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Biomedical subjects

D M Cooper

Publications and source records attributed to D M Cooper.

At least 109 records · Page 6Linked to original sources
PubMed1994

Capacitative Ca2+ entry regulates Ca(2+)-sensitive adenylyl cyclases.

A number of the currently described adenylyl cyclase species can be regulated by Ca2+ in the submicromolar concentration range in in vitro assays. The regulatory significance of these observations hinges on whether a physiological elevation in intracellular Ca2+ can regulate these cyclase activities in intact cells. However, achieving a physiological elevation in cytosolic Ca2+ is complicated by the fact that hormonal increases in cytosolic Ca2+ can be accompanied by additional effects, such as liberation of beta gamma-subunits of G-proteins and activation of protein kinase C, which can have disparate type-specific effects on cyclase activities. Therefore we have devised a strategy based on capacitative Ca2+ entry to show that, when types I and VI adenylyl cyclase are expressed in human embryonic kidney 293 cells, they are stimulated and inhibited respectively by Ca2+ entry. Blockade of Ca2+ entry by La3+ ions blocks the effects of Ca2+ entry on cyclic AMP synthesis. These studies establish that adenylyl cyclases deemed to be sensitive to Ca2+ in in vitro assays can be regulated by physiological Ca2+ entry, and therefore, such cyclases are poised to respond to changes in intracellular Ca2+ in tissues in which they are expressed.

Adenylyl Cyclases↗
PubMed1994

Cerebral abscess as a complication of cystic fibrosis.

Two male patients with cystic fibrosis (CF), both 18 years old, developed frontal lobe brain abscesses. Both patients presented with histories of intermittent headache over several days and occasional vomiting. Headache was not more evident in the mornings and not associated with visual disturbance in either patient. Neither was hypertensive nor had visual disturbance. Both patients had documented pansinusitis and nasal polyposis. Both men had had few admissions for pulmonary exacerbations, and neither was significantly malnourished. The abscess in neither patient grew Pseudomonas species.

Adolescent↗
PubMed1994

Effects of granulocyte-macrophage colony-stimulating factor on wound contraction.

The effect of topical recombinant murine and human GM-CSF, 1 or 10 micrograms/cm2 for one to ten days, on the contraction and healing of acute and chronic granulating wounds infected with Escherichia coli was studied in Sprague-Dawley rats. Bacterial contamination of wounds produced significant inhibition of wound contraction. Application of GM-CSF at either dose level to infected wounds markedly increased the rate of wound closure compared to the rate in infected untreated controls. Ten days treatment was found to be more effective than a single application. An advanced stage of wound healing was observed at ten days in the GM-CSF-treated rats compared with controls. Bacterial counts decreased in the GM-CSF-treated wounds which may suggest bactericidal activity. Topical treatment with GM-CSF was shown to effectively inhibit the retardation of wound closure produced by bacterial contamination and may therefore be useful in the management of patients with infected wounds.

Administration, Topical↗
PubMed1994

Selective expression of one Ca(2+)-inhibitable adenylyl cyclase in dopaminergically innervated rat brain regions.

Type I adenylyl cyclase, which can be stimulated by elevated cellular levels of Ca2+, has been proposed to provide a positive coincidence signal detection system, which can integrate signals arising via Gs- and Ca(2+)-mediated pathways. The occurrence of this adenylyl cyclase in brain regions implicated with associative learning in invertebrates and with the mammalian model of plasticity--hippocampal long-term potentiation, supports the notion that the ability of this species of adenylyl cyclase to detect two signals simultaneously may play a role in this neuronal function. In the present study, two recently cloned, closely-related adenylyl cyclases (Types V and VI), are shown to be inhibited by physiological elevation in [Ca2+]i. As a first step towards probing the neuronal significance of Ca(2+)-inhibitable adenylyl cyclases, their distribution was evaluated by in situ hybridization analysis of the rat brain. Strikingly distinct patterns of gene expression were found, ranging from a highly selective distribution of Type V mRNA within the striatum, nucleus accumbens and olfactory tubercle, to a weak and ubiquitous distribution of Type VI mRNA. Type V AC mRNA is expressed exclusively in medium-sized striatal neurons, which also express D1-dopaminergic (Gs-linked) and M1-muscarinic cholinergic (Ca(2+)-linked) receptors. Thus the adenylyl cyclase is primed for simultaneous detection of opposing regulatory influences. The utility of this novel mode of signal detection to dopaminergic function remains to be established.

Adenylyl Cyclase Inhibitors↗
PubMed1994

Definitions and guidelines for assessment of wounds and evaluation of healing.

Chronic wounds represent a worldwide problem. For laboratory and clinical research to adequately address this problem, a common language needs to exist. This language should include a system of wound classification, a lexicon of wound descriptors, and a description of the processes that are likely to affect wound healing and would healing end points. The report that follows defines wound, acute wound, chronic wound, healing and forms of healing, wound assessment, wound extent, wound burden, and wound severity. The utility of these definitions is demonstrated as they relate to the healing of a skin wound, but these definitions are broadly applicable to all wounds.

Journal Article↗
PubMed1994

Determination of endogenous cytokines in chronic wounds.

OBJECTIVE: This study objectively characterized the microenvironment of indolent, chronic wounds by developing a method by which minute quantities of cytokines could be extracted from chronic wounds and separately identified. SUMMARY BACKGROUND DATA: Recombinant DNA technology and the ability to clone compounds such as cytokines allow new management schemes for the treatment of acute and chronic wounds. Before treatment with an exogenous cytokine is started, it would be helpful to know the endogenous level of that cytokine in the wound. Although various methods of extracting cytokines from acute wounds have been reported, no techniques have existed to reliably measure endogenous levels of cytokines in chronic wounds. METHODS: Porous, inert hydrophilic dextranomer beads were tested for their ability to absorb or adsorb protein and cytokines in vitro with either albumin or albumin laced with various known amounts of cytokines, and then from chronic human pressure ulcers. The Bradford protein assay was used to determine protein levels. Enzyme-linked immunosorbent assay (ELISA) techniques were used to determine levels of platelet-derived growth factor (PDGF)-AB, basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), and transforming growth factor-Beta (TGF-beta) extracted by the beads. RESULTS: Between 88% and 98% of known amounts of albumin could be recovered. Similarly, more than 90% of the laced cytokines could be recovered. In 20 grade III/IV pressure ulcers, although protein concentrations were remarkably similar, endogenous levels of cytokine growth factors varied tremendously. Platelet-derived growth factor-AB ranged from 49 to 867 pg/mL; bFGF from 47 to 697 pg/mL; and EGF from nondetectable to 247.5 pg/mL. TGF-B was not detected in 17 of the 20 pressure ulcers. CONCLUSIONS: This new technique appears useful for measuring endogenous levels of cytokines. Levels of cytokines found in these chronic wounds are much lower than those reported from acute wounds. The marked variation found among the 20 wounds may help to explain the differences reported in recent wound healing trials with exogenous cytokines.

Chronic Disease↗
PubMed1994

Adenylyl cyclase mRNA expression does not reflect the predominant Ca2+/calmodulin-stimulated activity in the hypothalamus.

Only three (Types I, II, V) of the six currently-described subtypes of adenylyl cyclase are prominently expressed in the rat brain. These species are differently sensitive to Ca2+, beta gamma subunits of G-proteins and protein kinase C. A knowledge of the susceptibility of the cAMP-signalling system in particular brain regions to these diverse modes of regulation can shed light on the mechanism of action of the neurotransmitters that modify neuronal activity in such regions. Cyclic AMP is extensively involved in the physiological functions of the hypothalamus. We have used in situ hybridization histochemistry with synthetic oligonucleotides to examine the expression in the rat hypothalamus of the three major brain subtypes of adenylyl cyclase-Ca2+/calmodulin-stimulable (Type I), Ca(2+)-insensitive (Type II) and Ca(2+)-inhibitable (Type V). The hypothalamus expresses high levels only of Type II mRNA, particularly in the supraoptic and paraventricular nuclei. Curiously, the strong expression of the Ca(2+)-insensitive Type II mRNA and the lack of expression of the major brain specific Type I mRNA does not correlate with the adenylyl cyclase activity, which is largely Ca2+/calmodulin stimulable in plasma membranes prepared from the hypothalamus.

Adenylyl Cyclases↗
PubMed1994

Calf muscle cross-sectional area and peak oxygen uptake and work rate in children and adults.

It is often assumed that the inherent peak muscle metabolic capacity scales in direct proportion to muscle cross-sectional area and is the same in small and large animals (A. V. Hill. Sci. Prog. 38: 208-230, 1950). We wondered whether this relationship between size and function was true during the period of growth and development in humans. Magnetic resonance imaging (MRI) was used to determine calf muscle cross-sectional area (CSA) in 20 children (6-11 yr old, 11 boys) and in 18 adults (23-42 yr old, 10 men). Progressive cycle ergometer exercise was performed to determine peak oxygen uptake (VO2peak) and work rate (WRpeak). The scaling factor (determined by allometric analysis) relating maximal O2 uptake (VO2max) to muscle CSA for the whole sample population was 1.04 +/- 0.12 (SE), but the scaling factor relating WRpeak to muscle CSA was significantly greater (1.37 +/- 0.12). Consistent with this, VO2max/CSA was not affected by body weight, but the WRpeak/CSA increased as a function of weight both in males (P < 0.005) and females (P < 0.05). No differences in VO2max/CSA were found between children and adults. WRpeak/CSA was significantly higher in adults compared with children (P < 0.05). It appears that the inherent peak muscle metabolic capacity is smaller in children than in adults. Moreover, the coupling of muscle capacity with whole body metabolic rate changes during growth in humans.

Adult↗
PubMed1994

Effect of training and growth hormone suppression on insulin-like growth factor I mRNA in young rats.

The growth hormone (GH)-insulin-like growth factor I (IGF-I) axis plays a role in the adaptation to exercise training, but IGF-I gene expression in response to exercise training and GH suppression has not been studied. Twenty female rates underwent a 4-wk treadmill training program begun in the prepubertal period (day 14 of life). In 10 of the training rats, GH production was suppressed by anti-GH-releasing hormone antibodies (GH suppressed). IGF-I mRNA and protein levels were measured in liver and hindlimb skeletal muscle. GH suppression reduced IGF-I mRNA expression in the liver to a much greater extent than in the muscle. In the GH control rats, training induced significant increases in hepatic exon 1-derived IGF-I mRNA (mean increase 30%; P < 0.05) and muscle exon 2-derived mRNA (mean increase 35%; P < 0.05). In the GH-suppressed rats, only muscle exon 1-derived transcripts were significantly increased by training (55%; P < 0.05) and this was associated with a significant increase in muscle IGF-I protein levels (P < 0.05). We speculate that the anabolic response to training may involve both GH-dependent increases in IGF-I mRNA in the liver and GH-independent increases in the muscle.

Actins↗
PubMed1994

Effect of brief exercise on circulating insulin-like growth factor I.

An acute insulin-like growth factor I (IGF-I) response to 10 min of above-lactate threshold cycle ergometer exercise was studied in 10 subjects (age 22-35 yr). Each subject exercised on three separate mornings after ingesting one of two isocaloric isovolemic liquid meals high in either fat or glucose or an isovolemic noncaloric placebo. The high-fat meal attenuated the growth hormone (GH) response (Cappon et al., J. Clin. Endocrinol. Metab. 76: 1418-1422, 1993). In contrast, IGF-I increased equally for all protocols [e.g., after the placebo meal IGF-I increased from 21,716 (SE) ng/ml preexercise to 25,316 ng/ml at 10 min of exercise; P < 0.05]. IGF-I peaked by the 10th min of exercise, like GH, and remained significantly elevated for only 20 min of recovery. We tested for possible GH-dependent mechanisms in which circulating IGF-I would increase 12-24 h after exercise. Ten subjects (age 23-32 yr) performed 10 min of above-lactate threshold exercise at 9, 10, and 11 A.M. GH was elevated after the first exercise bout (peak GH 6.05 +/- 1.45 ng/ml; P < 0.001) but was significantly reduced for the second and third bouts (peak GH 2.52 +/- 0.76 and 1.50 +/- 0.40 ng/ml, respectively). No increase in IGF-I was observed by 8 A.M. on the following day. Heavy ergometer exercise led to brief and small increases in circulating IGF-I that were independent of circulating GH.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Muscle energetics and pulmonary oxygen uptake kinetics during moderate exercise.

The present study tested whether, during moderate exercise, 1) the dynamic responses of ADP and changes in free energy of ATP hydrolysis (delta GATP) were similar to those of phosphocreatine [PCr; as would be expected for a simple controller of muscle respiration (QO2)] and 2) the rise in pulmonary O2 uptake (VO2) during cycle exercise would reflect the rise in muscle QO2 indicated by the calf PCr kinetics. The responses of PCr, Pi, ADP, and delta GATP were measured from the calf in five subjects during supine treadle exercise using 31P-magnetic resonance spectroscopy and compared with those for VO2, measured breath by breath during upright cycle exercise. The time constants for delta GATP [24.2 +/- 14.2 (SE) s] were not significantly different from those for PCr (26.3 +/- 17.3 s) and Pi (30.7 +/- 22.5 s) (P > 0.05). The time constants for phase 2 VO2 (29.9 +/- 16.8 s) were also similar to those of PCr. In contrast, the dynamics of ADP were distorted from those of PCr due to dynamic changes in pH. These results are consistent with mechanisms of respiratory control that feature substrate control by PCr or thermodynamic control through changes in delta GATP. However, these results are not consistent with substrate control by ADP in a simple fashion. Furthermore, the similarity of time constants for phase 2 VO2 and muscle PCr suggests that phase 2 VO2 kinetics reflect those of muscle QO2 in healthy subjects during moderate exercise.

Adenine Nucleotides↗
PubMed1994

Changes in potential controllers of human skeletal muscle respiration during incremental calf exercise.

The purpose of this study was to evaluate the consequences of non-linear changes in phosphocreatine (PCr) and pH during incremental calf exercise on estimates of ADP and cytosolic free energy of ATP hydrolysis (delta GATP). Six subjects performed incremental plantar flexion exercise on a treadle ergometer while muscle P(i) metabolism (PCr, P(i), ATP) and pH were followed using 31P-nuclear magnetic resonance spectroscopy. Changes in ADP and delta GATP were estimated with the assumption that there was equilibrium of the creatine kinase reaction and homogeneous tissue metabolite pools. All six subjects showed a threshold for onset of cellular acidosis that occurred on average at 47.3 +/- 12.7% of peak work rate (PWR). In five of the six subjects, PCr and P(i) showed accelerated rates of change above the threshold for onset of cellular acidosis. In all six subjects, ADP, when correctly calculated considering changes in pH, rose in a curvilinear fashion that was well described by a Michaelis-Menten hyperbola through 60-100% of PWR, with a mean apparent Michaelis-Menten constant of 43.1 +/- 17.1 microM ADP and a predicted maximal oxidative rate at PCr = 0, which was 241 +/- 94% of PWR. delta GATP rose linearly with work rate from -62.9 +/- 1.8 kJ/mol during unloaded treadling to -55.0 +/- 1.8 kJ/mol at PWR. If we assume a linear O2 uptake-to-work rate relationship, these results are most consistent with control of respiration being exerted through delta GATP under these conditions (incremental exercise by human calf muscle).(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Diphosphate↗
PubMed1994

Exchange of CO2 and bicarbonate between the circulation and cerebrospinal fluid in piglets.

The dynamic exchange of CO2 and HCO-3 between the central circulation and peripheral sites such as the cerebrospinal fluid (CSF) is not completely understood. To examine this we administered a tracer dose of NaHCO3 labeled with the stable isotope 13C into the central circulation of nine 3- to 4-wk-old anesthetized, instrumented piglets. Serial samples of arterial and venous blood, breath, and CSF were obtained to determine the 13C/12C ratio by isotope-ratio mass spectrometry. Gas-exchange and hemodynamic parameters were obtained through standard techniques. The patterns of tracer washout in venous blood, arterial blood, and breath were nearly indistinguishable from each other, and the mean residence time was 113 +/- 24 min (average +/- SD). In contrast, the CSF 13C/12C ratio was not equivalent to that in venous blood, arterial blood, or breath until 20 min after tracer administration. Tracer washout data were used to determine the best-fit three-exponential-term equation and to calculate compartmental parameters of a three-compartment mammillary system in which CO2 and HCO3- residing in the central compartment (compartment 1) exchanges relatively rapidly with one peripheral compartment (compartment 2) and slowly with the other (compartment 3). The turnover time for the CSF was 6.8 +/- 2.5 min and the estimate for compartment 2 was 7.1 +/- 3.7 min. Accordingly, CSF appears to be one of the rapidly interchanging peripheral compartments.

Animals↗
PubMed1994

Effect of growth hormone suppression on exercise training and growth responses in young rats.

Exercise training improves maximal oxygen uptake and endurance times in adult human beings and other animals. The mechanism of this improvement results in part from anabolic effects of exercise and may be mediated by growth hormone (GH). Little is known about the role of GH in the adaptation to exercise in younger, still-developing organisms. To examine this role, we began a 4-wk treadmill exercise training protocol in 14-d-old female rats. GH was suppressed by passive immunization with anti-GH releasing hormone antisera. There were four experimental groups: 1) GH-control (normal GH secretory capacity), untrained (n = 21); 2) GH-suppressed, untrained (n = 13); 3) GH-control, trained (n = 14); and 4) GH-suppressed; trained (n = 11). At the end of the training period, maximal oxygen uptake and treadmill endurance running time were measured. Serum GH and IGF-I were assessed using RIA, and whole hind limb musculature succinate dehydrogenase (an indicator of mitochondrial function) was measured with standard fluorometric technique. Body weight gain was markedly reduced in GH-suppressed rats (mean, 54% of GH-controls in untrained rats and 55% in trained; p < 0.05). No apparent effect of training on linear growth was observed. As expected, serum IGF-I was markedly reduced by GH suppression, but no exercise-induced increase occurred in IGF-I as a result of training in either the GH-control or GH-suppressed rats. In GH-control rats, maximal oxygen uptake and succinate dehydrogenase were 69% and 25% greater, respectively, in trained compared with untrained rats (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adaptation, Physiological↗
PubMed1994

Evidence for and mechanisms of exercise modulation of growth--an overview.

This symposium was organized to highlight new information regarding the mechanisms through which physical activity and exercise may affect the process of growth. Exercise associated anabolic effects (i.e., constructive or biosynthetic metabolic processes involved in tissue adaptation to physical activity) are varied and modulated by maturational and nutritional factors. Nonetheless, identifying common processes responsible for the many anabolic effects of physical activity may improve the ways exercise can be used in rehabilitation programs and to promote health. Thus, the overall aim of this symposium is to explore the diverse mechanisms that link physical activity with growth at both the cellular and somatic level. A conceptual model is presented that includes the interaction of central and local components of exercise modulation of growth. Central components encompass the mechanisms through which exercise of skeletal muscle groups can seemingly affect cellular growth and function throughout the body. Local components encompass those mechanisms that stimulate growth, hypertrophy, and the appearance of new mitochondria and capillaries in the muscle, bone, vascular and connective tissues involved in the specific exercise. The physiology of these putative mechanisms and their clinical applications are developed from six different perspectives.

Animals↗