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Biomedical subjects

D A White

Publications and source records attributed to D A White.

At least 91 records · Page 5Linked to original sources
PubMed1995

The changing pharmacodynamics of metocurine identify the onset and offset of canine gastrocnemius disuse atrophy.

BACKGROUND: Immobilization of skeletal muscle results in disuse atrophy and resistance to nondepolarizing muscle relaxants. We studied the pharmacodynamics of metocurine (MTC) to identify the development and recovery of disuse-related resistance to MTC. METHODS: Nineteen dogs underwent cast immobilization of a hind limb for as long as 3 weeks. Before, during, and after casting, dogs were intermittently anesthetized with thiamylal-N2O-fentanyl. The blood concentration of MTC and the corresponding degree of paralysis after a brief infusion were recorded and were used to characterize the pharmacokinetics and pharmacodynamics of MTC. RESULTS: Pharmacodynamic study of the response to MTC demonstrated resistance by the 4th day of casting. The effect-site concentration associated with 50% paralysis of twitch increased after 3 weeks from approximately 250 to 750 ng/ml. After cast removal, resistance persisted for 2 more weeks. Six weeks after cast removal, the effect-site concentration associated with 50% paralysis of twitch was normal in every dog. CONCLUSIONS: Within the context of this study of immobilization disuse atrophy, pharmacokinetic and pharmacodynamic characterization of antagonist responses can be used to infer muscle disuse-related changes in acetylcholine receptors.

Acetylcholine↗
PubMed1995

Psychological outcome of ECMO-eligible neonates with severe respiratory failure treated using conventional medical therapy.

OBJECTIVE: The present study addressed a National Health and Medical Research Council (NHMRC) recommendation that the outcome of neonates who are treated conventionally for respiratory problems be further investigated before setting up additional extracorporeal membrane oxygenation (ECMO) centres in Australia. METHODOLOGY: The cognitive and behavioural outcome of ECMO eligible infants who received conventional treatment for respiratory problems at birth was assessed in 18 infants aged 1.5-3 years (index group). ECMO was not available at either of the treating hospitals. Index children were compared to a matched control group of children who did not experience any major complications at birth. Children were assessed using either the Bayley or McCarthy scales of infant development and the Child Behavior Checklist. RESULTS: Overall, a mortality rate of 19% and a psychological morbidity rate of 18% suggest that children born with severe respiratory failure, who meet existing ECMO eligibility criteria, have a good prognosis when treated using conventional medical therapy. CONCLUSIONS: Improvements to conventional treatments indicate that ECMO eligibility criteria may need to be revised to identify accurately those infants who are at extreme risk of mortality if treated conventionally.

Adaptation, Psychological↗
PubMed1995

Changes in cognitive performance in children with spastic diplegic cerebral palsy following selective dorsal rhizotomy.

Children with cerebral palsy who receive selective dorsal rhizotomy (SDR) for treatment of spasticity may show suprasegmental changes in upper limb function and control of speech musculature. Anecdotal reports suggest that supra-segmental effects may extend to cognitive functions such as attention and language. This study examined the performance of 16 children with spastic diplegic cerebral palsy on tests of visual attention and other cognitive functions 1 day prior to and 6 months following SDR. Children undergoing SDR were compared with 9 children with spastic diplegia, matched for severity of cerebral palsy and amount of therapy, who did not receive SDR, and 24 age- and sex-matched normal children tested at initial and 6-month follow-up sessions. Children with cerebral palsy treated with SDR showed disproportionately greater improvement in specific attentional and cognitive operations than either of the other groups. These results document cognitive changes following SDR which heretofore were reportedly anecdotally. This improvement may be due to improved mood, reduced physical discomfort, increased therapeutic intervention, or possible cortical effects of SDR.

Attention↗
PubMed1995

Pulmonary infection in the immunocompromised patient.

Pneumonia in the immunocompromised patient remains a significant cause of morbidity and mortality. These patients are susceptible to a wide variety of organisms, but specific infections tend to occur in well defined settings. The type of infection can be predicted based on the nature and severity of the immune defect, past patient exposures, chemotherapy given, radiographic presentation, and acuteness of illness. New treatments, including growth factors, the oral antifungal agents, and antiviral drugs, such as ganciclovir and acyclovir, have improved management and prognosis in some cases. However, some problems have increased with a significant risk of spontaneous pneumothorax now seen with Pneumocystis carinii infection. Bronchoscopy with bronchoalveolar lavage plays a major role in diagnosis, particularly for P carinii and cytomegalovirus infection. However, open lung biopsy remains essential for diagnosis in some settings. Surgical resection for control of hemoptysis and for removal of residual foci of disease also are an integral part of management of pulmonary fungal infections in the immunosuppressed patient.

AIDS-Related Opportunistic Infections↗
PubMed1995

Pulmonary infections in immunosuppressed patients.

Pulmonary infections continue to be a significant problem in patients immunosuppressed by cancer or by drugs given for malignancy, or rheumatologic or dermatologic problems. For the neutropenic patient, single-drug rather than combination antibiotic therapy is being increasingly used. The role of growth factors is also being defined. The availability of the new azoles and of alternative forms of amphotericin B have increased treatment options, particularly for invasive pulmonary aspergillosis. Pneumocystis carinii pneumonia continues to be a problem in this population, and controversy remains about the mode of transmission and the mechanism of disease caused by this infection. Exogenous infection rather than reactivation may play a small role. Appreciation of the role of community and opportunistic viruses in causing respiratory infection or other complications in the immunosuppressed population is also being further detailed.

AIDS-Related Opportunistic Infections↗
PubMed1994

The effects of two acylcoenzyme A: cholesterol acyltransferase (ACAT) inhibitors, cyclandelate and a non-hydrolysable ether analogue, benzyl3,3,5-trimethylcyclohexanol on low density lipoprotein metabolism in macrophages and hepatocytes.

Cyclandelate (3,3,5-trimethylcyclohexanylmandelate) caused a dose-dependent decrease in the metabolism of radioiodinated low density lipoprotein [125I-LDL] by J774 mouse macrophages. This was probably an indirect effect due to the inhibition of cholesterol esterification by the cells rather than a direct one on the interaction of LDL with its receptor, since no inhibition was seen in cells which had been cholesterol-depleted by prior incubation with lipoprotein-depleted serum for 48 hr. Cyclandelate also inhibited immediately de novo synthesis of cholesterol from [1-14C]acetate in J774 cells, suggesting a direct action of the drug on an enzyme of the cholesterol biosynthetic pathway. The drug was an efficient inhibitor of hamster and rat intestinal acylcoenzyme A: cholesterol acyltransferase (ACAT) activity in vitro with an IC50 of 20 microM. Addition of cyclandelate to the diet of meal-fed rats caused a marked inhibition of the rate of appearance of dietary [4-14C]cholesterol in the plasma. A nonhydrolysable ether analogue of cyclandelate, benzyl3,3,5-trimethylcyclohexanol, was prepared to compare hepatic and extrahepatic actions of the two molecules. The analogue inhibited cholesterol esterification in J774 cells, transformed human macrophages U937 and human umbilical vein endothelial cells with an IC50 of 20 microM and had effects similar to those of cyclandelate on 125I-LDL metabolism in J774 cells. Differences between the analogue and cyclandelate were seen in hepatocytes and hepatic microsomal fractions, where preincubation with the analogue inhibited cholesterol esterification in both systems while cyclandelate had no inhibitory action in either. Consequently, preincubation of rat hepatocytes with benzyl3,3,5-trimethylcyclohexanol for 17 hr caused a marked decrease in the binding of 125I-LDL to the cells, whereas binding to cells preincubated with cyclandelate was the same as to control cells.

Acyl Coenzyme A↗
PubMed1994

Effects of cholinesterase inhibitors on the neuromuscular blocking action of suxamethonium.

Prolonged neuromuscular block occurs when suxamethonium is given after neostigmine or pyridostigmine; however, studies of edrophonium and suxamethonium have yielded conflicting results. We have studied, therefore, interactions between suxamethonium and all three anticholinesterases in rats anaesthetized with pentobarbitone. After recovery from an initial bolus of suxamethonium, saline, edrophonium, pyridostigmine or neostigmine was administered and a second dose of suxamethonium was then given. All three anticholinesterases prolonged the duration of neuromuscular block (90% suppression to 50% twitch recovery) to 127 (SEM 9)%, 127(10)% and 138 (11)% of baseline for edrophonium, pyridostigmine and neostigmine, respectively. Recovery index (25% to 75% twitch recovery) was increased also to 125 (9)%; 149 (10%) and 185 (15)% of baseline, respectively for the three drugs.

Animals↗
PubMed1994

Regional myocardial function during contiguous ischaemia in an anaesthetized canine model: comparison of six methods of measurement.

During acute myocardial ischaemia, the function of the unaffected muscle is the primary determinant of residual cardiac performance. We compared six methods of measuring regional function in the remaining non-ischaemic segment after acute ligation of the left anterior descending (LAD) coronary artery in 16 dogs. Preparation included left ventricular micromanometers, regional sonomicrometer transducers to measure segment length and wall thickness, caval occluders and left atrial catheters for injection of radioactive microspheres to measure regional blood flow. Pulmonary artery, central venous and systemic arterial pressures were measured and regional coronary venous blood was collected for direct myocardial oxygen consumption (VO2) calculations. Under basal high-dose fentanyl-neuromuscular blocker anaesthesia, the LAD was occluded after addition of halothane or isoflurane at 0.5 or 1.5 MAC concentrations. Regional myocardial function of the non-ischaemic segment was assessed by the following computer-derived indices: percent systolic wall thickening (% WT), velocity of shortening (vs), percent systolic shortening (%SS), regional stroke work (RSW), regional preload recruitable stroke work (RPRSW) and regional end-systolic elastance (Ees). No index demonstrated enhanced function in the non-ischaemic segment after LAD ligation and all monitors, except Ees, were sensitive to depression of function represented by a decrease in values after administration of halothane and isoflurane (P < 0.05). Ees values increased with the addition of isoflurane and remained constant with halothane. Circulating concentrations of catecholamines were unchanged after ischaemia, while inhalation agents caused a decrease in the concentrations of adrenaline and dopamine (P < 0.05), but not noradrenaline.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

The inhibition of cholesterol esterification by cyclandelate in transformed mouse macrophages.

Cyclandelate (trimethylcyclohexanyl mandelate) inhibited cholesterol esterification in a transformed mouse macrophage cell line (J774) with a concentration of approximately 20 microM being required for half-maximal inhibition. The intact drug was required for its inhibitory action since neither of its hydrolysis products, trimethylcyclohexanol and mandelic acid, caused any inhibition even at high concentrations. The drug entered the cells very rapidly with inhibition being apparent within the shortest time possible to measure esterification (15 min after drug addition). The rate of cholesterol esterification returned to control values when drug-inhibited cells were incubated in drug-free medium indicating a rapid loss of drug from the cells. Loading of cells with cholesterol had no effect on the inhibitory action of cyclandelate, and the inhibition of esterification of cholesterol appeared to be specific, since the syntheses of phospholipid and triacylglycerol (which also involve the action of acyltransferases) were not affected by the drug. Similar inhibitions of cholesterol esterification were seen in four other cell lines, a human osteosarcoma, Chinese hamster ovary cells, a human transformed macrophage cell line (U937) and human umbilical cord vein endothelial cells, as well as in slices of pig aorta, indicating a general action in extra-hepatic tissues where the drug is not hydrolysed.

Animals↗
PubMed1993

The effects of tunicamycin on the metabolism of acetylated low density lipoproteins.

The effect of tunicamycin (TM) on the metabolism of acetylated low-density lipoprotein (AcLDL) was examined to determine whether N-linked glycosylation is required for the proper function of the AcLDL pathway. Proteolytic degradation of [125I]-AcLDL was increased twofold in the presence of TM. This did not occur via an increase in total lysosomal enzyme activity or extracellular proteolysis; rather, the rate of uptake of [125I]-AcLDL was increased. The enhanced degradation of AcLDL did not lead to a commensurate increase in the rate of synthesis of cholesteryl oleate. Conversely, the rate of cholesterol esterification was reduced in the presence of TM. The uptake of [125I]-AcLDL was more sensitive to inhibition by chloroquine in TM-treated cells. However, the presence of TM did not affect the ability of chloroquine to inhibit constitutive recycling of AcLDL binding sites. These results suggest that N-linked glycosylation may be involved in the regulation of AcLDL metabolism in J774 cells.

Acetylation↗
PubMed1993

Macrophages produce nitric oxide at allograft sites.

OBJECTIVE: The current study was designed to determine which cytokines produced during an alloimmune response stimulate macrophage nitric oxide (.N = O) production at allograft sites. SUMMARY BACKGROUND DATA: Previous work has demonstrated that rat sponge matrix allograft infiltrating cells produce more .N = O on stimulation with alloantigen than syngeneic graft-infiltrating cells. Addition of NG-monomethyl-L-arginine (NMA), an inhibitor of .N = O synthesis, promotes allospecific cytolytic T-lymphocyte effector function. METHODS: Polyurethane sponges were implanted subcutaneously in recipient Lewis rats and injected with 10 x 10(6) ACl splenocytes. On various days after grafting, graft-infiltrating cells were harvested for in vitro study. Adherent macrophages from the graft infiltrating cell population were obtained by a 2- to 3-hour incubation to plastic dishes with subsequent washing to remove nonadherent cells. RESULTS: Stimulation of unseparated graft-infiltrating cell populations with lipopolysaccharide or interferon-tau resulted in enhanced .N = O synthesis by allograft infiltrating cells compared with syngeneic graft-infiltrating cells, early after grafting. Macrophages recovered from an allograft site spontaneously produce more .N = O than macrophages recovered from syngeneic grafts (p < 0.001). Significantly enhanced levels of .N = O were produced by allograft macrophages compared with syngeneic graft macrophages on stimulation with lipopolysaccharide or interferon-tau (p < or = 0.025). CONCLUSIONS: Nitric oxide appears to be produced in response to the local cytokines secreted by an ongoing rejection reaction. Nitric oxide serves under these circumstances to modulate the alloimmune response.

Animals↗
PubMed1993

Ultrastructural morphology, cytochemistry, and morphometry of eosinophil granules in Chédiak-Higashi syndrome.

Lysosomal enlargement in Chédiak-Higashi Syndrome (CHS) occurs to varying degrees in different cell types and has provided insight into the pathophysiology of lysosomal granules. This study was undertaken to determine the extent of involvement of eosinophil crystalloid granules (CGs) and smaller non-crystalloid granules (NCGs) in giant granule formation. Eosinophils from two CHS patients were evaluated after glutaraldehyde fixation and staining for morphologic examination, peroxidase, and complex carbohydrate using uranyl acetate-lead citrate, diaminobenzidine-lead citrate, and periodate-thiocarbohydrazide-silver proteinate (PA-TCH-SP) methods, respectively. Although many CGs appeared normal in shape and size, several CGs appeared enlarged and a few measured over 5 microns in diameter, consistent with giant granule formation in CHS. These giant granules either occasionally contained a single large crystalloid or, more frequently, contained numerous normal-size crystalloids. Enlargement of granules was also observed in some precursor CGs of bone marrow early eosinophils, indicating that giant granule formation was initiated during granule genesis. Almost all NCGs in late eosinophils were small granules and stained strongly with PA-TCH-SP in contrast to CGs. Most, but not all small granules were peroxidase-positive in eosinophil precursors, whereas the percentage of peroxidase-negative small granules increased in late eosinophils. This indicated the presence of at least two small granule populations. Morphometric studies indicated CHS selectively involved CGs and demonstrated that neither the average size nor numbers of NCGs were significantly different from normal eosinophils. Thus, these studies indicate that CHS selectively involves CGs, and demonstrate preservation of normal granule size and heterogeneity for NCGs in late eosinophils. These observations suggest that the underlying CHS pathophysiology does not involve all lysosomal subpopulations.

Carbohydrate Metabolism↗
PubMed1993

Regulation of insulin-like growth factor binding proteins in young growing animals by alteration of energy status.

The regulation of plasma insulin-like growth factor binding proteins (IGFBPs) by energy status has been assessed in 2-month-old pigs. Energy balance was modified by altering thermoregulatory demand and energy intake, with litter-mates being kept for several weeks at either 35 or 10 degrees C on a high (H) or low (L) level of food intake (where H = 2L); plasma samples were taken 20-24 h after the last meal. The two major forms of circulating IGFBP, as estimated by Western blot analysis, were identified putatively as IGFBP-2 and IGFBP-3 (relative molecular weights of 34 and 40-45 kDa respectively). There were significant differences in IGFBP profiles between the four treatment groups of 35H, 35L, 10H and 10L: the 40-45 kDa IGFBP (putative IGFBP-3) was elevated both in the warm and on a high food intake (P < 0.001), and there was a marked reciprocal relation between the 40-45 and 34 kDa IGFBPs. The relative concentration of the 34 kDa IGFBP (putative IGFBP-2) was greatest in the 10L and least in the 35H group. It is concluded that long-term alterations in energy balance, induced by changes in either intake or thermoregulatory demand, can significantly affect the plasma profile of IGFBPs during the first two months of life.

Aging↗
PubMed1993

Acute effects of calcitonin gene-related peptide on the mechanical and electrical responses of the rat hemidiaphragm.

Calcitonin gene-related peptide (CGRP) acutely augments the contractile response of skeletal muscle to both direct and indirect stimulation. However, studies in whole muscle tissues have produced extremely variable results. To determine if differences in stimulation parameters are the source of this variation, the effects of increasing stimulus duration were evaluated in the isolated perfused rat hemidiaphragm. The effect of CGRP on the maximum force of contraction (Fc) was dependent upon the stimulus duration. CGRP (10(-6) M) produced an 11% increase in Fc with a 0.1-msec duration stimulus and a 32% increase with a 1.0-msec stimulus. In contrast, CGRP decreased the time for twitch relaxation and this effect was independent of stimulus duration. Additional studies demonstrated that CGRP shortened the relative refractory period. Compound muscle action potential recordings revealed that stimulus durations greater than 0.5 msec produced a second peak of electrical activity with an associated increased Fc. The effects of CGRP on Fc corresponded to the effects of CGRP on this second peak of compound muscle action potential activity. We conclude that, by decreasing the relative refractory period of the muscle tissue, CGRP enhances the potential for repetitive stimulation with commonly used experimental parameters.

Action Potentials↗