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Biomedical subjects

L Williams

Publications and source records attributed to L Williams.

At least 73 records · Page 4Linked to original sources
PubMed1999

Monocyte adhesion and spreading on human endothelial cells is dependent on Rho-regulated receptor clustering.

The GTPase Rho is known to mediate the assembly of integrin-containing focal adhesions and actin stress fibers. Here, we investigate the role of Rho in regulating the distribution of the monocyte-binding receptors E-selectin, ICAM-1, and VCAM-1 in human endothelial cells. Inhibition of Rho activity with C3 transferase or N19RhoA, a dominant negative RhoA mutant, reduced the adhesion of monocytes to activated endothelial cells and inhibited their spreading. Similar effects were observed after pretreatment of endothelial cells with cytochalasin D. In contrast, dominant negative Rac and Cdc42 proteins did not affect monocyte adhesion or spreading. C3 transferase and cytochalasin D did not alter the expression levels of monocyte-binding receptors on endothelial cells, but did inhibit clustering of E-selectin, ICAM-1, and VCAM-1 on the cell surface induced by monocyte adhesion or cross-linking antibodies. Similarly, N19RhoA inhibited receptor clustering. Monocyte adhesion and receptor cross-linking induced stress fiber assembly, and inhibitors of myosin light chain kinase prevented this response but did not affect receptor clustering. Finally, receptor clusters colocalized with ezrin/moesin/ radixin proteins. These results suggest that Rho is required in endothelial cells for the assembly of stable adhesions with monocytes via the clustering of monocyte-binding receptors and their association with the actin cytoskeleton, independent of stress fiber formation.

ADP Ribose Transferases↗
PubMed1999

An aerosol challenge model of Bordetella pertussis infection as a potential bioassay for acellular pertussis vaccines.

Whole cell and five different types of acellular pertussis vaccine were assayed using a mouse aerosol challenge model which permitted delivery of a controlled, consistent dose of Bordetella pertussis to the lower respiratory tract. Using this system, the viable counts in the lungs of vaccinated mice were immunisation dose-dependent and allowed the protective capacity of different vaccine preparations to be distinguished. This model may thus provide the basis for a protection assay for pertussis vaccines. Comparison of acellular vaccines with a whole cell pertussis vaccine showed that the latter gave better active protection in mice but with a different dose-response relationship. Thus the two types of vaccine are not directly comparable in the same assay and require different reference standards. A pentavalent type acellular vaccine is suggested as a possible candidate standard for the acellular vaccine potency test. The results suggest that this aerosol challenge model has potential for use as a potency test for acellular pertussis vaccines.

Aerosols↗
PubMed1999

Evaluation of transmission electron microscopy for examination of components of acellular pertussis and combination vaccines.

New acellular pertussis and combination vaccines vary in the concentration and presence or absence of specific components and in extent of adsorption to adjuvants. There is a pressing need to develop new control methods for acellular pertussis vaccines. Negative staining electron microscopy has been evaluated as a method for assessing the purity of individual vaccine components and the amount of adsorption to aluminium gels. Negative staining showed the characteristic morphology of vaccine components and permitted detection of contaminants and morphological changes. Reproducible results were obtained by use of a standardized negative staining technique and confidence in the technique was increased by comparison of previously unexamined specimens with a specimen that had been characterized by repeated observations. The degree of adsorption to aluminium adjuvants could only be assessed by observation of the amount of non-adsorbed material in the specimen. Negative staining electron microscopy can be used as one of a number of techniques for control of acellular pertussis combination vaccines.

Adsorption↗
PubMed1999

Physico-chemical analysis of Bordetella pertussis antigens.

Physico-chemical methods are being developed for use in the control and standardization of acellular pertussis vaccines and their individual components. We have compared native and detoxified preparations of the B. pertussis antigens, pertussis toxin (PT), filamentous haemagglutinin (FHA), and the 69-kDa outer membrane protein (P69) using circular dichroism (CD), fluorescence spectroscopy, SDS-PAGE and FPLC gel filtration chromatography. Upon aldehyde detoxification, PT underwent a large change in its intrinsic fluorescence maximum (8-10 nm red-shift) and a large increase in its apparent size, detected by chromatography. Polyacrylamide gels showed individual subunits of the same apparent molecular weight (M(r)) as well as some polypeptides of higher M(r). FHA also changed conformation (5-nm red-shift in intrinsic fluorescence) upon aldehyde detoxification, with a resultant increase in the M(r)of its major constituent. The P69 protein appeared quite robust to formaldehyde treatment as measured by the same methods. Its near-UV CD spectrum contains a prominent tryptophan band; so this method may be more suitable for observing differences in conformation. We also examined an aluminium-desorbed DTaP preparation by these methods. When used in conjunction with immunochemical and toxicological assays, these methods are informative and useful in the characterization of candidate standards and should be valuable methods for ensuring the consistency of manufactured vaccines.

Bordetella pertussis↗
PubMed1999

Acute tolerance to methylphenidate in the treatment of attention deficit hyperactivity disorder in children.

OBJECTIVES: To evaluate the efficacy of several drug delivery patterns of methylphenidate and to determine whether acute tolerance develops to this widely used stimulant medication in the treatment of children with attention deficit hyperactivity disorder. METHODS: Double-blind trials were conducted in a laboratory school setting in which multiple measures of efficacy were obtained frequently in the morning and afternoon across the school day. In study I, relative efficacy was determined for three dosing patterns of methylphenidate: a standard twice-daily profile, a flat profile, and an ascending profile. In study II, tolerance was assessed by comparison of three-times-a-day regimens in which the time of the middle dose varied. RESULTS: In study I, the efficacy of the ascending treatment increased across the day, and in the afternoon it was equal to the efficacy of the twice-daily treatment, indicating that an initial bolus was not required for efficacy. The efficacy of the flat treatment declined across the day, and in the afternoon it was significantly less than in the twice-daily treatment, suggesting that tolerance may be developing. In study II, acute improvements in efficacy were reduced to the second of two closely spaced but not to two widely spaced bolus doses, suggesting that shortly after exposure to high concentrations, efficacy is reduced to given concentrations of methylphenidate. In a concentration-effect model, a tolerance term was needed to account for counterclockwise hysteresis. CONCLUSIONS: Acute tolerance to methylphenidate appears to exist. This should be considered in the design of an optimal dosing regimen for the treatment of children with attention deficit hyperactivity disorder.

Analysis of Variance↗
PubMed1999

The relative influence of secondary versus primary prevention using the National Cholesterol Education Program Adult Treatment Panel II guidelines.

OBJECTIVES: This study was undertaken to project the population-wide effect of full implementation of the Adult Treatment Panel (ATP) II guidelines of the National Cholesterol Education Program (NCEP). BACKGROUND: The ATP II has proposed guidelines for cholesterol reduction, but the long-term epidemiologic influence of its components has not been fully examined. METHODS: We used a calibrated, validated simulation of the U.S. population, aged 35 to 84 years to estimate the potential for the NCEP guidelines, under varying assumptions, to reduce coronary heart disease morbidity and mortality and overall mortality from the years 2000 to 2020. RESULTS: Primary prevention would yield only about half of the benefits of secondary prevention despite requiring nearly twice as many person-years of treatment. The projected increase in quality-adjusted years of life per year of treatment for secondary prevention was 3- to 12-fold higher than for primary prevention. To yield population-wide epidemiologic benefits equivalent to NCEP recommendations for secondary prevention, primary prevention would require a nearly sixfold increase in the number of persons treated compared with NCEP recommendations. All benefits of universal success of the NCEP primary prevention "screen and treat" guidelines could be achieved by a 11 mg/dl (8%) population-wide reduction in low-density lipoprotein cholesterol levels among persons without preexisting coronary heart disease. CONCLUSIONS: The NCEP guidelines for targeted primary prevention can be a useful component of a rational public health strategy, but only as a complement to the more appealing strategies of secondary prevention and "across-the-board" programs to lower all cholesterol levels.

Adult↗
PubMed1999

Different psychopathological models and quantified EEG in schizophrenia.

BACKGROUND: This study compared the ability of two different models of psychopathology in schizophrenia to account for findings in the quantified electroencephalogram (qEEG) recorded from midline sites in a group of 40 subjects with schizophrenia. The first model was based on the positive and negative syndrome dichotomy, the second was a tripartite model that resembled Liddle's syndromes of psychomotor poverty, disorganization and reality distortion (Liddle, 1987a). METHODS: A group of 40 subjects with predominantly chronic schizophrenia was assessed with the Positive and Negative Syndrome Scale (PANSS) prior to the acquisition of their quantified electroencephalogram. The relationship between EEG data and symptomatology was explored, initially with the PANSS positive and negative subscales and then with a tripartite model derived From a principal component analysis of the 14 positive and negative subscale items. RESULTS: The tripartite syndrome model showed a greater concordance with the qEEG of the subjects than the dichotomous model. 'Psychomotor poverty' was significantly positively correlated with both delta and beta power and 'reality distortion' was significantly positively correlated with alpha-2 power. No significant correlations between the positive and negative syndrome dichotomy and the qEEG were observed. CONCLUSIONS: This study lends support to the factor analysis of psychopathology, and specifically the tripartite syndrome model of schizophrenia, as a step in explicating the biological dimensions of the disorder.

Adolescent↗
PubMed1999

Intergenerational influence in Singapore and Taiwan: the role of the elderly in family decisions.

This research examines intergenerational decision-making in Singapore and Taiwan. The focus is on elderly individuals and the extent to which they report being involved in influencing important family matters. The data used in the analysis were collected in focus group interviews and household-level surveys of the elderly (defined as ages 60 and over) in Singapore and Taiwan. Both survey samples were national probability samples. Everything else being equal, the extent to which seniors are consulted in family decisions declines with age and failing health in both countries. Whether they live in rural or urban places within Taiwan is also significant, and depending upon the context, socioeconomic variables such as home-ownership, employment status, and education further help predict to what degree the elderly are consulted in family decisions.

Journal Article↗
PubMed1999

A simple in vitro method for the evaluation of an ultrasonic nebulizer for drug delivery to intubated, ventilated patients and the effect of nebulizer and ventilator settings on the uptake of fluid from the nebulizer chamber.

Little is known about the performance of ultrasonic nebulizers during different ventilation patterns when these nebulizers are used to deliver drugs to intubated, ventilated patients. A method that enables the performance of an ultrasonic nebulizer to be evaluated is described. We used an in vitro model to examine the performance of the DeVilbiss Ultra-Neb 2000 ultrasonic nebulizer under positive pressure ventilation. Performance was measured at different rates of nebulization and under changing conditions of positive end-expiratory pressure (PEEP), inspiratory flow rate, inspiratory time and minute volume. The volume of saline nebulized was unchanged by variations in positive end expiratory pressure from 0 to 5 cm to 10 cm H2O, in minute ventilation and in inspiratory flow rate. An increase in the inspiratory time resulted in an increase in the volume of saline nebulized and this volume was greater as the power setting of the nebulizer was increased. We conclude that ultrasonic nebulizers may be affected by different patterns of ventilation and that this simple in vitro assessment of nebulizer function in an intensive care setting may be of value prior to nebulizer use.

Aerosols↗
PubMed1999

Rape attitudes amongst British medical students.

OBJECTIVES: To examine the rape attitudes of a sample of 252 British medical students. DESIGN: A 20-item questionnaire was used. SETTING: A London medical school. SUBJECTS: Fourth-year medical students. RESULTS: In general, students were well informed on legal and factual issues regarding rape and sexual assault. However, significant differences were found in the attitudes to rape between males and females. Female students were significantly more positive in their responses to victims. CONCLUSIONS: These results support findings from previous studies of rape attitudes in other professional groups. Better knowledge and enlightened attitudes amongst health care staff can have a significant impact on the management of sexual assault and influence the likelihood of victims presenting for treatment. In conclusion, this study emphasizes the importance of teaching about sexual violence in British medical schools.

Adult↗
PubMed1999

Should equine athletes commence training during skeletal development?: changes in tendon matrix associated with development, ageing, function and exercise.

In human athletes, conditioning, training and competition are commenced before skeletal maturity. Yet in equine athletics, racing of young (age 2 years) horses remains contentious. Tendon injury persists as major causes of wastage in equine athletes. Minimising injury and associated welfare issues could involve a radical approach to the timing and implementation of conditioning and training. Tendons were examined from Thoroughbreds, Dutch Warmblood foals, working horses and also a group of wild horses to evaluate effects of age, function and exercise. Gross mechanical properties did not differ significantly with age or exercise, but showed a high variance within each group. Mechanical properties of tendon tissue showed significant differences as a function of age and location. The collagen fibril crimp angle and length showed a regional reduction in the central core with exercise and age, with a synergistic effect. Regional differences in collagen fibril diameter were seen in long-term exercised older horses, but not in short-term exercised, or younger, horses. The higher proportion of small fibrils in the central region of the long-term exercised horses did not correlate with new collagen formation and therefore appear to result from disassembly of the larger diameter fibrils. Fibril diameter distributions were influenced by exercise regimens in the growing foal. Changes in molecular composition occurred in longer-term exercise and older horses, in the centre of the tendon, with higher levels of type III collagen and changes in glycosaminoglycan (GAG) content. Cartilage Oligomeric Matrix Protein (COMP) levels also appear to be modulated by age, function and superimposition of exercise. These changes were all exacerbated with age and exercise, suggesting appropriate exercise in young horses may lead to a lower incidence of injury than in older horses. An hypothesis is advanced that immature tendon can respond to exercise while mature tendon has limited, if any, ability to do so. These findings support potentially controversial earlier conditioning and racing of younger, rather than older, equine athletes.

Aging↗
PubMed1999

Epstein-Barr virus encodes a novel homolog of the bcl-2 oncogene that inhibits apoptosis and associates with Bax and Bak.

The sequenced gammaherpesviruses each contain a single viral bcl-2 homolog (v-bcl-2) which may encode a protein that functions in preventing the apoptotic death of virus-infected cells. Epstein-Barr virus (EBV), a gammaherpesvirus associated with several lymphoid and epithelial malignancies, encodes the v-Bcl-2 homolog BHRF1. In this report the previously uncharacterized BALF1 open reading frame in EBV is identified as having significant sequence similarity to other v-bcl-2 homologs and cellular bcl-2. Transfection of cells with a BALF1 cDNA conferred apoptosis resistance. Furthermore, a recombinant green fluorescent protein-BALF1 fusion protein suppressed apoptosis and associated with Bax and Bak. These results indicate that EBV encodes a second functional v-bcl-2.

Amino Acid Sequence↗
PubMed1999

Fetal diuretic responses to maternal hyponatremia: contribution of placental sodium gradient.

Maternal hyponatremia induces fetal hyponatremia and increased fetal urine flow. We sought to examine the relative contributions of the placental Na(+) gradient vs. the absolute decrease in fetal plasma Na(+) in the fetal diuretic response to hyponatremia. Seven ewes with singleton fetuses (130 +/- 2 days) were prepared. Ewes received intravenous 1-desamino-8-D-arginine vasopressin (20 microg) and warm tap water (2 liters). Maternal plasma Na(+) was decreased to achieve two levels of maternal hyponatremia. Maternal and fetal blood volume were measured with radiolabeled red blood cells. In response to the first decrease in maternal plasma Na(+), fetal plasma Na(+) did not change initially. Subsequently, fetal plasma Na(+) decreased, normalizing the gradient. The second decrease in maternal plasma Na(+) similarly induced a reduced and normalized placental gradient at lower fetal plasma Na(+) values. Fetal urine flow increased in direct proportion to the degree of fetal hyponatremia (13, 38, 63, 100%, respectively). Maternal, although not fetal, blood volume significantly increased in response to hyponatremia. These results suggest that chronic fetal hyponatremia will result in a persistent diuresis, despite placental equilibration.

Animals↗
PubMed1999

A database designed for utilization management in diagnostic imaging.

The methods and tools of health services research have been applied to a diverse number of health care areas. Surprisingly, they have been adopted only recently in diagnostic imaging, by a small number of professionals, in response to the severe fiscal constraints and widespread structural changes in the health industry, as well as to a growing concern that the value of social and individual investment in high-cost imaging services could not be validated objectively. As a result of the need for accountability for the use of scarce resources, regulators and payers of health services increasingly demand that a reasoned and objective evaluative process be adopted. To undertake a statistically driven evaluative approach that stands up to objective assessment of methodological rigour, an organized data-collection system is needed. Without this fundamental cornerstone, evaluators are left with little more than anecdotal evidence and professional and personal opinion to guide decision-making. It then becomes difficult to learn from both the successes and failures that are routinely experienced during times of rapid and fundamental change. This article describes the efforts made to integrate health services research in radiology into the routine daily activities and supporting systems of a large academic health system, the Hamilton Health Sciences Corporation and McMaster University Department of Radiology, in an attempt to move in the direction of evidence-based decision-making. The authors hope this will allow others to learn and improve on this work. Radiologists may then move the vast data systems and infrastructure associated with all imaging services to an evidence-based model for managing and guiding the vast resources entrusted to our collective stewardship.

Academic Medical Centers↗
PubMed1999

Mapping HLA for single nucleotide polymorphisms.

Knowledge of DNA sequence variation may help us understand how genetic variability gives rise to functional variability and, in so doing, revolutionize the development of strategies to combat and prevent disease. Single nucleotide polymorphisms (SNPs) are stable, inherited, biallelic, single base pair differences which are present in the human genome at a density of 1 to 10 per 1,000 nucleotides. It is anticipated that SNPs will account for much of the functional heterogeneity in gene expression and protein activity exhibited in the human population. Susceptibility to or protection from a number of diseases, particularly those of autoimmune etiology, has been associated with specific alleles of the human leukocyte antigen (HLA) complex. Interestingly, the precise molecular defects in the HLA genes are unknown and the notion that non-HLA genes, within the same chromosomal region, are involved remains a formal possibility. We have determined the nucleotide sequence of a contiguous 2.2 Mbp segment of chromosome six that includes all of the HLA class I region, and have identified over 10,000 SNPs therein. Because of the derivative knowledge of gene and SNP content and position, the scientific community is now uniquely poised to identify disease-contributory SNPs that lie within the MHC.

HLA Antigens↗