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Biomedical subjects

R L Clark

Publications and source records attributed to R L Clark.

At least 19 recordsLinked to original sources
PubMed2004

Different embryo-fetal toxicity effects for three VLA-4 antagonists.

BACKGROUND: VLA-4 (Very late antigen 4, integrin alpha4beta1) plays an important role in cell-cell interactions that are critical for development. Homozygous null knockouts of the alpha4 subunit of VLA-4 or VCAM-1 (cell surface ligand to VLA-4) in mice result in abnormal placental and cardiac development and embryo lethality. Objectives of the current study were to assess and compare the teratogenic potential of three VLA-4 antagonists. METHODS: IVL745, HMR1031, and IVL984 were each evaluated by the subcutaneous route in standard embryo-fetal developmental toxicity studies in rats and rabbits. IVL984 was also evaluated in mice. Fetuses were examined externally, viscerally, and skeletally. RESULTS: IVL745 did not cause significant maternal or fetal effects at doses up to 100 or 250 mg/kg/day in rats or rabbits, respectively. HMR1031 treatment resulted in marked maternal toxicity and slight fetal toxicity at the highest tested doses of 200 and 75 mg/kg/day in rats and rabbits, respectively. HMR1031 embryo-fetal effects consisted of slightly lower body weight and crown-rump length in rats and minor sternebral defects in rabbits. IVL984 treatment resulted in minimal maternal effects at doses up to 40, 15, and 100 mg/kg/day in rats, rabbits, and mice, respectively (excluding abortions in rabbits). However, marked developmental effects were observed at the lowest tested IVL984 doses, 1, 0.2, and 3 mg/kg/day in rats, rabbits, and mice, respectively. IVL984 embryo-fetal effects consisted of increased total post-implantation loss due to early resorptions and high incidences of cardiac malformations and skeletal malformations and/or variations. Notably, spiral septal defects were observed in up to 76% of rat fetuses and up to 58% of rabbit fetuses. CONCLUSIONS: Dramatic differences in teratogenic potential were observed: IVL745 was not teratogenic, HMR1031 caused slight embryo-fetal effects at maternally-toxic doses, and IVL984 was a potent teratogen at doses where direct maternal toxicity was limited to abortions in rabbits. Prominent effects of IVL984 included embryo lethality and cardiac malformations including spiral septal defects in three species.

Abnormalities, Drug-Induced↗
PubMed2003

A 17-year epidemiological study on changes in lung function in toluene diisocyanate foam workers.

OBJECTIVE: To determine whether longitudinal declines in ventilatory capacity and the occurrence of respiratory symptoms in workers manufacturing polyurethane foam were related to toluene diisocyanate (TDI) exposure. METHODS: A population of workers from 12 UK factories was studied between 1981 and 1986 [8]. A survivor cohort of 251, of whom 217 were in the 1981-1986 study, was examined again in 1997-1998. Modified British Medical Research Council respiratory questionnaires and lung function measurements were completed for each of the 251 subjects at the beginning and end of the 17-year study period. Mean TDI exposures for all jobs in which subjects were employed were assessed and related to their occupational histories. RESULTS: The annual declines in 1-second forced expiratory volume (FEV(1)) and forced vital capacity (FVC) were not related to TDI exposure, and were typical of those measured in other populations not exposed to TDI. Over the study period the cold-foam handling group ( n=26) showed an increase in breathlessness and a significant excess decline in FVC; the exposed group ( n=175) showed an increase in wheezing (mainly smokers), whilst the low-exposure group ( n=50) showed a decrease in chest illness. Smoking and an increase in body weight both caused excess declines in FEV(1). CONCLUSIONS: This study does not provide evidence that there was any TDI-related decline in FEV(1) or in FVC over a 17-year period in workers exposed to TDI at the levels prevailing in the UK factories that manufactured flexible polyurethane foam.

Adult↗
PubMed2001

Noise transmission from a curved panel into a cylindrical enclosure: analysis of structural acoustic coupling.

Much of the research on sound transmission through the aircraft fuselage into the interior of aircraft has considered coupling of the entire cylinder to the acoustic modes of the enclosure. Yet, much of the work on structural acoustic control of sound radiation has focused on reducing sound radiation from individual panels into an acoustic space. Research by the authors seeks to bridge this gap by considering the transmission of sound from individual panels on the fuselage to the interior of the aircraft. As part of this research, an analytical model of a curved panel, with attached piezoelectric actuators, subjected to a static pressure load was previously developed. In the present work, the analytical model is extended to consider the coupling of a curved panel to the interior acoustics of a rigid-walled cylinder. Insight gained from an accurate analytical model of the dynamics of the noise transmission from the curved panels of the fuselage into the cylindrical enclosure of an aircraft is essential to the development of feedback control systems for the control of stochastic inputs, such as turbulent boundary layer excitation. The criteria for maximal structural acoustic coupling between the modes of the curved panel and the modes of the cylindrical enclosure are studied. For panels with aspect ratios typical of those found in aircraft, results indicate that predominately axial structural modes couple most efficiently to the acoustic modes of the enclosure. The effects of the position of the curved panel on the cylinder are also studied. Structural acoustic coupling is found to not be significantly affected by varying panel position. The impact of the findings of this study on structural acoustic control design is discussed.

Journal Article↗
PubMed2001

Adopting hybrid pension plans: financial and communication issues.

This article provides a systematic framework for the evaluation of the movement toward hybrid pension plans by examining the reasons given by firms for converting their existing pension plans to hybrid plans, illustrating the impact of plan changes on expected pension benefits, and identifying winners and losers.

Communication↗
PubMed2001

Inhibition of tumor necrosis factor-alpha (TNF-alpha) production and arthritis in the rat by GW3333, a dual inhibitor of TNF-alpha-converting enzyme and matrix metalloproteinases.

Tumor necrosis factor-alpha (TNF)-converting enzyme (TACE) cleaves the precursor form of TNF, allowing the mature form to be secreted into the extracellular space. GW3333, a dual inhibitor of TACE and matrix metalloproteinases (MMPs), was compared with an anti-TNF antibody to evaluate the importance of soluble TNF and MMPs in rat models of arthritis. Oral administration of GW3333 completely blocked increases in plasma TNF after LPS for up to 12 h. In a model wherein intrapleural zymosan injection causes an increase in TNF in the pleural cavity, GW3333 completely inhibited the increase in TNF in the pleural cavity for 12 h. Under these dosing conditions, the plasma levels of unbound GW3333 were at least 50-fold above the IC(50) values for inhibition of individual MMPs in vitro. In a model wherein bacterial peptidoglycan polysaccharide polymers reactivate a local arthritis response in the ankle, a neutralizing anti-TNF antibody completely blocked the ankle swelling over the 3-day reactivation period. GW3333 administered b.i.d. over the same period also inhibited ankle swelling, with the highest dose of 80 mg/kg being slightly less active than the anti-TNF antibody. In a 21-day adjuvant arthritis model, the anti-TNF antibody did not inhibit the ankle swelling or the joint destruction, as assessed by histology or radiology. GW3333, however, showed inhibition of both ankle swelling and joint destruction. In conclusion, GW3333 is the first inhibitor with sufficient duration of action to chronically inhibit TACE and MMPs in the rat. The efficacy of GW3333 suggests that dual inhibitors of TACE and matrix metalloproteinases may prove therapeutic as antiarthritics.

ADAM Proteins↗
PubMed2000

Isocyanate exposure and occupational asthma: a case-referent study.

OBJECTIVE: To examine the quantitative relation between exposure to isocyanates and occupational asthma, and to explore the role of atopy and smoking in occurrence of the disease. METHOD: A case-referent study was undertaken of cases from two manufacturing companies (A and B) from which referents without disease could be selected and reliable exposure measurements were available. In company A, 27 cases mainly attributed to toluene diisocyanate (TDI) were matched to 51 referents on work area, start and duration of employment, sex, and age. Exposures were estimated from existing measurements by job category. In company B there were seven cases attributed to 4,4'-diphenylmethane diisocyanate (MDI) in two areas of the plant; 12 non-cases from the same areas were used as referents. Personal exposure measurements were available for all cases and 11 referents. RESULTS: No difference in peak exposures between cases and referents was found in either plant; but in both, time weighted average (TWA) exposures at the time of onset of asthma were higher for cases. In A, the mean TWA exposure for cases was 1.5 (95% confidence interval (95% CI) 1.2 to 1.8) ppb compared with 1.2 (1.0 to 1.4) ppb for referents. From a matched analysis, the odds ratio (OR) associated with 8 hour TWA exposure to isocyanates greater than 1.125 ppb (the median concentration for the referent group) was 3.2 (95% CI 0.96 to 10.6; p=0.06). Occupational asthma was associated with a pre-employment history of atopic illness (OR 3. 5, p=0.04) and, less strongly, with smoking (OR 2.1, p=0.14). In B, small numbers limited analysis, but three of seven cases had at least one TWA exposure measurement greater than 5 ppb compared with one of 11 referents (OR 7.5, p=0.09). CONCLUSION: Asthma can occur at low concentrations of isocyanates, but even at low concentrations, the higher the exposure the greater the risk. By contrast with other studies, smoking and atopy seemed to increase the odds of occupational asthma due to isocyanates, but did not affect the estimate of risk associated with exposure.

Adolescent↗
PubMed1999

Multivariable feedback active structural acoustic control using adaptive piezoelectric sensoriactuators.

An experimental implementation of a multivariable feedback active structural acoustic control system is demonstrated on a piezostructure plate with pinned boundary conditions. Four adaptive piezoelectric sensoriactuators provide an array of truly colocated actuator/sensor pairs to be used as control transducers. Radiation filters are developed based on the self- and mutual-radiation efficiencies of the structure and are included into the performance cost of an H2 control law which minimizes total radiated sound power. In the cost function, control effort is balanced with reductions in radiated sound power. A similarity transform which produces generalized velocity states that are required as inputs to the radiation filters is presented. Up to 15 dB of attenuation in radiated sound power was observed at the resonant frequencies of the piezostructure.

Acoustics↗
PubMed1999

Aeroelastic structural acoustic control.

Static, constant-gain, output-feedback control compensators were designed to increase the transmission loss across a panel subjected to mean flow on one surface and a stationary, acoustic half-space on the opposite surface. The multi-input, multi-output control system was based upon the use of an array of colocated transducer pairs. The performance of the static-gain, output-feedback controller was compared to that of the full state-feedback controller using the same control actuator arrays, and was found to yield comparable levels of performance for practical limitations on control effort. Additionally, the resulting static compensators proved to be dissipative in nature, and thus the design varied little as a function of the aeroelastic coupling induced by the fluid-structure interaction under subsonic flow conditions. Several parametric studies were performed, comparing the effects of control-effort penalty as well as the number of transducer pairs used in the control system.

Acoustics↗
PubMed1999

Implications of using colocated strain-based transducers for output active structural acoustic control.

Piezoceramic transducers have become popular elements of smart structures that are used for active vibration control and active structural acoustic control. A spatial differentiation is performed by the piezoceramic transducers since they couple into the strain field of the piezostructure. This differentiation causes higher-frequency modes to be emphasized more heavily, causing the effective compliance of the structure as seen by the piezoceramic transducer to increase with frequency. This nonuniform compliance has significant impact on the performance that can be achieved through colocated direct rate feedback control. It is shown that the rectangular piezoceramic transducer is a low-pass wave number filter with a cutoff frequency inversely proportional to the aperture size. Thus DRFB performance can be greatly improved simply by making the size of the piezoceramic transducer large relative to the size of the structure. The resulting increase in coupling to the lower-frequency modes, which are generally targeted by the control system, results in a much reduced control effort. In the event that a large aperture is not practical, it is shown that dynamic compensation can be used to obtain good performance at the cost of much increased computational complexity. Analytical open and closed loop results for an acoustically radiating simply supported plate piezostructure are presented.

Acoustics↗
PubMed1999

A curved piezo-structure model: implications on active structural acoustic control.

Current research in Active Structural Acoustic Control (ASAC) relies heavily upon accurately capturing the application physics associated with the structure being controlled. The application of ASAC to aircraft interior noise requires a greater understanding of the dynamics of the curved panels which compose the skin of an aircraft fuselage. This paper presents a model of a simply supported curved panel with attached piezoelectric transducers. The model is validated by comparison to previous work. Further, experimental results for a simply supported curved panel test structure are presented in support of the model. The curvature is shown to affect substantially the dynamics of the panel, the integration of transducers, and the bandwidth required for structural acoustic control.

Acoustics↗
PubMed1999

The economic status of the elderly.

The economic status of the elderly improved greatly since the 1960s. This is true in terms of poverty rates, real cash income and broader income measures that include in-kind benefits. Yet, many older Americans remain at risk of economic deprivation, especially the less educated, those living alone, and the oldest old. Most elderly Americans rely heavily on Social Security and Medicare for their economic well-being.

Aged↗
PubMed1999

Getting billing right.

Explore the source record for details and available documents.

Financial Management, Hospital↗
PubMed1998

An epidemiology study of lung function changes of toluene diisocyanate foam workers in the United Kingdom.

OBJECTIVE: To determine whether longitudinal declines in ventilatory capacity and the occurrence of respiratory symptoms in workers manufacturing polyurethane foam were related to toluene diisocyanate (TDI) exposure. METHODS: A population of 780 workers in 12 United Kingdom factories was followed for 5 years. Modified United Kingdom Medical Research Council (MRC) respiratory questionnaires and three or more lung function measurements were completed for each subject. Mean TDI exposures for all jobs in which subjects were employed were assessed by personal monitoring (2294 measurements) and related to their occupational histories. RESULTS: The United Kingdom 8-h and 15-min maximum exposure limits for TDI were exceeded in 4.7% and 19.0% of the samples taken, respectively. There was some increase in reported respiratory symptoms amongst exposed workers, but the annual declines of 1-s forced expiratory volume (FEV1) and forced vital capacity (FVC) were not related to TDI exposure and were typical of those observed in other longitudinal populations. FEV1 declines were smoking-related. Evidence was found suggesting that a small excess decline in FEV1 and FVC occurred in the first few years of employment for workers not previously exposed to TDI. CONCLUSION: This study does not provide evidence that there is a TDI-related decline in FEV1 and FVC in workers exposed to less than the United Kingdom 8-h occupational exposure limit of 5.8 ppb.

Adult↗
PubMed1997

Terminology of developmental abnormalities in common laboratory mammals (version 1).

This paper presents the first version of an internationally-developed glossary of terms for structural developmental abnormalities in common laboratory animals. The glossary is put forward by the International Federation of Teratology Societies (IFTS) Committee on International Harmonization of Nomenclature in Developmental Toxicology, and represents considerable progress toward harmonization of terminology in this area. The purpose of this effort is to provide a common vocabulary that will reduce confusion and ambiguity in the description of developmental effects, particularly in submissions to regulatory agencies worldwide. The glossary contains a primary term or phrase, a definition of the abnormality, and notes, where appropriate. Selected synonyms or related terms, which reflect a similar or closely related concept, are noted. Nonpreferred terms are indicated where their usage may be incorrect. Modifying terms used repeatedly in the glossary (e.g., absent, branched) are listed and defined separately, instead of repeating their definitions for each observation. Syndrome names are generally excluded from the glossary, but are listed separately in an appendix. The glossary is organized into broad sections for external, visceral, and skeletal observations, then subdivided into regions, structures, or organs in a general overall head to tail sequence. Numbering is sequential, and not in any regional or hierarchical order. Uses and misuses of the glossary are discussed. Comments, questions, suggestions, and additions from practitioners in the field of developmental toxicology are welcomed on the organization of the glossary as well as on the specific terms and definitions. Updates of the glossary are planned based on the comments received.

Animals↗
PubMed1997

Efficacy and feasibility of breast shielding during abdominal fluoroscopic examinations.

RATIONALE AND OBJECTIVES: The purpose was to measure radiation exposure to the breasts during abdominal fluoroscopic examinations and evaluate the efficacy of breast shielding with a leaded vest. MATERIALS AND METHODS: Sixty-six women underwent routine abdominal fluoroscopic examinations. During the examinations one breast was covered with a leaded shield. Radiation doses to both breasts were measured with a thermoluminescent dosimeter. The amount of radiation at the skin of the shielded breast was then compared with that at the skin of the nonshielded breast. RESULTS: Radiation exposure to the breasts varied substantially with the type of examination being performed and with the individual patient. The average radiation level at the skin of the unshielded breast was 119 mR (range, 0-6,320 mR), compared with 59.6 mR (range, 0-1,640 mR) at the shielded breast. The average reduction in radiation exposure was 50% with shielding. CONCLUSION: Although the average level of radiation exposure to the breast during abdominal fluoroscopic examinations is generally low, use of a leaded vest can further reduce radiation to the breast for different types of examinations.

Adolescent↗