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Biomedical subjects

P A Clark

Publications and source records attributed to P A Clark.

At least 19 recordsLinked to original sources
PubMed1995

Function of the interleukin-2 (IL-2) receptor gamma-chain in biologic responses of X-linked severe combined immunodeficient B cells to IL-2, IL-4, IL-13, and IL-15.

The interleukin-2 (IL-2) receptor gamma-chain is a common component of several members of the cytokine receptor superfamily including those for IL-2, IL-4, IL-7, IL-9, IL-15, and possibly IL-13, and has recently been renamed the common gamma-chain (gamma c-chain). Transfection experiments have shown that the gamma c-chain participates in signal transduction by IL-2, IL-4 and IL-7, but a functional role for the gamma c-chain in biological responses by normal T cells and B cells to these cytokines has not been established. In this study, we have used X-linked severe combined immunodeficiency (X-SCID) as a naturally occurring gamma c-chain gene disruption model to examine the role of the gamma c-chain in human B-cell responses to IL-2, IL-4, IL-13, and IL-15. Our experiments show that B cells from two X-SCID patients with characterized gamma c-chain gene mutations do not respond to IL-2 or IL-15, but respond as well or better than normal B cells to both IL-4 and IL-13 in assays for B-cell activation, proliferation, and IgE secretion. This finding raises important questions about the function of the gamma c-chain in receptors for IL-4 and IL-13, and the nature of the immune defect in X-SCID.

B-Lymphocytes↗
PubMed1995

Screening for mutations causing X-linked severe combined immunodeficiency in the IL-2R gamma chain gene by single-strand conformation polymorphism analysis.

Mutations in the common gamma chain (gamma c or IL2RG) of the interleukin-2, -4, -7, -9 and -15 receptors have been found to cause X-linked severe combined immunodeficiency (SCIDX1). We report here on the mutations identified in a further ten families. Two of the mutations identified have occurred twice in unrelated families, indicating two possible mutational hotspots. Seven of the mutations, which were identified by single-strand conformational polymorphism (SSCP) analysis, are point mutations, and the eighth is a small deletion. We also report on the first use of assays based on these mutations within IL2RG for unambiguous carrier determination. The consequences for the gamma c proteins produced as a result of these mutations are discussed.

Base Sequence↗
PubMed1994

Trisomy X in a female member of a family with X linked severe combined immunodeficiency: implications for carrier diagnosis.

We describe a family affected by X linked severe combined immunodeficiency (SCIDX1) in which genetic prediction of carrier status was made using X chromosome inactivation studies together with limited genetic linkage analysis. Linkage studies in this family showed a confusing pattern of inheritance for the X chromosome. A female with a random pattern of X chromosome inactivation in her T cells appeared to have inherited an X chromosome with four recombinations within 10 cM. The odds of this happening in a single meiotic event make this an unlikely explanation. Data obtained from studying the X chromosomes of her two unaffected sons showed that this could be explained simply on the basis of her having inherited three alleles each of the relevant polymorphic DNA loci. We used fluorescent in situ hybridisation (FISH) to confirm that this person had inherited three complete X chromosomes. Thus, although the results from X chromosome inactivation analysis indicated that this subject was not a carrier of the affected chromosome, FISH and genetic linkage analysis showed clearly that the affected chromosome had been inherited. The implications of this finding for diagnosis of carrier status in this family and for other families with X linked inherited immunodeficiencies is discussed.

Chromosome Mapping↗
PubMed1992

Prospective evidence of a circadian rhythm for out-of-hospital cardiac arrests.

OBJECTIVES: Published studies have indicated a circadian rhythm in the occurrence of sudden cardiac death. However, these studies have involved either retrospective analyses of death certificates or analyses of data collected during studies of pharmacologic agents in selected populations. PURPOSE: To determine whether a circadian pattern could be clearly demonstrated in a prospective study of out-of-hospital sudden cardiac death in a large, unselected population. DESIGN: All adult cases of sudden death of presumed primary cardiac cause from a large urban population were prospectively evaluated over a 12-month period. The incidence of sudden cardiac death was analyzed using harmonic regression of the data tabulated by hour of the day. RESULTS: During the year of study, 1019 consecutive primary cardiac arrests were analyzed. A significant circadian pattern was found (P less than .0001) with the frequency of cardiac arrests increasing dramatically from 6 AM until noon. CONCLUSIONS: This prospective study of out-of-hospital cardiac arrest confirms the existence of a circadian rhythm. These data have important implications for future investigations concerning the pathophysiology of sudden cardiac deaths.

Ambulatory Care↗
PubMed1991

The gene organisation of the human beta 2 integrin subunit (CD18).

We have studied the gene of the human beta 2 integrin subunit (CD18) and found it to be organised into 16 exons spanning a region of about 40 kb. All exon/intron boundaries conform to the GT/AG splicing consensus. The exons coding for the cysteine-rich region, which has been postulated to consist of 3 or 4 repeating elements, are not organised correspondingly. Transcription of the gene initiates from multiple sites which may be due to the absence of an upstream TATA box. The polyadenylation site is also heterogeneous. Five different sites were identified over a stretch of 10 bases.

Amino Acid Sequence↗
PubMed1991

Arteriovenous oxygen diffusion shunt is negligible in resting and working gracilis muscles.

Distribution of O2 within and among arterioles and venules was determined in dog and rat gracilis muscles with a cryospectrophotometric method. Saturation in 40-microns arterioles was not demonstrably different from saturation in the aorta even when flow was abnormally low. Arterioles greater than 40 microns ran parallel to venules. Measurements and a mathematical model indicate that diffusive shunting is negligible for typical separation distances between arterioles and venules. Most separation distances were greater than 30 microns. In some venule segments less than 15 microns from an arteriole, saturation within 10 microns of the wall facing the arteriole was higher than at other locations within the venule. However, saturation in the population of venules did not increase with venule diameter, and mean venular saturation was not different from saturation in effluent blood. We make the following conclusions: 1) a small arteriovenous diffusive O2 flux exists in postural muscles; 2) contribution of this flux to O2 mass balance is negligible; 3) O2 diffusivity of the arteriolar wall and surrounding tissue in vivo cannot be much higher than O2 diffusivity determined in vitro; and 4) effluent PO2 closely approximates mean end-capillary PO2.

Animals↗
PubMed1989

Buffering of muscle tissue PO2 levels by the superposition of the oxygen field from many capillaries.

High resolution measurement in both exercised skeletal and cardiac tissue made radially outward from capillaries and longitudinally parallel to capillaries by Gayeski and Honig (1986, 1986a,b) and Honig and Gayeski (1987) indicate shallow variation of tissue PO2 and the absence of strong causal relation between the PO2 at a point and the proximity of that point to the nearest active capillary. Proposed as a model for the analysis of this tissue PO2 distribution, so contrary to the expectations of Krogh type models, are a class of multicellular tissue cylinder models. Each cylinder is penetrated by many parallel capillaries. In order to better represent the natural irregularities of the skeletal and cardiac tissue both with regard to radial placement and the stagger of the capillary inlets, the following types of models both with and without yoglobin are examined: regular square arrays where the capillary PO2 levels are random, uniform capillary PO2 levels but random capillary positions, and those with both the capillary PO2 levels and the positions are random. The results of the model calculations show that the superposition of the oxygen diffusion fields of all the capillaries produce a tissue PO2 distribution with the properties: (1) lower tissue PO2 levels than those predicted by Krogh theory, (2) significant non-local contributions to the PO2 at a point in the tissue which greatly reduces this correlation between PO2 at a point and its proximity to an active capillary, (3) shallow transcellular PO2 variation.

Animals↗
PubMed1987

Noncomparative, open label, multicenter trial of cefixime for treatment of bacterial pharyngitis, cystitis and pneumonia in pediatric patients.

Cefixime, a new third generation oral cephalosporin antibiotic, was evaluated for safety and efficacy in the treatment of 206 children with acute bacterial pharyngitis, cystitis or pneumonia. Each patient had a throat, urine or sputum culture before therapy and was treated with a 10- to 14-day course of cefixime, 8 mg/kg once daily. Bacterial pathogens were isolated in 167 of 206 (81.1%). Streptococcus pyogenes (73.7% of isolates) and Escherichia coli (9.6%) were the most common Gram-positive and Gram-negative organisms, respectively. All patients were evaluable for safety, and 109 (52.9%) with pharyngitis (96) or cystitis (13) were evaluable for efficacy. Clinical failure occurred in 2 of 109 (1.8%) patients, both with pharyngitis; bacteriologic failure occurred in 1 patient with pharyngitis and 1 with cystitis. Five patients with pneumonia caused by possible pathogens also improved while taking cefixime. Drug-related adverse side effects occurred in 50 of 206 patients (24.3%); these were generally mild and led to discontinuing the antibiotic in only 4 patients (1.9%). The most common were diarrhea or loose stools (33 of 206, or 16%). Results of this study suggest that cefixime given once daily to children is safe and effective in the treatment of streptococcal pharyngitis and bacterial cystitis.

Adolescent↗
PubMed1987

How large is the drop in PO2 between cytosol and mitochondrion?

The subject of this brief review is the size of the local drops in PO2 around consuming mitochondria. We show that large drops (several Torr or more) are in conflict with the predictions of basic diffusion theory, when one uses accepted values for relevant parameters. In particular, oxygen diffusion coefficients must be reduced by at least a factor of 10 below measured values to reconcile Fick's law with large PO2 drops. Experimental evidence offered for large drops is often ambiguous because of system heterogeneities. In those cases where tractable models of heterogeneous systems can be developed, the experimental data are consistent with drops in PO2 on the order of a few hundredths of a Torr between cytosol and mitochondrion.

Cytosol↗
PubMed1985

Local oxygen gradients near isolated mitochondria.

The oxygen concentration in tissue can vary on several length scales. The basic scale of variation is determined by capillary spacing. It is this scale that is manifest in the simplest Krogh cylinder model. A second, smaller scale of variation is associated with the consumption of oxygen by mitochondria. This paper gives a theoretical analysis of these smaller-scale oxygen variations near an isolated mitochondrion. To illustrate the effects of shape, we have carried out the calculations for prolate spheroids as well as for spheres. The principal result is that the local drop in oxygen pressure around a consuming mitochondrion is of the order of (gamma/3K) (3V/4 pi)2/3, where gamma is the oxygen consumption rate per unit mitochondrial volume, K is the Krogh oxygen diffusivity of the surrounding tissue, and V is the mitochondrial volume. The theory is applied to skeletal muscle in vivo and to hepatocytes in cell suspension experiments. In both cases, we find that local oxygen variations produced by oxygen consumption are much smaller than the cell-wide variations produced by the collective effect of all the mitochondria. For example, in maximally consuming skeletal muscle, the drop in oxygen pressure around a consuming mitochondrion is only of the order of 0.03 Torr.

Animals↗
PubMed1985

Oxygen delivery from red cells.

This paper deals with the theoretical analysis of the unloading of oxygen from a red cell. A scale analysis of the governing transport equations shows that the solutions have a boundary layer structure near the red-cell membrane. The boundary layer is a region of chemical nonequilibrium, and it owes its existence to the fact that the kinetic time scales are shorter than the diffusion time scales in the red cell. The presence of the boundary layer allows an analytical solution to be obtained by the method of matched asymptotic expansions. A very useful result from the analysis is a simple, lumped-parameter description of the oxygen delivery from a red cell. The accuracy of the lumped-parameter description has been verified by comparing its predictions with results obtained by numerical integration of the full equations for a one-dimensional slab. As an application, we calculate minimum oxygen unloading times for red cells.

Biological Transport, Active↗
PubMed1983

Capture of spatially homogeneous chemical reactions in tissue by freezing.

A useful technique in studying the saturation of hemoglobin in erythrocytes or myoglobin in tissue is cryophotometry, in which tissue is frozen for later spectrophotometric analysis. A general question associated with this technique is whether the freezing process alters the chemical state. This paper presents a theoretical analysis of the simplest model relevant to that question. We study the effect of rapid cooling on a spatially homogeneous chemical reaction. The analysis shows that changes during freezing are negligible near the boundary to which the heat sink is applied, but can be significant deeper in the sample. The distance from the boundary at which the changes during freezing become appreciable can be expressed simply in terms of the chemical reaction rates and the thermal diffusivity of the tissue. Detailed results are given for the case of oxygen and myoglobin in skeletal muscle.

Animals↗
PubMed1983

Rhesus monkey intervertebral disk viscoelastic response to shear stress.

A viscoelastic model of the shear response of the Rhesus monkey intervertebral disk, represented by a series chain of four Kelvin units is presented. Two types of investigations are carried out to assess the validity of the model: 1) determination of material properties by comparison with experimental strain creep behavior of the disk; and 2) validation of this viscoelastic model by accurately predicting the experimental results of stress relaxation tests. The use of the series Kelvin units approach provides the first analytical mechanical model capable of predicting the creep and relaxation functions for the intervertebral disk in shear.

Animals↗