Biomedical subjects

G D Thomas

Publications and source records attributed to G D Thomas.

At least 37 records · Page 2Linked to original sources

PubMed1996

Differential sympathetic neural control of oxygenation in resting and exercising human skeletal muscle.

Metabolic products of skeletal muscle contraction activate metaboreceptor muscle afferents that reflexively increase sympathetic nerve activity (SNA) targeted to both resting and exercising skeletal muscle. To determine effects of the increased sympathetic vasoconstrictor drive on muscle oxygenation, we measured changes in tissue oxygen stores and mitochondrial cytochrome a,a3 redox state in rhythmically contracting human forearm muscles with near infrared spectroscopy while simultaneously measuring muscle SNA with microelectrodes. The major new finding is that the ability of reflex-sympathetic activation to decrease muscle oxygenation is abolished when the muscle is exercised at an intensity > 10% of maximal voluntary contraction (MVC). During high intensity handgrip, (45% MVC), contraction-induced decreases in muscle oxygenation remained stable despite progressive metaboreceptor-mediated reflex increases in SNA. During mild to moderate handgrips (20-33% MVC) that do not evoke reflex-sympathetic activation, experimentally induced increases in muscle SNA had no effect on oxygenation in exercising muscles but produced robust decreases in oxygenation in resting muscles. The latter decreases were evident even during maximal metabolic vasodilation accompanying reactive hyperemia. We conclude that in humans sympathetic neural control of skeletal muscle oxygenation is sensitive to modulation by metabolic events in the contracting muscles. These events are different from those involved in either metaboreceptor muscle afferent activation or reactive hyperemia.

Adult↗

PubMed1996

Sympathetic neural mechanisms of cyclosporine-induced hypertension.

The immunosuppressant drug cyclosporine A (CsA) has emerged as an important new cause of hypertension in both organ transplant recipients and patients with autoimmune diseases. Despite the clinical importance of this hypertension, the underlying mechanisms have been enigmatic. This article presents a conceptual framework for understanding the pathophysiologic basis of CsA-induced hypertension and focuses on the hypothesis that a common molecular mechanism is involved in mediating the immunosuppressive and the hypertensive effects of CsA. This mechanism involves the binding of CsA to a newly discovered class of cytoplasmic receptors (termed "immunophilins") not only in T lymphocytes but also in the kidney, vascular smooth muscle, and central nervous system, which are the main target tissues mediating CsA-induced hypertension. Binding of CsA to its receptor leads to inhibition of calcineurin, the Ca2+/calmodulin-dependent protein phosphatase. Evidence is reviewed to support the hypothesis that calcineurin inhibition plays a pivotal role in mediating both CsA-induced immunosuppression and hypertension, the latter being produced at least in part by sympathetic neural activation. The elucidation of novel CsA-sensitive cellular signaling pathways has lead to the search for the ideal immunosuppressant drug, one which retains CsA's immunosuppressive efficacy but without its toxicity.

Amino Acid Isomerases↗

PubMed1996

The Yorkshire slide exchange external quality assessment (EQA) scheme.

A slide circulation scheme measuring cervical screening performance of individual cytologists in 15 laboratories in Yorkshire Regional Health Authority is described. The advantages and disadvantages are compared with the current National Proficiency Testing (NPT) scheme. The results indicate that a slide circulation scheme can be successfully used in cervical cytology external quality assessment (EQA). Levels of participation are better than those currently achieved by regional variations of the NPT scheme, and the use of laboratory consensus in the selection of scoring slides appears to be no less valid than the use of a pre-selected slide pool assembled by an expert panel. The volume of data accumulated in one round is considerably greater than that achieved by proficiency testing and the educational value is regarded as high. However, the scheme is very time consuming for participants and consequently expensive for laboratories. The lack of external supervision increases the risk of unfair practices within individual laboratories. Because of these problems, Yorkshire has now switched to an NPT scheme.

Cytodiagnosis↗

PubMed1996

Scheduled sanitation to reduce stable fly (Diptera: Muscidae) populations in beef cattle feedlots.

Sanitation has been long recommended as a means of reducing stable fly, Stomoxys calcitrans (L.), populations at cattle feedlots, but there is little published research to support this recommendation. In each of the 2 yr of this study, 4 feedlots received complete sanitation and 4 feedlots received no cleaning. The objective was to have the initial cleaning done before 1 June and then to reclean as needed every 2 wk thereafter. The feedlots that were cleaned had significantly fewer flies than the uncleaned feedlots, with 50.9% fewer stable flies during the 1st yr and 36.2% fewer flies in the 2nd yr. These reductions were realized even though initial cleaning was not done by 1 June in either year: bad weather delayed completion until 20 June the 1st yr and 29 June the 2nd yr. Sanitation at cattle feedlots significantly reduces stable fly populations and sanitation may have been more effective if initial cleaning was done by 1 June.

Animals↗

PubMed1996

Comparison of core sampling and pupal traps for monitoring immature stable flies and house flies (Diptera: Muscidae) in beef feedlot pens.

Core samples and cylindrical pupal traps were used to monitor immature stages of the stable fly, Stomoxys calcitrans (L.), and house fly, Musca domestica L., from 5 sample areas in beef feedlot pens: the feed apron-soil interface, the back fence, the side (pen dividing) fence, the mound, and the general lot. One feedlot was sampled during 1986, two feedlots were sampled in 1987, and three samples were taken at random from each sample area on each sample date. Core samples showed that both populations were highest from the feed apron sample area. Pupal traps tended to show the same result but differences between sample areas were not significant for immature stable flies. Both sampling methods generally indicated similar population trends of the 2 fly species over the season; correlation coefficients between the 2 sampling methods were generally significant but few correlations were strong and large divergences between population trends were present. Only approximately 69% of the total number of pupal traps placed were recovered; the loss of traps could have contributed to differences between the 2 sampling methods. Core sampling would be preferred if lower variance of samples is important; if collecting pupae of known age is important, then pupal traps may be useful if they are protected from trampling by cattle.

Animals↗

PubMed1995

Presynaptic modulation of cortical synaptic activity by calcineurin.

Synaptic plasticity is modulated by Ca(2+)-induced alterations in the balance between phosphorylation and dephosphorylation. Recent evidence suggests that calcineurin, the Ca(2+)-calmodulin-dependent phosphatase (2B), modulates the activity of postsynaptic glutamate receptors. However, in rat cortex, calcineurin is enriched mainly in presynaptic, not postsynaptic, fractions. To determine if calcineurin modulates glutamatergic neurotransmission through a presynaptic mechanism, we used whole-cell patch clamp experiments to test effects of two specific calcineurin inhibitors, cyclosporin A (CsA) and FK506, on synaptic activity in fetal rat cortical neurons. The rate of spontaneous action-potential firing was markedly increased by either CsA or FK506 but was unaffected by rapamycin, a structural analog of FK506 which has no effect on calcineurin. In voltage-clamp experiments, CsA increased the rate but not the amplitude of glutamate receptor-mediated, excitatory postsynaptic currents, suggesting an increased rate of glutamate release. CsA had no effect on the amplitude of currents evoked by brief bath application of selective glutamate receptor agonists, providing further evidence for a pre- rather than postsynaptic site of action. In conclusion, these data indicate that calcineurin modulates glutamatergic neurotransmission in rat cortical neurons through a presynaptic mechanism.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed1994

Overwintering of the stable fly (Diptera: Muscidae) in southeastern Nebraska.

Adult stable flies, Stomoxys calcitrans (L.), were monitored during three winters at two, four, and 13 locations with Alsynite fiberglass traps and by examination of the interiors of buildings. No stable flies were found inside buildings during the winter. Adult stable flies were consistently caught on Alsynite traps at one location during two winters and at two other locations during one winter. Distribution and physiological age of these flies indicate that they emerged from pupae that had developed at or near the location where they were captured. Potential breeding sites were examined. A few third instars were found in silage in midwinter, but silage should not be considered a major source for overwintering stable flies.

Animals↗

PubMed1994

Inhibition of alpha 2-adrenergic vasoconstriction during contraction of glycolytic, not oxidative, rat hindlimb muscle.

Previous studies have produced conflicting evidence as to whether sympathetic vasoconstriction is impaired in active skeletal muscle. Because alpha 2-, not alpha 1-, adrenergic vasoconstriction is attenuated by mild acidosis, we hypothesized that alpha 2-mediated sympathetic vasoconstriction would be attenuated in contracting glycolytic muscle, which produces more acidosis than oxidative muscle. We compared effects of lumbar sympathetic nerve stimulation and alpha-adrenergic agonists on arterial pressure, femoral blood flow, and force output during contractions of oxidative or glycolytic muscles in anesthetized rats. We found that 1) sympathetic vasoconstriction was preserved during contractions of oxidative soleus muscle and during low-intensity contractions of glycolytic gastrocnemiusplantaris muscles but was abolished during maximal contractions of these glycolytic muscles; 2) this sympatholytic effect was caused by impaired alpha 2-, not alpha 1-, vasoconstriction; and 3) the increased muscle blood flow resulting from a combination of impaired vasconstriction and increased arterial pressure was paralleled by increased force of gastrocnemius-plantaris muscle contraction. Thus contraction-induced impairment of alpha 2-vasoconstriction can augment muscle blood flow and muscle contraction, but the degree of impairment depends on fiber type and intensity of muscle contraction.

Adrenergic alpha-Agonists↗

PubMed1994

Muscle metaboreflex triggers parallel sympathetic activation in exercising and resting human skeletal muscle.

Activation of a metabolically generated reflex in exercising skeletal muscle (muscle metaboreflex) in humans is known to trigger increases in sympathetic nerve activity (SNA) to resting skeletal muscles. In seven healthy human subjects, to determine whether this reflex mechanism also increases SNA to the exercising muscles, we recorded muscle SNA with microelectrodes in the right peroneal nerve and in fascicles of the left peroneal nerve selectively innervating the exercising muscles of the left foot. Subjects performed static toe extension at 20% maximal voluntary contraction alone or in combination with foot ischemia. Only static toe extension at 20% MVC during ischemia activated the muscle metaboreflex. This paradigm caused increases in SNA to exercising muscle that paralleled those to the resting muscles: during the first minute of exercise SNA was unchanged, but during the second minute SNA increased from 29 +/- 2 to 38 +/- 2 bursts/min (P < 0.05) to the exercising muscles and from 30 +/- 3 to 40 +/- 2 bursts/min (P < 0.05) to the resting muscles. These bilateral increases in SNA were maintained when metaboreflex activation was sustained by postexercise foot ischemia. In conclusion, these data provide neurophysiological evidence that the muscle metaboreflex evokes parallel sympathetic activation in exercising and resting human skeletal muscle.

Adult↗

PubMed1993

Average daily gains of Brahman-crossbred and English x exotic feeder heifers exposed to low, medium, and high levels of stable flies (Diptera: Muscidae).

Brahman-crossbred and English x Exotic feeder heifers were exposed to low (5 per leg), medium (12 per leg), and high (30 per leg) stable fly, Stomoxys calcitrans (L.), population levels to test relative tolerance of these cattle breeds to stable flies. The Brahman-crossbred heifers were tolerant to stable flies only when they were 12-13 mo old. At the same age, the English x Exotic heifers sustained reductions in average daily gain (ADG) at all three stable fly population levels of 0.22 kg/d (11.2%). At 14-15 mo of age, both breeds were affected only by the high stable fly level. The reduction in ADG was approximately 0.16 kg/d (10.6%) for both breeds. Stable fly numbers on the heifers varied with time of day. Both breeds appeared equally attractive to stable flies. With or without stable flies, the Brahman-crossbred heifers consistently gained less weight than the English x Exotic heifers by 0.24 kg/d (15%).

Analysis of Variance↗

PubMed1991

Optimal tumor targeting by antibodies: development of a mathematical model.

A mathematical model has been developed to optimize tumor targeting with labeled antibodies. The model is compartmental and nonlinear, incorporating saturable binding. Published parameter values have been used in the model, and the resulting stiff differential equations have been solved using FACSIMILE, a computer package that can simulate very stiff differential systems. Results show that successful tumor targeting depends on an optimal combination of antibody dose, affinity, and molecular size. The model has allowed an assessment to be made of the complicated and interrelated dynamic relationships that these factors have on tumor targeting. It has also offered an explanation for previously unsatisfactory results from tumor targeting with labeled antibodies. The structural identifiability of the model parameters is also analyzed and it is shown that, with the prior knowledge of some parameters which is likely in practice, the remaining model parameters are uniquely identifiable.

Algorithms↗

PubMed1991

Developmental sites and relative abundance of immature stages of the stable fly (Diptera: Muscidae) in beef cattle feedlot pens in eastern Nebraska.

A 3-yr study was done to determine where and at what relative frequency stable fly, Stomoxys calcitrans (L.), immatures develop in beef cattle feedlot pens and the relationship of stable fly immature versus adult sample densities. Pens within feedlots were divided into five areas (the feed apron, back fence, side fences, mound, and the general lot); from each area, three core samples were randomly taken weekly. In 1986 and 1987, the feed apron yielded the most immature stable flies (62.5%). The mound and side fences yielded a significant percentage of flies (24.6 and 8.4%, respectively). There was a strong correlation (overall r = 0.86) between numbers of immatures and numbers of adults 2 wk later. In 1988, a drought year, low numbers of immatures were collected, and only one correlation between numbers of immatures and adults was significant. In all 3 yr, sample densities of stable fly immatures peaked and began to decline by midseason. Waste management along the feed apron and mound areas could significantly reduce stable fly populations. Sampling immatures from these areas could permit prediction of adult numbers.

Animals↗

PubMed1991

Chemical sympathectomy alters the development of hypertension in miniature swine.

To determine if the neurotoxin 6-hydroxydopamine could be used to chemically sympathectomize neonatal miniature swine, eight newborn swine were treated with 6-hydroxydopamine beginning on the first day after birth and continuing at regular intervals for the next 6 months. Six littermates served as controls and received vehicle injections. A significant reduction in the pressor response to intravenous tyramine (95%) and in the tissue norepinephrine content of the kidneys, left ventricle, and gastrocnemius muscle (more than 93%) provided evidence for an effective long-term sympathectomy in the 6-hydroxydopamine-treated animals. In addition, the blood pressure response of these young, chemically sympathectomized swine to chronic deoxycorticosterone acetate treatment was evaluated. Mean arterial pressure before deoxycorticosterone was similar in the 6-hydroxydopamine-treated (116 +/- 2 mm Hg) and control (125 +/- 5 mm Hg) groups. One week after deoxycorticosterone, mean arterial pressure had risen significantly by 20-22 mm Hg in both groups. Blood pressure continued to increase in the control group, reaching a value of 163 +/- 6 mm Hg by the third week after treatment. In contrast, mean arterial pressure in the 6-hydroxydopamine group did not increase further during weeks 2 and 3 after deoxycorticosterone. In conclusion, chronic treatment of neonatal swine with 6-hydroxydopamine produced an animal model with an effective, general, peripheral sympathectomy. The significant attenuation of the hypertensive response in these sympathectomized animals lends further support to the hypothesis that an intact sympathetic nervous system is necessary for the full expression of deoxycorticosterone hypertension in miniature swine.

Animals↗

PubMed1991

Acute renal function in chronically sympathectomized deoxycorticosterone acetate-treated miniature swine.

We recently validated a swine model in which chronic treatment with 6-hydroxydopamine (6-OHDA) produced an effective sympathectomy. These sympathectomized swine demonstrated a significantly attenuated hypertensive response when treated with deoxycorticosterone acetate (DOCA). Because renal nerve activity is elevated and important in controlling renal function and blood pressure in the DOCA swine model, we wanted to study the effect of chronic sympathectomy on acute renal hemodynamics and tubular function. Kidney function was assessed in 14 DOCA-treated miniature swine, 8 of which were sympathectomized by chronic treatment with 6-OHDA, while 6 served as controls. Effective renal sympathectomy in this model has been previously confirmed by a significant reduction (97%) of norepinephrine in renal cortical tissue. When anesthetized, mean arterial pressure and renal blood flow were similar between the two groups. Glomerular filtration rate was lower by 43%, urine flow rate by 71%, sodium excretion by 66%, and potassium excretion by 48% in the 6-OHDA DOCA animals. All of these parameters were significantly different from the intact DOCA controls. These results indicate that anesthetized, chronically sympathectomized swine exhibit decreased renal excretory function. The changes in renal function may have been due to the development of a tubular or glomerular supersensitivity to circulating antinatriuretic factors, since the 6-OHDA group had a 28% greater pressor response to the alpha-agonist phenylephrine and a significantly greater fall in mean arterial pressure in response to alpha-blockade with prazosin when compared with the controls. These changes in renal function may also explain why the 6-OHDA animals demonstrated a slight increase in mean arterial pressure in response to DOCA. Because acute renal denervation in DOCA-treated swine produces a diuresis and natriuresis, this study affirms that there may be important functional differences in acutely versus chronically denervated kidneys for which the implications under normal physiologic conditions are unknown.

Animals↗

PubMed1990

Renal denervation decreases blood pressure in DOCA-treated miniature swine with established hypertension.

The role of renal sympathetic nerve activity (RSNA) in the maintenance phase of essential hypertension has not yet been clearly defined. Renal function and mean arterial pressure (MAP) were studied in four Yucatan miniature swine (YMS) with established DOCA hypertension prior to and for 3 weeks after surgical renal denervation (RDX). During the first week post-RDX, MAP decreased from 141 /+- 6 to 121 +/- 3 mm Hg (P less than .05), while sodium balance increased from 0.32 +/- 0.05 to 0.95 +/- 0.14 mEq/kg/day (P less than .05). By 3 weeks post-RDX, MAP remained below normotensive levels while sodium balance returned to the pre-RDX value. There was no significant change in potassium or water balance after RDX. Thus, in DOCA-YMS the renal nerves are important in the maintenance of hypertension. The reduction in MAP with RDX in the absence of a natriuresis suggests a role for renal afferent nerve activity.

Analysis of Variance↗

PubMed1990

Increased ischemic injury but decreased hypoxic injury in hypertrophied rat hearts.

The purpose of this study was to compare the degree of ischemic and hypoxic injury in normal versus hypertrophied rat hearts to investigate basic mechanisms responsible for irreversible myocardial ischemic injury. Hearts from rats with bands placed on the aortic arch at 23 days of age (BAND) and sham-operated rats (SHAM, 8 weeks postoperative) were isolated, perfused with Krebs buffer, and had a left ventricular balloon to measure developed pressure. Hearts were made globally ischemic until they developed peak ischemic contracture and were reperfused for 30 minutes. Additional hearts were perfused for 15 minutes with glucose-free hypoxic buffer followed by 20 minutes of oxygenated perfusion. There was an 87% increase in heart weight of BAND compared with SHAM (p less than 0.01). During ischemia, lactate levels increased faster in BAND compared with SHAM, ischemic contracture occurred earlier in BAND than in SHAM despite no difference in ATP levels, and postischemic recovery of left ventricular pressure was less in BAND (26.8 +/- 5.6% of control left ventricular pressure, mean +/- SEM) compared with SHAM (40 +/- 4.6%, p less than 0.05). During hypoxic perfusion, lactate release was greater in BAND than in SHAM (48.8 +/- 1.2 versus 26.6 +/- 0.97 mumols/g, p less than 0.01), and with reoxygenation, lactate dehydrogenase release was less in BAND than in SHAM (13.2 +/- 0.7 versus 19.5 +/- 0.2 IU/g, p less than 0.01). After hypoxia and reoxygenation, left ventricular pressure recovery was greater in BAND than in SHAM (93 +/- 8.4% versus 66 +/- 5.3%, p less than 0.01). Thus, this study suggests that hypertrophied hearts have a greater potential for glycolytic metabolism, resulting in an increased rate of by-product accumulation during ischemia, which may be responsible for the increased susceptibility of hypertrophied hearts to ischemic injury.

Adenosine Triphosphate↗

PubMed1990

Effects of 6-hydroxydopamine in hypertensive adult miniature swine.

To validate a miniature swine model of sympathectomy, six swine that had chronic high blood pressures for unknown reasons and five DOCA hypertensive swine were treated with a single dose of the neurotoxin 6-hydroxydopamine (6-OHDA) (50 mg/kg i.v.). One week after 6-OHDA, conscious mean arterial pressure (MAP) had fallen by 47-49 mmHg and the pressor response to tyramine was attenuated in both groups. Norepinephrine content was significantly decreased in the kidneys (greater than 85%) and left ventricle (greater than 94%) in both 6-OHDA treated groups. These results indicate that 6-OHDA can be used to effectively sympathectomize adult swine. Chemical sympathectomy of swine with either unexplained high blood pressure or experimentally induced DOCA hypertension resulted in an equivalent fall in MAP in both of these populations. Further studies using 6-OHDA in miniature swine may help to elucidate the mechanisms involved in maintaining hypertension in this animal model.

Animals↗

PubMed1990

Theoretical considerations for improving tumour targeting.

To determine the relative importance of factors influencing tumour uptake of antibodies, we used a mathematical model to simulate intravenous injection of substances of varying molecular sizes and tumour-binding affinities at several dose levels. The FACSIMILE program was used to simulate the time course of tumour uptake of the tumour-binding substance by calculating the instantaneous tumour content (TC) and tumour:background uptake ratios (UR). Relative total doses to tumour and normal tissue were calculated by integration of TC/time curves. The model was used to make theoretical predictions on the effects of altering different parameters. The size of the injected dose in relation to the number of tumour receptors was crucial:if too low, uptake could not be improved by manipulating other variables, and if too high, the UR for large binding molecules was reduced. Using the standard scanning dose of labelled antibody, absolute numbers of labelled molecules binding to tumour could be increased by injection of a large excess of unlabelled molecules. Given an adequate dose, peak tumour content increased with increasing affinity up to receptor saturation. The peak uptake ratio rose progressively with affinity for a small ligand, but reached a relatively low plateau for antibody due to constant high background levels. At low doses such as those currently administered for diagnostic scanning with antibody, no effect of increasing affinity was predicted.

Antibodies, Monoclonal↗