. However, the most effective site was the VMN. Implants of OHF into the AME were only partially effective in stimulating male sexual behavior, whereas implants into the SEPT had no effect. The OHF was discontinued and 1 week later males were retested for sexual behavior. The majority of these animals ejaculated, indicating, that the effects of OHF are reversible. The result of this study demonstrate that the functional integrity of androgen receptors in some, but not all, androgen-concentrating brain loci is necessary for the expression of the complete pattern of male sexual behavior. These data lend support to the view that androgen receptor populations in specific brain loci differentially express proteins involved in mediating the masculine copulatory response.

Amygdala↗
PubMed1995

Affinities of muscarinic drugs for [3H]N-methylscopolamine (NMS) and [3H]oxotremorine (OXO) binding to a mixture of M1-M4 muscarinic receptors: use of NMS/OXO-M ratios to group compounds into potential agonist, partial agonist, and antagonist classes.

The relative affinities of various muscarinic drugs in the antagonist ([3H]N-methyl scopolamine ([3H]NMS)) and agonist ([3H]Oxotremorine-m ([3H]OXO-M)) binding assays using a mixture of tissues containing M1-M4 receptor subtypes have been determined. [3H]NMS bound with high affinity (Kd = 25 +/- 5.9 pM; n = 3) and to a high density Bmax = 11.8 +/- 0.025 nmol/g wet weight) of muscarinic receptors. [3H]OXO-M appeared to bind to two binding sites with differing affinities (Kd1 = 2.5 +/- 0.1 nM; Kd2 = 9.0 +/- 4.9 microM; n = 4) and to a different population of binding sites (Bmax1 = 5.0 +/- 0.26 nmol/g wet weight; Bmax2 = 130 +/- 60 nmol/g wet weight). Well known antagonists exhibited high affinity for [3H]NMS binding but a lower affinity for [3H]OXO-M binding. The opposite was true for acetylcholine and other known agonists. However, pilocarpine and McN-A-343 had similar affinities for sites labeled by both radioligands. Using the ratios of antagonist-to-agonist binding affinities, it was possible to group compounds into apparently distinct full agonist (ratios of 180-665; e.g. carbachol, muscarine, OXO-M, OXO-S and arecoline), partial agonist (ratios of 14-132; e.g. McN-A-343, pilocarpine, aceclidine, bethanechol, OXA-22 and acetylcholine) and antagonist (ratios of 0.22-1.9; e.g. atropine, NMS, pirenzepine, methoctramine, 4-DAMP and p-fluorohexahydrosialo-difenidol) classes. These data suggest that the NMS/OXO-M affinity ratios using a mixture of M1-M4 muscarinic receptors may be a useful way to screen and group a large number of compounds into apparent agonist, partial agonist, and antagonist classes of cholinergic agents.

Animals↗
PubMed1993

Monitoring of clinical trials and interim analyses from a drug sponsor's point of view.

This paper illustrates aspects of data monitoring of clinical trials in the pharmaceutical industry. Formal interim analyses are performed at least in part to address the question of whether the trial should proceed or whether there should be an early termination of the trial. For formal interim analyses, frequently independent data and safety monitoring committees are utilized for monitoring clinical trials, and adjustments to nominal significance levels for test statistics are required. Various statistical methods developed during the last fifteen years are utilized. Administrative interim analyses are those analyses that are performed without any intention to stop the trial as a consequence of those analyses. For administrative interim analyses, adjustments to significance levels may not be required, but results must still be carefully interpreted. Regardless of the interim analyses performed, it is critical that the plans for interim analyses be identified in the study protocol, and the dissemination of interim results be carefully restricted. The following clinical trials sponsored by Merck Sharp and Dohme Research Laboratories (MSDRL) will illustrate these points: CONSENSUS; CONSENSUS II; 4S; Haemophilus influenza type b efficacy trial; famotidine in upper gastrointestinal haemorrhage, and a phase II analgesic study. It is anticipated that data monitoring and interim analysis activities will increase for future clinical trials due to the availability of appropriate statistical methods and improved data management systems.

Clinical Trials as Topic↗
PubMed1993

Comparison of the pharmacokinetics and pharmacodynamics of the aldose reductase inhibitors, AL03152 (RS), AL03802 (R), and AL03803 (S).

The pharmacokinetics of AL03152 (RS) and its enantiomers, AL03802 (R) and AL03803 (S), were studied in the Sprague-Dawley rat following intravenous bolus administration. The enantiomers had differing pharmacokinetic profiles, while the racemic compound exhibited pharmacokinetic parameters approximating the mean values of the individual enantiomers. The total clearance (CLT) values of the two enantiomers were similar, but the intrinsic clearance (Cl(int)) was much greater for the S-enantiomer than for the R-enantiomer. The volume of distribution (Vss) for AL03802 (R) was threefold greater than that for AL03803 (S). The stereoselectivity in Vss could not be totally accounted for by the slight difference in serum protein binding of the isomers and resulted in a difference in the half-lives of the enantiomers. Only the R-isomer exhibited a persistent terminal elimination phase, consistent with more extensive tissue binding than the S-isomer. AL03152 enantiomers were equivalent in potency assessed from in vitro IC50 values toward rat lens aldose reductase and rat kidney L-hexonate dehydrogenase and lens EC50 values in diabetic rats.

Aldehyde Reductase↗
PubMed1992

The effects of olfactory bulbectomy and chronic psychosocial stress on serum glucocorticoids and sexual behavior in female rats.

The effects of olfactory bulb removal (OBX) and chronic psychosocial stress on serum glucocorticoids and sexual behavior were assessed in female rats primed with a subthreshold level of estradiol (E2). Ovariectomized females underwent either OBX or sham surgery. Half of the OBX and half of the sham animals were exposed to chronic psychosocial stress (crowding, strobe light, and intermittent noise) for one-half h per day for 27 days. On day 22, three blood samples were collected from each animal for serum corticosterone analysis; 1) before, 2) during, and 3) after acute stress (one-half h restraint). On day 28, females were exposed to either 4 or 24 h of E2. On day 29, all females received 500 micrograms progesterone (P) 4 h prior to sexual behavior testing. Sexual receptivity was measured using the lordosis quotient (LQ = [number of lordotic responses/10 mounts] x 100). Sexual proceptivity (dart and ear wiggling sequences) and rejection (number of nonlordotic responses to mount attempts) were measured throughout a 10-min test period. Results showed that chronic psychosocial stress dramatically increased sexual receptivity and proceptivity while decreasing sexual rejection in female rats primed with a subthreshold level of E2. Chronic psychosocial stress also elevated serum glucocorticoids and significantly exacerbated the glucocorticoid response to acute stress. OBX, while increasing sexual receptivity and decreasing sexual rejection, had no effect on serum glucocorticoids. These findings support the hypothesis that OBX potentiates female sexual behavior directly through an increase in neural sensitivity to E2. In contrast, the enhancing effect of chronic psychosocial stress on female sexual behavior may result from alterations of the hypothalamo-pituitary-adrenal system.

Animals↗
PubMed1992

The UK Human Genome Mapping Project online computing service.

This paper presents an overview of computing and networking facilities developed by the Medical Research Council to provide online computing support to the Human Genome Mapping Project (HGMP) in the UK. The facility is connected to a number of other computing facilities in various centres of genetics and molecular biology research excellence, either directly via high-speed links or through national and international wide-area networks. The paper describes the design and implementation of the current system, a 'client/server' network of Sun, IBM, DEC and Apple servers, gateways and workstations. A short outline of online computing services currently delivered by this system to the UK human genetics research community is also provided. More information about the services and their availability could be obtained by a direct approach to the UK HGMP-RC.

Computer Communication Networks↗
PubMed1992

Doppler velocimetry in concordant and discordant twin gestations.

Doppler blood flow studies in 63 pairs of concordant and 17 pairs of discordant twins were compared with those of 277 appropriate for gestational age singleton fetuses. Discordancy was defined as a more than 20% intra-pair actual birth weight difference. The data were divided into five groups: singletons and large and small concordant and discordant twins. Statistical comparisons of the regression lines for the large concordant and discordant twins and the singletons showed no significant differences among the three lines, either in slopes (P = .1) or intercepts (P = .08). Comparisons of the regression lines for small concordant and discordant twins and the singletons indicated a significant interaction among the three lines (P = .01). Additional analysis leads us to conclude that the systolic-diastolic ratio (S/D) decreases with advancing gestational age for all groups except small discordant twins. The S/D of small discordant twins differed significantly from that of singletons and tended to differ from that of small concordant twins.

Blood Flow Velocity↗
PubMed1991

Effects of ovarian hormones on sexual receptivity, proceptivity, and motivation in olfactory bulbectomized female rats.

The purpose of the present experiment was to assess the effect of olfactory bulbectomy and ovarian hormones on female sexual motivation. Ovariectomized female rats underwent either bilateral bulbectomy or sham surgery. Females received one of four subthreshold hormone treatments: 0% estradiol (E2) plus 500 micrograms progesterone (P), 100% E2 alone, 10% E2 plus 500 micrograms P, or 100% E2 plus 500 micrograms P. Sexual motivation (as indicated by a female's preference for a sexually active male over a castrated male) and proceptivity (dart and ear wiggling sequences) were measured in a three compartment partner preference apparatus. Sexual receptivity (lordosis) was measured separately in a glass arena with a sexually active male. Results showed that olfactory bulb removal facilitates sexual receptivity and proceptivity in females exposed to 10% or 100% E2 in combination with 500 micrograms P. In contrast, sexual motivation was only demonstrated by olfactory bulbectomized females which received 100% E2 in combination with 500 micrograms P. These findings support the hypothesis that olfactory bulbectomy induces a behavioral hypersensitivity to estrogen, and suggest that sexual motivation is an estrogen-mediated response which requires a higher level of estrogen stimulation than sexual receptivity and proceptivity.

Animals↗
PubMed1991

Design and statistical issues of the Modification of Diet in Renal Disease Trial. The Modification of Diet in Renal Disease Study Group.

The Modification of Diet in Renal Disease Trial is a multicenter randomized clinical trial for men and women aged 18-70 years with chronic renal disease who are not on dialysis and who have not had a kidney transplant. Study participants are randomized in a 2 x 2 factorial design to diets containing different amounts of protein and phosphorus and to two levels of blood pressure control. The prescribed modifications differ depending on the level of a patient's kidney function. The primary outcome variable to compare diet or blood pressure groups is each patient's slope (or the change) in glomerular filtration rate with time. This paper describes the study design with particular emphasis on sample size determination. Special statistical analysis issues that arise with slope as the outcome are also discussed.

Adolescent↗
PubMed1991

Glomerular function in Pima Indians with noninsulin-dependent diabetes mellitus of recent onset.

Differential solute clearances were used to characterize glomerular function in 20 Pima Indians with noninsulin-dependent diabetes mellitus (NIDDM) of less than 3 yr duration. 28 Pima Indians with normal glucose tolerance served as controls. In the diabetic group, the glomerular filtration rate (GFR, iothalamate clearance) exceeded the control value by 15% (140 +/- 6 vs. 122 +/- 5 ml/min, P less than 0.01). A corresponding 12% increase in renal plasma flow (RPF) was not statistically significant and did not account fully for the observed hyperfiltration, suggesting a concomitant elevation of the ultrafiltration pressure or coefficient. The median albumin excretion ratio in NIDDM exceeded control by almost twofold (10.1 vs. 5.8 mg/g creatinine), a trend which just failed to achieve statistical significance (P = 0.06). Fractional clearances of dextrans of broad size distribution were also elevated in diabetic subjects, significantly so for larger dextrans of between 48 and 60 A radius. A theoretical analysis of dextran transport through a heteroporous membrane revealed glomerular pores in NIDDM to be uniformly shifted towards pores of larger size than in controls. We conclude that an impairment of barrier size selectivity combined with high GFR elevates the filtered protein load in NIDDM of recent onset. We propose that enhanced transglomerular trafficking of protein may predispose to sclerosis of glomeruli in those Pima Indians with NIDDM who ultimately develop diabetic nephropathy.

Adolescent↗
PubMed1990

A simple, sensitive liquid chromatographic method for quantitation of D-galactose and D-glucose in blood plasma.

The concentrations of D-glucose and D-galactose in plasma of galactosemic rats were quantitatively measured by a liquid chromatographic method, based on retention of the weakly ionized monosaccharides by an anion exchange column under alkaline conditions, elution with 9 mmol/L NaOH, and electrochemical detection. This method is both simple and sensitive, since very dilute plasma samples can be directly analysed.

Animals↗
PubMed1990

Automatic updating of the EMBL database via EMBNet.

The paper describes a procedure for updating the EMBL (European Molecular Biology Laboratory, Heidelberg) database of nucleic acid sequences and its indexes used by the University of Wisconsin Genetics Computer Group (GCG) software package, using updated entries for this database distributed via EMBNet. At present the procedure is being run on a MRC Clinical Research Centre's (CRC) SUN 4/280 server using SUNOS version 4.0.1 operating system.

Abstracting and Indexing↗
PubMed1990

Steroid-related osteonecrosis of the knee. Two case reports and a literature review.

Steroid-related osteonecrosis of the knee has been only rarely reported, especially without concomitant hip involvement. Two such cases are documented with correlated roentgenographic and magnetic resonance imaging. A comprehensive review of the literature illustrates the diverse circumstances in which this rare condition may occur.

Adult↗