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Biomedical subjects

A E Weber

Publications and source records attributed to A E Weber.

At least 37 records · Page 2Linked to original sources
PubMed2000

Determinants of hospital admission among HIV-positive people in British Columbia.

BACKGROUND: This study was initiated to evaluate the demographic and clinical determinants of admission to hospital among HIV-positive men and women receiving antiretroviral therapy in British Columbia. METHODS: The analysis was restricted to participants enrolled in the HIV/AIDS Drug Treatment Program between September 1992 and March 1997 who had completed an annual participant survey, had a viral load determination and had signed a consent form allowing electronic access to their inpatient hospital records. A record linkage was conducted with the BC Ministry of Health to obtain all records of hospital admissions from April 1991 to March 1997. Statistical analyses were carried out using parametric and nonparametric methods and multivariate logistic analyses. RESULTS: The study sample comprised 947 participants (859 men, 88 women). Of these, 165 (17%) were admitted to hospital during the study period from May 1, 1996, to Mar. 31, 1997. The median number of admissions was 1 (interquartile range [IQR] 1-2 admissions), and the median length of stay per admission was 3 days (IQR 1-8 days). Admission to hospital was associated with being unemployed (82% of those admitted v. 58% of those not admitted), being an injection drug user (24% v. 17%), reporting a fair or poor health status (46% v. 29%) and having a physician experienced in the management of HIV/AIDS (31% v. 24%). Examination of clinical determinants demonstrated that hospital admission was associated with a previous admission (72% v. 46%), a high viral load (median 74,000 v. 14,000 HIV-1 RNA copies/mL), a low CD4 count (median 0.16 v. 0.27 x 10(9)/L) and an AIDS diagnosis (44% v. 24%). Multivariate logistic regression analysis revealed that being admitted to hospital was independently associated with being unemployed (odds ratio [OR] 2.64, 95% confidence interval [CI] 1.66-4.20), having been previously admitted to hospital (OR 2.30, 95% CI 1.53-3.46), having a high viral load at baseline (OR 1.45, 95% CI 1.16-1.80), being an injection drug user (OR 1.63, 95% CI 1.02-2.62) and having an experienced physician (OR 1.98, 95% CI 1.29-3.03). INTERPRETATION: Hospital admission among participants in this study was found to be associated with marginalization and poor health status.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Potent, elective human beta3 adrenergic receptor agonists containing a substituted indoline-5-sulfonamide pharmacophore.

A series of compounds possessing an N-substituted indoline-5-sulfonamide pharmacophore was prepared and evaluated for their human beta3 adrenergic receptor agonist activity. The SAR of a wide range of urea and heterocyclic substituents is discussed. 4-Octyl thiazole compound 8c was the most potent and selective compound in the series, with 2800-fold selectivity over beta1 binding and 1400-fold selectivity over beta2 binding.

Adrenergic Agonists↗
PubMed1999

L-770,644: a potent and selective human beta3 adrenergic receptor agonist with improved oral bioavailability.

L-770,644 (9c) is a potent and selective agonist of the human beta3 adrenergic receptor (EC50 = 13 nM). It shows good oral bioavailability in both dogs and rats (%F = 27), and is a full agonist for glycerolemia in the rhesus monkey (ED50 = 0.21 mg/kg). Based on its desirable in vitro and in vivo properties, L-770,644 was chosen for further preclinical evaluation.

Administration, Oral↗
PubMed1999

Human beta3 adrenergic receptor agonists containing cyclic ureidobenzenesulfonamides.

Human beta3 adrenergic receptor agonists containing 5-membered ring ureas were shown to be potent partial agonists with excellent selectivity over beta1 and beta2 binding. L-760,087 (4a) and L-764,646 (5a) (beta3 EC50 = 18 and 14 nM, respectively) stimulate lipolysis in rhesus monkeys (ED50 = 0.2 and 0.1 mg/kg, respectively) with minimal effects on heart rate. Oral absorption in dogs is improved over other urea analogs.

Administration, Oral↗
PubMed1999

Recording sexual behavior: comparison of recall questionnaires with a coital diary.

OBJECTIVE: To compare sexual behavior data obtained using a weekly-recall questionnaire, a daily-recall questionnaire, and a coital diary. DESIGN: Cross-sectional survey of female sex workers from KwaZulu-Natal, South Africa between August and October 1998. METHODS: In this study, 52 weekly-recall questionnaires, 27 daily-recall questionnaires, and 79 coital diaries for dates corresponding to the questionnaires were obtained from female sex workers. Variables examined included: number of clients, number of condoms used with clients and partners, and number and type of sexual acts with clients and partners. Statistical analyses were conducted to examine the degree of agreement between the data collection methods and to assess differences between the mean values of the variables in the questionnaires versus the diary. RESULTS: Comparison of weekly-recall questionnaires with coital diaries indicated a significantly greater mean number of clients (P < 0.001), number of condoms used (P < 0.001), vaginal acts (P < 0.001), and anal acts (P = 0.044) reported in the diary versus the questionnaire. On comparison of daily-recall questionnaire with coital diary, significant differences were revealed between the means detected for the number of clients (P = 0.027), number of days worked (0.009), and anal acts with clients (P = 0.004). CONCLUSIONS: The use of coital diaries for the collection of sexual behavior data may be limited to cross-sectional community surveys. A recall questionnaire may provide more reliable and a better quality of data for longitudinal studies and for human immunodeficiency virus/sexually transmitted disease evaluation programs.

Adolescent↗
PubMed1999

Potent and selective human beta(3)-adrenergic receptor antagonists.

Although the functional presence of beta(3)-adrenergic receptors (beta(3)-AR) in rodents is well established, its significance in human adipose tissue has been controversial. One of the issues confounding the experimental data has been the lack of potent and selective human beta(3)-AR ligands analogous to the rodent-specific agonist BRL37344. Recently, we described a new class of aryloxypropanolamine beta(3)-AR agonists that potently and selectively activate lipolysis in rhesus isolated adipocytes and stimulate the metabolic rate in rhesus monkeys in vivo. In this article, we describe novel and selective beta(3)-AR antagonists with high affinity for the human receptor. L-748,328 and L-748,337 bind the human cloned beta(3)-AR expressed in Chinese hamster ovary (CHO) cells with an affinity of 3.7 +/- 1.4 and 4.0 +/- 0.4 nM, respectively. They display an affinity of 467 +/- 89 and 390 +/- 154 nM for the human beta(1)-AR. Their selectivity for human beta(3)-AR versus beta(2)-AR is greater than 20-fold (99 +/- 43 nM) and 45-fold (204 +/- 75 nM), respectively. These compounds are competitive antagonists capable of inhibiting the functional activation of agonists in a dose-dependent manner in cells expressing human cloned beta(3)-AR. Moreover, both L-748,328 and L-748,337 inhibit the lipolytic response elicited by the beta(3)-AR agonist L-742,791 in isolated nonhuman primate adipocytes. The aryloxypropanolamine benzenesulfonamide ligands illustrated here and elsewhere demonstrate high-affinity human beta(3)-AR binding. In addition, we describe specific 3'-phenoxy substitutions that transform these compounds from potent agonists into selective antagonists.

Adipocytes↗
PubMed1998

One world, one hope: the cost of providing antiretroviral therapy to all nations.

OBJECTIVE: To estimate the potential direct cost of making triple combination antiretroviral therapy widely available to HIV-positive adults and children living in countries throughout the world. METHODS: For each country, antiretroviral costs were obtained by multiplying the annual cost of triple antiretroviral therapy by the estimated number of HIV-positive persons accessing therapy. Per capita antiretroviral costs were computed by dividing the antiretroviral costs by the country's total population. The potential economic burden was calculated by dividing per capita antiretroviral costs by the gross national product (GNP) per capita. All values are expressed in 1997 US dollars. RESULTS: The potential cost of making triple combination antiretroviral therapy available to HIV-positive individuals throughout the world was estimated to be over US$ 65.8 billion. By far the greatest financial burden was on sub-Saharan Africa. The highest per capita drug cost in this region would be incurred in the subregions of Southern Africa (US$ 149) followed by East Africa (US$ 116), Middle Africa (US$ 44), and West Africa (US$ 42). In the Americas, subregional data indicated the highest per capita drug cost would be in the Latin Caribbean (US$ 22), followed by the Caribbean (US$ 17), Andean Area (US$ 7), the Southern Cone (US$ 6), North America (US$ 6), and Central American Isthmus (US$ 5). In Asia and Europe the percentage of the GNP necessary to finance drug therapy was less than 1% in most countries examined. CONCLUSION: Our results demonstrate that the cost of making combination antiretroviral therapy available worldwide would be exceedingly high, especially in countries with limited financial resources.

Adult↗
PubMed1998

3-Pyridyloxypropanolamine agonists of the beta 3 adrenergic receptor with improved pharmacokinetic properties.

Pyridyloxypropanolamines L-749,372 (8, beta 3 EC50 = 3.6 nM) and L-750,355 (29, beta 3 EC50 = 13 nM) are selective partial agonists of the human receptor, with 33% and 49% activation, respectively. Both stimulate lipolysis in rhesus monkeys (ED50 = 2 and 0.8 mg/kg, respectively), with minimal effects on heart rate. Oral bioavailability in dogs, 41% for L-749,372 and 47% for L-750,355, is improved relative to phenol analogs.

Adrenergic beta-Agonists↗
PubMed1998

Potent, selective benzenesulfonamide agonists of the human beta 3 adrenergic receptor.

A cloned human beta 3 adrenergic receptor assay was used to identify phenoxypropanolamine agonist 1. SAR studies led to the identification of benzenesulfonamide derivative 20, a 6.3 nM beta 3 agonist which shows 30-fold selectivity for beta 3 agonist activity over beta 1 and beta 2 receptor binding. Further refinement of this lead provided 4-bromo derivative 39, a subnanomolar agonist with 660-fold and 230-fold selectivity over beta 1 and beta 2, respectively.

Adrenergic beta-Agonists↗
PubMed1998

Discovery of L-755,507: a subnanomolar human beta 3 adrenergic receptor agonist.

A study of 4-acylaminobenzenesulfonamides in a cloned human beta 3 adrenergic receptor assay resulted in the discovery of n-hexylurea, L-755,507 (22). This 0.43 nM beta 3 agonist, which is > 440-fold selective over both beta 1 and beta 2 binding, is among the most potent human beta 3 agonists reported to date.

Adrenergic beta-Agonists↗
PubMed1995

Visual responses and connectivity in the turtle pretectum.

1. Using an isolated turtle brain preparation, we made extracellular spike recordings in the dorsal midbrain during visual stimulation. Single units were isolated by their response to a slow-moving full-field visual pattern imaged on the contralateral retina. This stimulus elicits responses from the basal optic nucleus (BON) and the cerebellar cortex using a similar preparation. Direction and speed tuning were then analyzed, as well as the size and position of the receptive field. 2. In one brain stem region, anterior to the optic tectum and deep to the dorsal surface, all of the visually responsive neurons were direction sensitive (DS) to contralateral retinal stimulation. The location and properties of these cells indicate that they are in the mesencephalic lentiform nucleus (nLM). Anterograde transport of intravitreally injected horseradish peroxidase revealed that this pretectal nucleus receives direct input from the contralateral eye. 3. All but 2 of the 48 cells of the nLM were strongly DS. The most effective stimulus was a slowly moving complex visual pattern that drifted nasally in the contralateral visual field. Brief flashes of spots, patterns, or diffuse light were much less effective. Receptive fields were large and usually (9 of 13 cells) centered in the superior visual field near the horizon and nasal to the blind spot. 4. The visual responses of nLM cells were compared to those of cells in the superficial layers of the optic tectum. In contrast to nLM, the responses of tectal cells were heterogeneous and frequently not DS. Neither tectum or nLM cells had much spontaneous spike activity during darkness or stationary patterns. On the other hand, visual responses of nLM cells were very similar to those of the BON, where neurons also had low spontaneous activity, preferred slow-moving patterns, and were DS. However, nLM and BON exhibit different distributions of preferred directions. Most nLM cells preferred temporal-to-nasal motion, whereas BON cells preferred almost any direction, although few preferred the nasal direction. nLM cell responses were not affected by removal of the ventral brain stem including the BON. 5. The visual properties of nLM cells recorded in vitro were very similar to those that were recorded in intact turtles.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Highly potent, orally active diester macrocyclic human renin inhibitors.

Replacing one amide bond in macrocyclic renin inhibitors of the general structure 1 and 2 with an ester linkage gave glutamate-derived inhibitors 3 and serine-derived inhibitors 4. While this oxygen-for-nitrogen exchange had little effect on potency in the glutamate series, potency was dramatically increased in the serine series. In this series, the 14-membered ring compounds proved to be more potent than the corresponding 13-membered ring derivatives. Substitution of the ring at the position corresponding to P2' generally increased potency. The absolute configuration at this center was shown to be R for the 4-morpholinomethyl derivative (4o), both by asymmetric synthesis and X-ray crystallography. Replacing the "Boc-Phe" moiety of inhibitor 4o with a variety of substituents led to subnanomolar inhibitors, one of which (the "3(S)-quinuclidinyl-Phe" derivative 33) lowered blood pressure 20 mmHg and completely inhibited plasma renin activity for 6 h in sodium-depleted rhesus monkeys. This compound proved to have limited bioavailability (1% in rats) due to cleavage of the serine ester bond and rapid hepatic extraction.

Administration, Oral↗
PubMed1991

The effect of the partition locus on plasmid stability and expression of a prolonged chemostat culture.

The stability, copy number, and gene expression of the pBR322 plasmid containing the par-locus under prolonged cultivation were studied. In the initial stage of the experiment it was observed that the par-locus had a stabilization effect on plasmid maintenance. This observation was consistent with previously reported results. However, after approximately 225 h, a mixed population of plasmid-containing and plasmid-free cells appeared. The mixed culture was stably maintained for approximately 200 h. In addition, the relative plasmid copy number showed an increase as compared to the par- culture. After 100 h the copy number decreased, reached a minimum, then stabilized. The beta-lactamase activity, was not significantly affected by the par-locus.

Base Sequence↗