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Biomedical subjects

K Williams

Publications and source records attributed to K Williams.

At least 253 records · Page 14Linked to original sources
PubMed1996

Dynamic mechanical thermal analysis of denture soft lining materials.

The purpose of this study was to characterize the deformation properties of a range of long-term denture soft lining materials using dynamic mechanical thermal analysis. Specimens were subjected to sinusoidal shear deformation at a frequency of 1 Hz and a strain of 64 microns peak to peak over a temperature range of 30-70 degrees C. The technique simulated the type and rate of deformation soft lining materials would experience clinically, thus producing more relevant results than previously used methods. Shear modulus G', dissipative modulus G' and mechanical loss tangent G'/G' were obtained for each material. With increasing temperature the moduli of the acrylic materials decreased, indicating an increased compliance and greater deformation. The silicone (Molloplast B) and alternative formulation (Novus) properties were generally insensitive to temperature over the range chosen. The mechanical loss tangent values of the acrylics fell continuously with temperature, suggesting that the plasticization process lowered the Tg values below 30 degrees C, the lowest temperature of testing.

Acrylates↗
PubMed1996

IL-10 production by adult human derived microglial cells.

Microglia, a population of central nervous system (CNS) macrophages, have been demonstrated to support immune accessory and effector functions in the CNS. Numerous studies support the role of microglia in CNS development and pathology, where activation of microglia is consistently noted. The current study investigated microglial immune functions under basal and activation conditions and assessed the ability of interleukin-10 (IL-10), added exogenously or produced by microglia, to down-regulate microglial functions. This report demonstrates that microglia from the adult human brain produce IL-10 following interferon-gamma/lipopolysaccharide activation. Functionally, recombinant human IL-10 down-regulated basal HLA-DR expression by microglia and inhibited, in a dose-dependent response, the ability of microglia to stimulate CD4+ T-cells in antigen presentation assays. These data, together with recent observations of the inhibition of experimental allergic encephalomyelitis (EAE) following IL-10 administration and reduced CNS infection by Listeria monocytogenes after anti-IL-10 treatment, suggest that IL-10 production by microglia may have important immune-regulatory functions in CNS disease and disease models.

Adult↗
PubMed1996

Colonization with antibiotic-resistant Streptococcus pneumoniae in children with sickle cell disease.

OBJECTIVE: Because of susceptibility to severe pneumococcal infection, children with sickle cell disease (SCD) routinely receive penicillin prophylaxis. Increasing rates of penicillin resistance have been reported throughout the world. Our objective was to assess the prevalence of nasopharyngeal colonization with Streptococcus pneumoniae and to assess the antimicrobial susceptibility of the organisms in children with SCD. STUDY DESIGN: Nasopharyngeal cultures for S. pneumoniae were obtained from all children with SCD attending clinics in a statewide university-based network. Background colonization rates were determined in children attending day care centers in some of the same locations. All recovered S. pneumoniae organisms were tested for susceptibility to penicillin, and all resistant strains were examined for susceptibility to other antibiotics. RESULTS: Overall nasopharyngeal pneumococcal colonization rates among children with SCD were 12%. Colonization was associated with age less than 2 years (p <0.001) and day care attendance for more than 20 hr/wk (p = 0.00005). More than half of these strains (62%) were resistant to penicillin, 33% having intermediate resistance (minimal inhibitory concentration 0.06 to 1 microgram/ml) and 29%, high level resistance (minimal inhibitory concentration > or = 2.0 microgram/ml). Penicillin resistance was associated with penicillin prophylaxis (p <0.01). Many of these organisms were also resistant to other classes of antibiotics. CONCLUSIONS: Although penicillin prophylaxis and pneumococcal vaccine for patients with SCD have reduced overall nasopharyngeal colonization and disease caused by S. pneumoniae (p <0.001), a higher percentage of colonizing strains are now resistant both to penicillin and to other antimicrobial agents (p <0.01). Newer strategies for preventing disease and early management of suspected pneumococcal infection in these children must be developed.

Anemia, Sickle Cell↗
PubMed1996

Malpractice claims against emergency physicians in Massachusetts: 1975-1993.

This study reviewed 549 malpractice claims filed against emergency physicians in Massachusetts from 1975 through 1993, with a total of $39,168,891 of indemnity and expense spent on the 549 closed claims. High-risk diagnostic categories (chest pain, abdominal pain, wounds, fractures, pediatric fever/meningitis, epiglottitis, central nervous system bleeding, and abdominal aortic aneurysm) accounted for 63.75% of all closed claims and 64.23% of the total indemnity and expense spent on closed claims. Missed myocardial infarction (chest pain) claims accounted for 25.47% of the total cost of closed claims but only 10.38% of closed claims. The number of claims for missed myocardial infarction increased in the post-1988 closed claim group compared to the pre-1988 group; fractures and wounds were significantly less frequent in the post-1988 group. The frequency of high-risk claims decreased in the post-1988 group, largely because of the decline in fracture and wound claims. The category of missed myocardial infarction had a larger percentage of claims closed with indemnity payment than without indemnity payment. This parameter may serve as a marker for the overall seriousness of claims associated with a particular allegation, unlike the average cost per claim, which may be skewed by a few large awards.

Diagnostic Errors↗
PubMed1996

Cytometric analysis and maturation characteristics of reticulocytes from myelodysplastic patients.

Myelodysplasia is characterized by a hypoproliferative anaemia with ineffective intramedullary erythropoiesis. We have used the novel technology of the Bayer H3 analyser to characterize reticulocytes (RNA containing red cells) from 32 MDS patients and 10 elderly normal subjects. In comparison with reticulocytes from normal subjects, those from MDS patients were larger with a lower haemoglobin concentration. Reticulocytes from sideroblastic patients had a lower haemoglobin content and concentration than for refractory anaemia patients but no other differences between FAB subtypes were found. H3 reticulocyte RNA content parameters correlated poorly with those derived by the Sysmex R-1000, particularly in the MDS group. On reticulocyte maturation to red cells MDS patients concentrated haemoglobin more than normal subjects and this was most evident in the sideroblastic group. Platelet depletion of whole blood suggested that large platelets in the sideroblastic group may have partly contributed to this observation. Prospective evaluation of changes towards normal reticulocyte cytometric parameters may assist in assessment of early erythroid response to therapy in MDS patients.

Adult↗
PubMed1996

Comparison of standardized patients and faculty in teaching medical interviewing.

PURPOSE: This randomized controlled study compared the interviewing skills of first-year medical students receiving feedback primarily from standardized patients (SPs) with those of students receiving feedback primarily from faculty. METHOD: All 154 first-year students at the University of Oklahoma College of Medicine in 1993-94 were video-taped to assess baseline and post-instruction interviewing skills. All the students, randomized to one of three study groups, attended two four-hour workshops on interviewing skills. Instruction in the groups was as similar as possible except in the matter of who provided feedback. Two rating systems were used to rate the videotaped interviews for performances of targeted skills. RESULTS: Complete, usable data were available for 120 (78%) of the students. Skill ratings using the Arizona Clinical Interview Rating Scale were significantly higher for the "types of questions used" and "use of empathy" items in the SP-led feedback group. No significant difference in ratings was detected among the groups as measured by the Rotor Interactional Analysis System. CONCLUSION: The SPs were at least as effective as the faculty in effecting behavioral changes in the first-year medical students' interviewing skills.

Education, Medical, Undergraduate↗
PubMed1996

Cerebral palsy: effects of twinning, birthweight, and gestational age.

AIMS: To determine the effects of birthweight and gestational age on the risk of cerebral palsy for multiple and singleton births. METHODS: Children on the North East Thames Regional Health Authority Interactive Child Health System, born between 1 January 1980 and 31 December 1986, and notified as having cerebral palsy, were included. Cases of postneonatal onset, of known progressive, or non-cerebral pathology and with only mild signs were excluded. Rates and relative risks were calculated using the most complete data, which related to 1985-86, and comprised 102,059 singletons and 2367 twins. Logistic regression was used to examine the associations between being a twin, gestational age, and birthweight. RESULTS: The crude rate per 1000 survivors at 1 year of age was 1.0 in singletons and 7.4 in twins. The relative risk was greatest in twins weighing more than 2499 g (4.5). However, after adjusting for reduced birthweight of twins it was the relative risk of twins weighing less than 1400 g that was significantly increased. Logistic regression confirmed that lower fetal growth, lower gestational age, and being a twin are all independent risk factors for cerebral palsy. CONCLUSION: The increased risk to twins of cerebral palsy is not entirely explained by their increased risk of prematurity and low birthweight.

Birth Weight↗
PubMed1996

An aspartate residue in the extracellular loop of the N-methyl-D-aspartate receptor controls sensitivity to spermine and protons.

To study the role of acidic residues in modulation of NMDA receptors by spermine, we used site-directed mutagenesis of receptor subunits and voltage-clamp recording in Xenopus oocytes. Sixteen glutamate and aspartate residues, located in the first two thirds of the putative extracellular loop of the NR1A subunit, were individually mutated. This region of NR1A shows homology with bacterial amino acid binding proteins, a bacterial polyamine binding protein, and a bacterial spermidine acetyltransferase. Mutation of D669 to asparagine (D669N), alanine (D669A), or glutamate (D669E) abolished the "glycine-independent" form of spermine stimulation in heteromeric NR1A/NR2B receptors. These mutations also markedly reduced inhibition by ifenprodil and by protons at NR1A/NR2B receptors. Mutations at the equivalent position (D690) in NR1B, which contains the insert encoded by exon 5, reduced the pH sensitivity of NR1B/NR2B receptors. Thus, the effects of mutations at D669 are not prevented by the presence of exon 5, and the influence of exon 5 is not prevented by mutations at D669 (D690 in NR1B). Mutations at NR1A (D669) had little or no effect on the potencies of glutamate and glycine and did not alter voltage-dependent block by Mg2+ or the "glycine-dependent" form of spermine stimulation. Surprisingly, the D669N and D669A mutations, but not the D669E mutation, reduced voltage-dependent block by spermine at NR1A/NR2 receptors. Mutations in NR2B at a position (D668) equivalent to D669 did not alter spermine stimulation or sensitivity to pH and ifenprodil. However, mutations D668N and D668A but not D668E in NR2B reduced voltage-dependent block by spermine. Screening of the negative charges at NR1A(D669) and NR2B(D668) may be involved in voltage-dependent block by spermine. D669 in NR1A could form part of a binding site for polyamines and ifenprodil and/or part of the proton sensor of the NMDA receptor. Alternatively, this residue may be critical for coupling of modulators such as spermine, protons, and ifenprodil to channel gating.

Amino Acid Sequence↗
PubMed1996

Activation of N-methyl-D-aspartate receptors by glycine: role of an aspartate residue in the M3-M4 loop of the NR1 subunit.

Glutamate and glycine are coagonists that act at distinct sites to activate N-methyl-D-aspartate (NMDA) receptors. In the NR1 subunit of the NMDA receptor, mutation of D732 to glutamate (D732E), asparagine (D732N), alanine (D732A), or glycine (D732G) reduced the potency of glycine by > 4000-fold, but these mutations had no effect on sensitivity to glutamate. Mutations at NR1(D732) also changed sensitivity to the glycine-site agonists D-serine and D-alanine, reducing the potencies and, in some cases, the efficacies of these compounds. Thus, D-serine was a full agonist at the glycine site of receptors containing NR1(D732N) and NR1(D732A), a partial agonist at receptors containing NR1(D732G), and a competitive antagonist at receptors containing NR1(D732). Mutations at NR1(D732) had no effect or produced an increase in sensitivity to the glycine-site antagonists 6,7-dichloroquinoxaline-2,3-dione and 5,7-dichlorokynurenic acid. These mutations did not affect the reversal potential, voltage-dependent block by extracellular Mg2+, block by ifenprodil, or stimulation by spermine at NR1/NR2B receptors. NR2 subunits containing mutations at NR2A(D731) and NR2B(D732), which correspond to NR1(D732), did not produce functional receptors when coexpressed with NR1. Residue D732 in NR1 may be close to a glycine binding site on the NMDA receptor and may directly affect the properties of this site or be critical for coupling of glycine binding to channel activation.

Amino Acid Sequence↗
PubMed1995

Potent in vitro and in vivo inhibitors of platelet aggregation based upon the Arg-Gly-Asp sequence of fibrinogen. (Aminobenzamidino)succinyl (ABAS) series of orally active fibrinogen receptor antagonists.

Our initial orally active fibrinogen receptor antagonist benzamidinopentanoyl (BAP) series which was discovered through truncation of our i.v. antiplatelet agent (SC-52012) demonstrated modest oral activity in canine studies (ethyl [5-(4-amindinophenyl)pentanoyl]-3-amino-3-(3-pyridyl)propionate, 1e). Introduction of an amide bond adjacent to the benzamidine led to a novel series with an (aminobenzamidino)succinyl (ABAS) Arg-Gly surrogate that had improved in vitro potency (5-17 times) relative to the BAP series. Four ester prodrug/acid active metabolite pairs (2a/2e, 60a/60e, 62a/62e, 63a/63e) from the ABAS series which varied in their 3-substituent on the beta-amino ester "aspartate mimetic" were prepared in enantiomerically enriched form (> 95:5), and they were evaluated in canine studies for their ability to block collagen-induced aggregation in platelet-rich plasma, the elimination profile (t1/2 beta-phase), repeated oral dosing studies, and oral systemic availability. Of the four ester prodrug/acid active metabolite pairs, 2e/2a (SC-54684A/SC-54701A) has the most favorable properties in the above studies with an IC50 = 67 +/- 5 nM (dog platelet-rich plasma, collagen), t1/2 beta = 1.6 h (ester) and 6.5 h (acid), no adverse effects upon repeated dosing, and a drug oral systemic availability of 62% (area under curve (AUC) of acid 2a (drug) following ig administration of ester 2e (prodrug, 2.5 mg/kg) divided by AUC of acid 2a (drug) following i.v. administration of ester 2e (prodrug, 2.5 mg/kg) as determined by HPLRC). In further pharmacokinetic studies using nonlabeled 2e/2a, the oral systemic availability (ester 2e ig/ester 2e i.v.) of 2e was measured to be in the range of 44.7-53.0%. The more biologically relevant oral systemic availability (ester 2e ig/acid 2a i.v.) of 2e was found to be in the range of 22.0-26.4%. A pharmacophore model based on inhibitors from several different benzamidine classes including 2a (ABAS class) was developed using a combination of molecular modeling (MM2) and pharmacophore identification (APOLLO) methods.

Administration, Oral↗
PubMed1995

Pharmacological properties of recombinant N-methyl-D-aspartate (NMDA) receptors containing the epsilon 4 (NR2D) subunit.

The modulatory effects of spermine, histamine, and ifenprodil on recombinant N-methyl-D-aspartate (NMDA) receptors expressed from the NR1A and epsilon 4 (NR2D) subunits were studied by voltage-clamp recording in Xenopus oocytes. Spermine had no effect on responses to glutamate and glycine at NR1A/epsilon 4 receptors. None of the four previously described effects of spermine, all of which are seen at NR1A receptors and at NR1A/NR2B receptors, was seen at NR1A/epsilon 4 receptors. Similarly, NR1A/epsilon 4 receptors were insensitive to potentiation by histamine and to blockade by ifenprodil. The properties of NR1A/epsilon 4 receptors thus resemble those of NR1A/NR2C receptors and are markedly different from those of homomeric NR1A receptors. In heteromeric NR1A/epsilon 4 receptors the epsilon 4 subunit may alter properties associated with the NR1A subunit, as has been previously suggested for NR2A, NR2B, and NR2C subunits in NR1A/NR2 receptors.

Animals↗
PubMed1995

Preconditioning with a single short episode of global ischemia in the isolated working rat heart: effect on structure, mechanical function, and energy metabolism for various durations of sustained global ischemia.

PURPOSE: Preconditioning in the setting of global ischemia, using functional recovery during reperfusion as the endpoint, has recently been demonstrated in the isolated perfused rat heart. It has been suggested that its beneficial actions have a metabolic basis. The isolated rat heart has not been fully characterized with respect to the metabolic, functional, and structural changes associated with this phenomenon in the setting of global ischemia. The purpose of this study was to determine (1) the time course of protection conferred by a single episode (5 minutes) of preconditioning; (2) changes in tissue high energy phosphates, lactate, and glycogen levels at different time intervals; and (3) morphological appearance of the heart at the end of ischemia as well as after reperfusion. METHODS: Isolated perfused working rat hearts were used. Preconditioning consisted of a single episode of 5 minutes of global ischemia and 15 minutes of reperfusion. Preconditioned and non-preconditioned hearts were subjected to global ischemia of 20-35 minutes duration. Functional recovery, energy metabolism (high energy phosphates, lactate, and glycogen), and structural appearance were studied at different stages. RESULTS: The functional recovery of the preconditioned hearts was significantly higher than in the corresponding nonpreconditioned group during reperfusion for all durations of ischemia longer than 25 minutes. The degree of protection observed was less than reported previously. A minor degree of energy sparing was reflected by differences in the rate of depletion of glycogen and accumulation of tissue lactate during the sustained episode of ischemia. Semiquantitative light microscopy evaluation revealed that ischemia-induced structural damage was less in the preconditioned hearts, both at the end of the sustained ischemic episode as well as after reperfusion. CONCLUSIONS: A single episode of global ischemia successfully preconditions the isolated working rat heart. The protection elicited was demonstrated on a functional and structural level, and was accompanied by a small energy-sparing effect.

Animals↗
PubMed1995

A novel series of orally active antiplatelet agents.

A novel series of orally active fibrinogen receptor antagonists has been discovered through structural modification of our lead intravenous (iv) antiplatelet agent, 5-(4-amidinophenyl)pentanoyl-Asp-Phe 1 (SC-52012). The Asp-Phe amide bond was removed through truncation to a 3-substituted beta-amino acid aspartate mimetic which resulted in a tripeptide mimetic inhibitor of lower molecular weight (from 482 to the 330-390 g mol-1). The zwitterionic nature of the inhibitor was masked through the preparation of an ethyl ester prodrug. A lead compound from this series, 5-(4-amidinophenyl)pentanoyl-3-(3-pyridyl)propanoic acid 19a, was found to be a potent inhibitor of canine platelet aggregation in vitro (collagen, platelet rich plasma, PRP, IC50 = 270 nM). In further canine studies, oral administration of different ester pro-drugs of 19a at 10 mg kg-1 resulted in the following oral systemic activities: pivaloyloxymethyl ester derivative 19p (5.1 +/- 1.5% OSA), cyclohexyl ester derivative 19c (9.2 +/- 1.9% OSA), and ethyl ester derivative 19e (9.9 +/- 2.3% OSA).

Administration, Oral↗
PubMed1995

Finite element analysis of stress distribution at the tooth-denture base interface of acrylic resin teeth debonding from the denture base.

Acrylic resin teeth present a problem when they detach unexpectedly from the denture base resin. Detachment is caused by stress concentrations at the tooth/denture base resin interface. In this study, the finite element method was used to examine the stress distribution at this interface when a single static force that resembled incisal bite force was applied. The results indicated that irrespective of the type of acrylic resin teeth used, maximum tensile stresses were found at the palatal aspect of the interface. It is suggested that boxing the tooth in the acrylic resin will help redistribute stress concentrations favorably.

Acrylic Resins↗