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Biomedical subjects

R L Williams

Publications and source records attributed to R L Williams.

At least 181 records · Page 10Linked to original sources
PubMed1993

Use of antibiotics in preventing recurrent acute otitis media and in treating otitis media with effusion. A meta-analytic attempt to resolve the brouhaha.

OBJECTIVE: To determine the efficacy of antibiotics for prophylaxis of recurrent otitis media and treatment of otitis media with effusion (OME) in children. DATA SOURCES: MEDLINE from 1966 through April 1993, textbooks, Current Contents, and bibliographies of selected articles. STUDY SELECTION: Thirty-three studies initially identified were reviewed by three blinded reviewers assessing study quality and suitability for inclusion. Twenty-seven met inclusion criteria for the meta-analyses. DATA EXTRACTION: We abstracted quantitative data and calculated rate differences (RDs) using tympanometry as the preferred outcome measure. DATA SYNTHESIS: Nine studies of antibiotic prophylaxis of recurrent otitis media with 958 subjects had an RD of 0.11 (95% confidence interval [Cl], 0.03 to 0.19) favoring antibiotic treatment. Twelve studies of short-term patient outcomes of OME with 1697 subjects had an RD favoring antibiotics of 0.16 (95% Cl, 0.03 to 0.29), while eight studies using the ear as the outcome measure with 2052 ears studied had an RD of 0.25 (95% Cl, 0.10 to 0.40). No significant difference was shown between placebo and antibiotics (RD, 0.06; 95% Cl, -0.03 to 0.14) in the eight studies of longer-term outcome of OME. Subgroup analyses by antibiotic grouping, duration of treatment, and duration of disease did not show significant differences. CONCLUSIONS: Antibiotics appear to have beneficial but limited effect on recurrent otitis media and short-term resolution of OME. Longer-term benefit for OME has not been shown. The findings are limited by the failure of most studies to consider potential confounders and by inability to identify groups of patients most likely to benefit.

Acute Disease↗
PubMed1993

Crystal structure of human immunodeficiency virus type 1 reverse transcriptase complexed with double-stranded DNA at 3.0 A resolution shows bent DNA.

The crystal structure of a ternary complex of human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) heterodimer (p66/p51), a 19-base/18-base double-stranded DNA template-primer, and a monoclonal antibody Fab fragment has been determined at 3.0 A resolution. The four individual subdomains of RT that make up the polymerase domains of p66 and p51 are named fingers, palm, thumb, and connection [Kohlstaedt, L. A., Wang, J., Friedman, J. M., Rice, P. A. & Steitz, T. A. (1992) Science 256, 1783-1790]. The overall folding of the subdomains is similar in p66 and p51 but the spatial arrangements of the subdomains are dramatically different. The template-primer has A-form and B-form regions separated by a significant bend (40-45 degrees). The most numerous nucleic acid interactions with protein occur primarily along the sugar-phosphate backbone of the DNA and involve amino acid residues of the palm, thumb, and fingers of p66. Highly conserved regions are located in the p66 palm near the polymerase active site. These structural elements, together with two alpha-helices of the thumb of p66, act as a clamp to position the template-primer relative to the polymerase active site. The 3'-hydroxyl of the primer terminus is close to the catalytically essential Asp-110, Asp-185, and Asp-186 residues at the active site and is in a position for nucleophilic attack on the alpha-phosphate of an incoming nucleoside triphosphate. The structure of the HIV-1 RT/DNA/Fab complex should aid our understanding of general mechanisms of nucleic acid polymerization. AIDS therapies may be enhanced by a fuller understanding of drug inhibition and resistance emerging from these studies.

Base Sequence↗
PubMed1993

Mice with a null mutation of the TGF alpha gene have abnormal skin architecture, wavy hair, and curly whiskers and often develop corneal inflammation.

Mice homozygous for a disrupted transforming growth factor alpha (TGF alpha) gene are healthy and fertile, although some older mice show evidence of corneal inflammation. In contrast with TGF alpha +/- and +/+ animals, TGF alpha -/- mice have a pronounced waviness of the coat. Histological examination of the skin from TGF alpha -/- mice reveals a dramatic derangement of hair follicles. Mice with a disrupted TGF alpha gene also have curly whiskers, first evident on the day of birth. The phenotype of TGF alpha -/- mice is remarkably similar to that of the mouse mutant waved-1 (wa-1). Offspring resulting from crosses between TGF alpha -/- and wa-1 mice display the curly whisker-coat phenotype, indicating that the basis of the wa-1 phenotype is a mutation in the TGF alpha gene. These observations suggest that TGF alpha plays a pivotal role in determining skin architecture and in regulating hair development.

Animals↗
PubMed1993

Structure determination of antiviral compound SCH 38057 complexed with human rhinovirus 14.

SCH 38057 (1-[6-(2-chloro-4-methoxyphenoxy)-hexyl]imidazole hydrochloride) is a new, water-soluble antiviral compound that has inhibitory activities against a number of picornavirus infections. The structure of the human rhinovirus 14 (HRV14) complex with SCH 38057 was determined at 3.0 A resolution by single-crystal diffraction techniques using synchrotron X-radiation. SCH 38057 was found to bind at the innermost end of the hydrophobic pocket within the capsid protein VP1, a locus of binding of other antipicornaviral agents; however, the complex differs from previously reported complexes in two important aspects. It leaves a considerable volume near the entrance to the binding pocket unoccupied. In addition, the alterations in the conformation of the VP1 polypeptide are similar to, but more extensive than those observed in HRV14 complexes with other antiviral agents. Although only 9 amino acids of VP1 have close contacts with the SCH 38057 molecule (within 3.6 A), at least 36 amino acids from both VP1 and VP3 have significantly altered conformations (C alpha movement > 0.5 A versus native). The structures of complexes of HRV14 with SCH 38057 and WIN 51711 are compared. Aromatic ring interactions between picornavirus capsid residues and antiviral inhibitors are proposed to be among the major determinants for positioning of these compounds.

Antiviral Agents↗
PubMed1993

Circadian variation in tolerance to the hypothermic action of CNS drugs.

Male SAF mice (30-35 g) or male Sprague-Dawley rats (180-250 g) were used to study the circadian variation in tolerance to the hypothermic action of ethanol, apomorphine, and nicotine. Animals were treated for 2 or 3 consecutive days during the light phase (1000, 1400, or 1800 h) or the dark phase (2200, 0200, or 0600 h) and hypothermia produced measured. In one experiment, repeated injections of 20% ethanol (3 g/kg, IP) to mice resulted in varying degrees of hypothermia depending upon the time of injection. Tolerance to hypothermic action was observed only in animals treated during the light phase. On the contrary, the hypothermic response in animals treated during the dark phase increased. In another experiment, apomorphine (15 mg/kg, IP) was used and tolerance to apomorphine-induced hypothermia observed following repeated injections during the light phase with maximum tolerance noticed at 1400 h. In the third experiment, nicotine (2 mg/kg, IP) was repeatedly administered and resulted in tolerance development when given during the light phase. These results indicate that the rapid development of tolerance to CNS drugs studied is a diurnally controlled phenomenon.

Animals↗
PubMed1993

Non-invasive magnetic resonance imaging of the soft tissue response to a biomaterial.

Magnetic resonance imaging (MRI) has been employed to visualize the tissue response to hydrogel implants in rats. High contrast MR images of the implant site were obtained. Distinct tissue variations in the MR images have been observed. These can be attributed to either the surgical procedure or the application of a tissue irritant to produce inflammation and have been verified histologically. This study demonstrates that MRI is potentially a useful tool for the non-invasive in-vivo evaluation of biomaterials.

Animals↗
PubMed1993

Long-term mortality of Nazi concentration camp survivors.

Nazi concentration camp survivors have been shown to have excess mortality in the first 20 years following their release. To determine if this excess persists, Israeli civil servants were studied. Mortality of camp survivors and of other post-war European immigrants was compared 20-41 years following World War II. Using survival analysis and proportional hazards models, no difference in mortality rates was found.

Adult↗
PubMed1993

Neurological reactions in HIV-infected patients treated with trichosanthin.

Trichosanthin is a ribosome-inactivating protein that is being studied as a possible treatment for patients infected with human immunodeficiency virus (HIV). We report the clinical and pathological features in two patients who experienced neurological reactions to trichosanthin. Both patients were neurologically asymptomatic prior to treatment but developed coma and multifocal neurological deficits after treatment. Neuropathological examination revealed regions of severe, multifocal necrosis with histiocytic infiltrates. These reactions to trichosanthin may be mediated by soluble factors released by HIV-infected macrophages.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Haloperidol effects on the developing dopamine system: conflicting results and implications for neurobehavioral teratology research.

In an attempt to further develop basic principles to guide research in neurobehavioral teratology, six experiments were conducted to examine the effects of prenatal haloperidol (a D2 dopamine antagonist) exposure on striatal D1 and D2 binding sites. Another laboratory has repeatedly reported that prenatal exposure to this dopamine antagonist reduces striatal dopamine binding sites in exposed offspring. Our initial studies were successful in replicating and extending these previously reported reductions in D2 dopamine binding sites in caudate of rats exposed prenatally to haloperidol. However, additional experiments in our laboratory, in which pups were exposed to a range of haloperidol doses over gestational periods when the dopamine system has been reported to be most vulnerable to prenatal haloperidol exposure effects, have repeatedly failed to replicate our initial findings. Three other laboratories have also failed to duplicate this effect. The results of these studies suggest that beyond "standard" confounding variables, neurobehavioral teratologists are faced with as yet poorly understood factors that influence replication of findings within and between laboratories. These findings also emphasize the importance of within- and between-laboratory replication of experimental findings.

Animals↗
PubMed1993

Ratio estimates, the delta method, and quantal response tests for increased carcinogenicity.

This paper demonstrates the use of the delta method for estimating the variance of ratio statistics derived from animal carcinogenicity experiments. The Cochran-Armitage test (Cochran, 1954, Biometrika 10, 417-451; and Armitage, 1955, Biometrics 11, 375-386) is routinely applied to carcinogenicity data as a test for linear trend in lifetime tumor incidence rates. The computing formula for this test derives from the assumption that the denominators of the quantal response rates are fixed. However, when time-at-risk weights are introduced to correct for treatment-related differences in survival, the denominators of the quantal response rates are subject to random variation. The delta method and weighted least squares techniques are applied here to approximate the variance of such ratio statistics and test for a linear dose-response relationship among treatments. This technique is compared to that of Bailer and Portier (1988, Biometrics 44, 417-431), who introduced a survival-adjusted quantal response test for trend in lifetime tumor incidence rates. Their test modifies the usual Cochran-Armitage computing formula by weighting the denominators of the response rates to reflect less-than-whole-animal contributions to risk. Within the framework of a weighted least squares linear regression model that underlies the Cochran-Armitage test, the time-at-risk weights of Bailer and Portier are incorporated using the delta method. Although the delta method approach is slightly more computationally intensive, small-sample simulations indicate that it has superior operating characteristics over the Poly-3 trend test of Bailer and Portier when background tumor incidence rates are low (under 3%) and survival patterns differ markedly across treatments.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1992

The intrinsic helix-forming tendency of L-alanine.

Conformational energy calculations have been carried out for three hexadecapeptides in water--namely, a copolymer with the sequence acetyl-AAAAKAAAA-KAAAAKA-amide, 3K(I), in both the charged and neutral forms; a neutral peptide with the sequence acetyl-AAQAAAAQAAAAQAAY-amide, AQY; and a 16-residue L-alanine homopolymer with acetyl and amide terminal groups. The conformational energy was a sum of the empirical conformational energy program for peptides (ECEPP/2) potential energy plus continuum hydration free energy. An empirical (JRF) parameter set was used for the hydration free energy, together with an electrostatic contribution to the solvent effect from charged lysines. The computed relatively high helix content of the most probable conformation of charged 3K(I) and the intermediate helix content of AQY agree reasonably well with experimental values. The computed very low helix content of the alanine homopolymer agrees with experiments on block copolymers and on host-guest random copolymers. The calculations suggest that the high helix content computed for 3K(I) is due to the sum of internal and hydration free energies of the lysine residues rather than to a high intrinsic helix-forming tendency of alanine. The principal component lowering the computed helix contents of AQY and the alanine copolymer relative to 3K(I) is hydration.

Acetylation↗
PubMed1992

Structure of HIV-1 reverse transcriptase/DNA complex at 7 A resolution showing active site locations.

AIDS, caused by human immunodeficiency virus (HIV), is one of the world's most serious health problems, with current protocols being inadequate for either prevention or successful long-term treatment. In retroviruses such as HIV, the enzyme reverse transcriptase copies the single-stranded RNA genome into double-stranded DNA that is then integrated into the chromosomes of infected cells. Reverse transcriptase is the target of the most widely used treatments for AIDS, 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxyinosine (ddI), but resistant strains of HIV-1 arise in patients after a relatively short time. There are several nonnucleoside inhibitors of HIV-1 reverse transcriptase, but resistance to such agents also develops rapidly. We report here the structure at 7 A resolution of a ternary complex of the HIV-1 reverse transcriptase heterodimer, a monoclonal antibody Fab fragment, and a duplex DNA template-primer. The double-stranded DNA binds in a groove on the surface of the enzyme. The electron density near one end of the DNA matches well with the known structure of the HIV-1 reverse transcriptase RNase H domain. At the opposite end of the DNA, a mercurated derivative of UTP has been localized by difference Fourier methods, allowing tentative identification of the polymerase nucleoside triphosphate binding site. We also determined the structure of the reverse transcriptase/Fab complex in the absence of template-primer to compare the bound and free forms of the enzyme. The presence of DNA correlates with movement of protein electron density in the vicinity of the putative template-primer binding groove. These results have important implications for developing improved inhibitors of reverse transcriptase for the treatment of AIDS.

Base Sequence↗
PubMed1992

Dose-dependent effects of betaxolol in hypertension: a double-blind, multicenter study.

This study determined the dose-response relationship among three doses of betaxolol compared with placebo in patients with mild-to-moderate hypertension. In this double-blind, placebo-controlled trial, 317 hypertensive patients were randomly assigned to receive placebo or betaxolol 5, 10, or 20 mg once daily for 4 weeks. A significant (P less than .05) decrease in supine diastolic blood pressure (BP) compared with concurrent placebo was evident with all three doses of betaxolol after 1 week of active treatment. Each dose of betaxolol maintained a significant reduction in diastolic and systolic BP and heart rate responses throughout the 4-week treatment period. At the fourth week (final treatment evaluation), BP and heart rate were significantly (P less than .05) reduced by all three doses of betaxolol compared with placebo. For supine systolic and diastolic BP, the decreases with betaxolol 20 mg were significantly (P less than .05) greater than with the 5 mg dose, but there was no statistically significant difference between the 10-mg and either the 5- or 20-mg doses. For standing diastolic BP, the effect of betaxolol 5 mg once daily was significantly (P less than .05) less than that of 10 and 20 mg. The overall supine diastolic BP response to betaxolol was dose dependent, and more patients responded to the 10- and 20-mg doses of betaxolol (66% and 76%, respectively) than to the 5-mg dose (59%). For each efficacy variable, the absolute magnitude of the reduction was greater with increasing dose. In subgroup analyses, BP responses were analyzed by race, age, baseline BP, and age combined with baseline BP.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Bioequivalence of racemic drugs.

Although pharmacokinetic and pharmacodynamic differences between the enantiomers of a chiral drug have been known or suspected for many years, racemate drugs have frequently been developed and approved without clinical pharmacologic consideration of their chiral components. In the late 1970s, the technology to isolate, manufacture, and detect pure enantiomers of racemate drugs became generally available. This availability has created new demands on both pharmaceutical firms and regulatory agencies. To prepare for this new technology, the Center for Drug Evaluation and Research at the Food and Drug Administration is formulating a policy statement to guide evaluation of new chiral drugs. At this time, it appears that whatever new policies are developed will not necessarily be applied retroactively to previously approved racemate drugs. Additional policies to guide the development and approval of generic and OTC chiral drugs may be required. In the Office of Generic Drugs in the Center, abbreviated new drug or antibiotic applications are approved on the basis of adequate chemistry, manufacturing, and control procedures and comparative pharmacokinetics (bioequivalence). The generic drug must be a racemate or single enantiomer if the corresponding innovator drug is a racemate or single enantiomer respectively. Whether a generic firm will be required to provide bioequivalence information on enantiomers of a racemate is determined on a case-by-case basis. Although it might be claimed that a generic drug product should be required only to undergo the same general kind of pharmaceutical evaluation as did the innovator, there may be instances when the approval of a generic drug or antibiotic will require measurement of specific enantiomers of a chiral drug.

Drug Approval↗
PubMed1992

Dosage regimen design: pharmacodynamic considerations.

Pharmacokinetic methodology to define the time course of drug in an accessible biologic fluid is now well established as are models that relate concentration to effect. When steady-state conditions are not readily available to define a dose- or concentration-effect relationship, non-steady-state pharmacokinetic/pharmacodynamic models can be applied. Despite these methodologic advances, many aspects of clinical drug development and therapy do not readily lend themselves to pharmacokinetic/pharmacodynamic scrutiny. Barriers to this scrutiny include: drug assay problems or lack of an accessible biologic fluid that can be sampled to measure drug concentration; lack of a immediate pharmacologic effect in the clinic that can be related to concentration; and lack of a relationship between an immediate measurable pharmacologic effect and long-term clinical benefit. In the evaluation and application of any drug, the following questions are useful: 1) what is the pharmacologic effect of interest? 2) is it a positive (benefit) or negative (risk) effect? 3) are there more than one positive or negative effects of interest? 4) how is the effect measured and can the measurement be applied reasonably in a clinical setting? 5) is the effect immediate (for example, blood pressure reduction) or long-term (for example, prevention of stroke with an antihypertensive)? 6) can the effect be usefully related to a concentration to guide dosimetry? and 6) if a concentration/effect relationship is likely, can it be defined at steady state or must non-steady-state pharmacokinetic/pharmacodynamic models be constructed?(ABSTRACT TRUNCATED AT 250 WORDS)

Humans↗
PubMed1992

Empirical solvation models in the context of conformational energy searches: application to bovine pancreatic trypsin inhibitor.

Continuum solvation models that estimate free energies of solvation as a function of solvent accessible surface area are computationally simple enough to be useful for predicting protein conformation. The behavior of three such solvation models has been examined by applying them to the minimization of the conformational energy of bovine pancreatic trypsin inhibitor. The models differ only with regard to how the constants of proportionality between free energy and surface area were derived. Each model was derived by fitting to experimentally measured equilibrium solution properties. For two models, the solution property was free energy of hydration. For the third, the property was NMR coupling constants. The purpose of this study is to determine the effect of applying these solvation models to the nonequilibrium conformations of a protein arising in the course of global searches for conformational energy minima. Two approaches were used: (1) local energy minimization of an ensemble of conformations similar to the equilibrium conformation and (2) global search trajectories using Monte Carlo plus minimization starting from a single conformation similar to the equilibrium conformation. For the two models derived from free energy measurements, it was found that both the global searches and local minimizations yielded conformations more similar to the X-ray crystallographic structures than did searches or local minimizations carried out in the absence of a solvation component of the conformational energy. The model derived from NMR coupling constants behaved similarly to the other models in the context of a global search trajectory. For one of the models derived from measured free energies of hydration, it was found that minimization of an ensemble of near-equilibrium conformations yielded a new ensemble in which the conformation most similar to the X-ray determined structure PTI4 had the lowest total free energy. Despite the simplicity of the continuum solvation models, the final conformation generated in the trajectories for each of the models exhibited some of the characteristics that have been reported for conformations obtained from molecular dynamics simulations in the presence of a bath of explicit water molecules. They have smaller root mean square (rms) deviations from the experimentally determined conformation, fewer incorrect hydrogen bonds, and slightly larger radii of gyration than do conformations derived from search trajectories carried out in the absence of solvent.

Animals↗
PubMed1992

Nocturnal penile tumescence in cigarette smokers with erectile dysfunction.

We examined the relationship between cigarette smoking and erectile physiology in 314 men with erectile dysfunction. All of the men studied were currently cigarette smokers. Evaluations included interviews, physical examinations, and polysomnographic assessment of sleep-related erections. Penile rigidity during nocturnal erection inversely correlated with the number of cigarettes smoked per day. Smoking was also associated with indices of impairment on autonomic function tests and some measures of penile blood pressure. The group of men who smoked the most (more than 40 cigarettes per day) had the fewest minutes of nocturnal tumescence and detumesced fastest. These data are discussed with respect to the results of studies performed in dogs that demonstrated smoking-related reduction in arterial flow and venous restriction. Our findings suggest that smoking may further compromise penile physiology in men experiencing difficulty in maintaining erections long enough for satisfactory intercourse.

Adult↗