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Biomedical subjects

D P Thomas

Publications and source records attributed to D P Thomas.

At least 19 recordsLinked to original sources
PubMed1995

Human Rh D monoclonal antibodies (BRAD-3 and BRAD-5) cause accelerated clearance of Rh D+ red blood cells and suppression of Rh D immunization in Rh D- volunteers.

The use of prophylactic anti-D to prevent Rh D immunization in Rh D- women and subsequent hemolytic disease in Rh D+ infants is widespread, but has led to shortages of the anti-D Ig. With the aim of substituting monoclonal anti-D for Rh D prophylaxis, we have compared the abilities of monoclonal and polyclonal anti-D to clear Rh D+ red blood cells (RBCs) infused into Rh D- male volunteers and to suppress Rh D immunization. Two human monoclonal antibodies (MoAbs), BRAD-3 (IgG3) and BRAD-5 (IgG1), produced from stable Epstein-Barr virus-transformed B-lymphoblastoid cell lines, were selected because of their proven in vitro activity in promoting RBC lysis in antibody-dependent cell-mediated cytotoxicity assays. RBC clearance was assessed by intravenous injection of 3 mL of 51chromium-labeled D+ RBCs into 27 volunteers 48 hours after intramuscular injection of monoclonal or polyclonal anti-D. Further 3-mL injections of unlabeled D+ cells were administered at 6 and 9 months to induce immunization. Blood samples were taken throughout the 12-month period of study for the serologic detection of anti-D. The mean half-life (t50%) of RBCs in 7 recipients of 300 micrograms BRAD-5 (5.9 hours) was similar to that in 8 recipients of 500 IU polyclonal anti-D (5.0 hours), whereas D+ cells were cleared more slowly in some of the 8 subjects injected with 300 micrograms BRAD-3 (mean t50% 12.7 hours) and in 1 individual administered 100 micrograms BRAD-3 (t50% 41.0 hours). The rate of RBC clearance in both groups administered 300 micrograms monoclonal anti-D correlated with the amount of antibody bound per cell, determined by flow cytometry. There was no evidence of primary immunization having occurred in any subject after 6 months of follow-up. Five of 24 subjects produced anti-D after one or two further injections of RBCs, confirming that they were responders who had been protected by the monoclonal or polyclonal anti-D administered initially. Four of these responders were recipients of monoclonal anti-D (3 BRAD-3, 1 BRAD-5). One individual who received BRAD-5 produced accelerated clearance of D+ RBCs at the third unprotected RBC challenge but did not seroconvert. This study shows that the human MoAbs BRAD-3 and BRAD-5 can prevent Rh D immunization, and indicates that they may be suitable replacements for the polyclonal anti-D presently used in prophylaxis of Rh D hemolytic disease of the newborn.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1992

The effect of pedaling frequency on glycogen depletion rates in type I and type II quadriceps muscle fibers during submaximal cycling exercise.

This study was conducted to determine whether the pedaling frequency of cycling at a constant metabolic cost contributes to the pattern of fiber-type glycogen depletion. On 2 separate days, eight men cycled for 30 min at approximately 85% of individual aerobic capacity at pedaling frequencies of either 50 or 100 rev.min-1. Muscle biopsy samples (vastus lateralis) were taken immediately prior to and after exercise. Individual fibers were classified as type I (slow twitch), or type II (fast twitch), using a myosin adenosine triphosphatase stain, and their glycogen content immediately prior to and after exercise quantified via microphotometry of periodic acid-Schiff stain. The 30-min exercise bout resulted in a 46% decrease in the mean optical density (D) of type I fibers during the 50 rev.min-1 condition [0.52 (0.07) to 0.28 (0.04) D units; mean (SEM)] which was not different (P > 0.05) from the 35% decrease during the 100 rev.min-1 condition [0.48 (0.04) to 0.31 (0.05) D units]. In contrast, the mean D in type II fibers decreased 49% during the 50 rev.min-1 condition [0.53 (0.06) to 0.27 (0.04) units]. This decrease was greater (P < 0.05) than the 33% decrease observed in the 100 rev.min-1 condition [0.48 (0.04) to 0.32 (0.06) units). In conclusion, cycling at the same metabolic cost at 50 rather than 100 rev.min-1 results in greater type II fiber glycogen depletion. This is attributed to the increased muscle force required to meet the higher resistance per cycle at the lower pedal frequency.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Effect of recovery mode following hind-limb suspension on soleus muscle composition in the rat.

The purpose of this study was to compare the effects of two different recovery modes from hind-limb suspension-induced hypodynamia on whole body and muscle (soleus) growth as well as soleus composition and size changes of different fiber types within this same muscle. Following 28 days of tail-suspension, rats were returned to their cages and sedentarily recovered (HS), or were exercised by running on a treadmill 5 days/wk, at progressively increasing workloads (HR) for one month. Sedentary and running control groups of animals (CS, CR) were also evaluated for comparative purposes. The exercise program, which was identical for CR and HR groups, had no effect on body wt., soleus wt., soleus muscle composition or fiber size in CR rats. Atrophied soleus muscle and reduced soleus wt./body wt. ratio (both 60% of control) had returned to control values by day 7 of recovery in both suspended groups despite the fact that whole body wt. gain was significantly reduced (p less than 0.05) in HR as compared to HS rats. Atrophied soleus Type I fiber mean cross-sectional area in both HR and HS groups demonstrated similar and significant (p less than 0.01) increases during recovery. Increases in Type IIa and IIc fiber area during this same period were significant only in the HR group. While the percentage area of muscle composed of Type I fibers increased in both hypodynamic groups during recovery, the reduction in area percentage of muscle made up of Type IIa fibers was again only significant in the HR group.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Aging- and training-induced alterations in collagen characteristics of rat left ventricle and papillary muscle.

We evaluated the single and interactive effects of aging and exercise training on selected parameters of myocardial interstitium in both the left ventricle (LV) and LV papillary muscle of female Fischer 344 specific pathogen-free rats. Ten weeks of treadmill running resulted in significant LV hypertrophy as well as elevated plantaris muscle citrate synthase activity in both young adult (5-mo-old) and senescent (23-mo-old) trained animals (YT, young trained; OT, old trained) compared with age-matched sedentary controls (YC, young control; OC, old control). Proline and hydroxyproline pools were significantly higher (both P less than 0.05) in 23-mo-old vs. 5-mo-old papillary muscles. Degree of maturation (nonreducible cross-linking) of LV collagen was evaluated by measurement of hydroxylysylpyridinoline concentration ([HP]). In a comparison of YC with OC rats, ventricular [HP] increased approximately fivefold from 0.059 +/- 0.007 to 0.285 +/- 0.018 (SE) mol HP/mol collagen (P less than 0.001). Whereas training had no effect on ventricular [HP] in young adult rats, it significantly reduced LV collagen cross-linking in OT rats (0.131 +/- 0.027) so that HP values in this group were less than one-half of those observed in OC rats. Because both collagen concentration and degree of cross-linking are thought to affect muscle stiffness characteristics, we conclude that the observed changes should be considered in any explanation for aging- and training-induced alterations in LV and papillary muscle contractile indexes.

Aging↗
PubMed1992

Exercise-induced satellite cell activation in senescent soleus muscle.

The purposes of this study were 1) to determine satellite cell mitotic activity and myofiber nuclear density in the soleus muscle of aged rats and 2) to examine the effect of exercise training on these same parameters. Twenty-four-month-old specific pathogen-free female Fischer 344 rats were assigned to either a training or a control group. The trained group performed 10 wk of progressive treadmill running that resulted in a significant increase (P less than or equal to 0.05) in vastus lateralis muscle malate dehydrogenase activity compared with control rats. Training produced a doubling of soleus muscle satellite cell mitotic activity (trained 1.28 +/- 0.33, control 0.52 +/- 0.13 thymidine-labeled satellite cells per 1,000 nuclei; P less than or equal to 0.05). Training also resulted in a doubling in the number of damaged fibers in the soleus muscle (P less than or equal to 0.05). Mean myofiber nuclear density was unaltered by exercise training but varied as a function of soleus muscle fiber size. Nuclear density of a subpopulation of small fibers (cross-sectional area less than one standard deviation below the mean cross-sectional area of all fibers examined) was significantly higher (P less than or equal to 0.05) than in other fibers in the soleus muscle. A high nuclear density and small size suggest that these fibers were immature. In addition, the soleus muscle from trained rats had significantly more (P less than or equal to 0.05) small fibers with high nuclear density than muscle from control animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1992

Training-induced alterations in young and senescent rat diaphragm muscle.

The current study sought to examine the effects of chronic endurance treadmill running on oxidative capacity and capillary density in specific diaphragm muscle fiber types in young (5 mo) and senescent (greater than or equal to 23 mo) female Fischer 344 rats. Both young and senescent animals trained at approximately 75% of maximal O2 consumption for 1 h/day 5 days/wk for 10 wk. Plantaris citrate synthase activity was significantly increased (P less than 0.01) in both young and old trained groups. Densitometric analysis of succinate dehydrogenase (SDH) activity in diaphragm type I, IIa, and IIb muscle fibers was done using a computerized image-processing system. There were no age-related differences in SDH activity between the young and old groups for any of the fiber types. In addition, SDH activity was found to be significantly increased (P less than 0.05) in all three fiber types in both the young and senescent trained animals compared with their sedentary counterparts. Fiber size and capillary density did not differ between young and senescent rats, nor did exercise affect this measure. Each fiber, irrespective of type, had an average of approximately four capillaries in contact with it. However, type IIb fibers had a significantly lower capillary density per unit area than type I or IIa muscle fibers. The results indicate that the senescent costal diaphragm maintains its ability to adapt to an increased metabolic demand brought about by locomotor exercise. Of further interest is the finding that training adaptations occurred in all three fiber types, suggesting that increased work of breathing from moderate exercise leads to recruitment of all three fiber types.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1992

Myosin heavy chain composition in the rat diaphragm: effect of age and exercise training.

Increases in aerobic capacity in both young and senescent rats consequent to endurance exercise training are now known to occur not only in locomotor skeletal muscle but also in diaphragm. In the current study the effects of aging and exercise training on the myosin heavy chain (MHC) composition were determined in both the costal and crural diaphragm regions of female Fischer 344 rats. Exercise training [treadmill running at 75% maximal oxygen consumption (1 h/day, 5 day/wk, x 10 wk)] resulted in similar increases in plantaris muscle citrate synthase activity in both young (5 mo) and old (23 mo) trained animals (P < 0.05). Computerized densitometric image analysis of fast and slow MHC bands revealed the ratio of fast to slow MHC to be significantly higher (P < 0.005) in the crural compared with costal diaphragm region in both age groups. In addition, a significant age-related increase (P < 0.05) in percentage of slow MHC was observed in both diaphragm regions. However, exercise training failed to change the relative proportion of slow MHC in either the costal or crural region.

Aerobiosis↗
PubMed1991

The effect of interleukin-1 on venous endothelium--an ultrastructural study.

The effect of systemic interleukin-1 (IL-1) on venous endothelium in the presence and absence of stasis has been studied by scanning electron microscopy (SEM). Recombinant human IL-1 beta at a concentration of 1 micrograms/kg or saline was injected intravenously into rabbits and allowed to circulate for 0.5 or 4.0 h after which complete stasis was induced for 1 h in an isolated segment of each jugular vein. One vein segment was then excised and the contents examined macroscopically for thrombi, while the other segment was fixed for SEM examination. When examined by SEM the endothelium from rabbits injected with IL-1 beta was perturbed with increased surface microvilli, blebs and gaps at cell junctions when compared with saline controls. Fibrin deposition was also observed after IL-1 beta, as was the adherence of essentially non-activated platelets to intact endothelium. However, macroscopic thrombi were not formed in isolated vein segments. We conclude that although fibrin strands and platelets were deposited on the endothelium, IL-1 is not a sufficiently powerful procoagulant stimulus to lead to an occlusive thrombus in acute experiments.

Animals↗
PubMed1991

Experimental studies on a recombinant hirudin, CGP 39393.

The in vitro anticoagulant activities of recombinant desulphatohirudin (r-hirudin) were studied in the activated partial thromboplastin time (APTT) and the thrombin generation test systems. In the APTT, at concentrations below 5 micrograms/ml, r-hirudin showed a dose-response curve. At concentrations above 5 micrograms/ml, the plasma became unclottable, but in the thrombin generation test, at least 10 micrograms/ml of r-hirudin was required for full inhibition of thrombin generation. The antithrombotic effect was assessed using a rabbit venous stasis model; 150 micrograms/kg r-hirudin completely prevented thrombus formation at 10 and 20 min stasis. At this full antithrombotic dose, the mean bleeding time ratio measured in a rabbit ear template model, was not prolonged over control values. At higher doses, the bleeding time ratios were higher than those observed for the same dosage of heparin. These data indicate that while r-hirudin is an effective antithrombotic agent, antithrombotic doses have to be carefully titrated to avoid excessive bleeding.

Animals↗
PubMed1991

Effect of exercise training on antioxidant and metabolic functions in senescent rat skeletal muscle.

Aging is known to be associated with alterations of both oxidative capacity and antioxidant status in skeletal muscle. In the present investigation we compared the activity of enzymes involved in both metabolic functions and antioxidant defense capacity in young adult (5 months old) and senescent (27.5 months old) Fischer 344 rats. In addition, we studied the effects of chronic exercise training on these enzymes in the senescent skeletal muscle. Old sedentary rats had significantly lower glutathione peroxidase (GPX) activity (-22%, p less than 0.05) in the deep portion of vastus lateralis muscle (DVL) than young sedentary rats, but after a progressive 10-week treadmill training program GPX activity in DVL was significantly increased in old rats to a level higher than that seen in young sedentary rats. Superoxide dismutase and catalase activities in the DVL were not altered significantly with aging or by training. Glutathione S-transferase activity in the same muscle was elevated (p less than 0.05) with aging but unaffected by training. Citrate synthase and malate dehydrogenase activities in the DVL muscle were significantly decreased in senescence, whereas training increased these two enzyme activities by 71 and 48%, respectively (both p less than 0.05). Lactate dehydrogenase activity in the same muscle decreased with age but increased 23% (p less than 0.05) in old rats. These data indicate that while aging may significantly affect antioxidant and metabolic capacities in skeletal muscle, regular exercise can preserve functions of these enzyme systems at old age.

Aging↗
PubMed1991

Effect of training on VO2max, thigh strength, and muscle morphology in septuagenarian women.

The purpose of this study was to determine the effects of a long-term (50 wk) combined aerobic-resistance training program on maximal oxygen consumption (VO2max, thigh strength, and vastus lateralis fiber morphology in healthy septuagenarian women (mean age = 72 +/- 6 yr). Subjects volunteered to be in either an exercise (Ex; N = 17) or control (Con; N = 10) group. Con subjects were 34% less active in winter than in summer, Ex subjects maintained their summer activity level on exercise days in winter. Initial, intermediate (20 wk), and final (50 wk) measurements were made for isokinetic knee extension/flexion strength; VO2max and morphological measurements from a muscle biopsy were made at the initial and final times only. Both groups gained in leg strength (Ex = +6.5%; Con = +7.8%; P less than or equal to 0.05) during the summer; in the winter the Ex group maintained leg strength and the Con group declined 12.2% (P less than or equal to 0.05). The fast-twitch muscle fiber area (Type IIb) increased 29% (P less than or equal to 0.001) in the Ex group and declined 26% (P = 0.014) in the Con group. VO2max increased only in the Ex group (16%; P less than 0.001). We conclude that healthy septuagenarian women can increase aerobic capacity, leg strength, and Type IIb muscle fiber area with a long-duration, combined aerobic-resistance exercise program.

Aged↗
PubMed1990

Potentiation of the antithrombotic action of dermatan sulphate by small amounts of heparin.

We have examined the effect in impairing thrombus formation of a preparation of dermatan sulphate (DS) alone and DS plus small amounts of unfractionated heparin (UFH). In rabbits given a dose of 150 micrograms/kg of DS alone, there was minimal reduction in serum-induced stasis thrombosis (Wessler model), with an overall score of 92.5% (100% = no impairment of thrombus formation). When the same dose of DS containing UFH was given (two different subgroups given DS containing 0.25 and 2.5% heparin by dry weight, respectively), the overall thrombus score was reduced to 60% (P less than 0.003), with no significant difference between the two subgroups. To achieve a comparable result with DS alone, a dose of 1 mg/kg was required. We conclude that very small amounts of UFH significantly enhance the antithrombotic action of DS, by a mechanism that has yet to be determined.

Animals↗
PubMed1990

Bone mechanical properties after exercise training in young and old rats.

The effects of a 10-wk training regimen on the mechanical properties of the femur and humerus were evaluated in 2.5- and 25-mo-old Fischer 344 female rats. The rats trained on a rodent treadmill 5 days/wk for 10 wk. Duration, grade, and speed increased until the rats maintained 1 h/day at 15% grade and either 15 m/min (old rats) or 36 m/min (young rats). Excised bones were mechanically tested with a 3-point flexure test for mechanical properties of force, stress, and strain. Fat-free dry weight (FFW) and moment of inertia were also obtained. With aging, similar increases were observed in both the femur and humerus for FFW, moment of inertia, and force. Ultimate stress was reduced in the senescent femur while strain was elevated; a similar but nonsignificant trend was observed in the humerus. Irrespective of age, training increased FFW in the femur and, to a lesser degree, in the humerus. Breaking force was elevated for both bones after training. In young and old bones, the training-induced differences in bone mass and force were similar, despite differences in training intensity. In the old trained rats, femur ultimate stress was greater than that in control rat femurs and similar to that in young rat femurs. The results of the present study indicate that training effects were not limited by age.

Aging↗
PubMed1990

Exercise training attenuates diet-induced reduction in metabolic rate.

The combined influence of exercise training and dietary restriction on daily energy expenditure was evaluated by exposing 48 male Sprague-Dawley rats to one of three food intake conditions [ad libitum (AL), moderately restricted (MR), or severely restricted (SR)] and to one of two exercise conditions [treadmill exercised (E) or cage confined (CC)]. After 10 wk of exercise and dietary restriction, the MR-CC and MR-E rats weighed 84 and 86%, respectively, of AL-CC, whereas the SR-CC and SR-E rats weighed 66 and 68% of AL-CC. Dietary restriction and subsequent weight loss produced significant reductions in both total and resting daily energy expenditure. Exercise partially reversed this effect, but the extent of this reversal diminished as the severity of dietary restriction was increased. These results raise the distinct possibility that inconsistencies in the current literature concerning the effects of exercise on whole body metabolism during periods of dietary restriction might be reconciled by an appreciation and an understanding of the influence that duration of exercise training and severity of food restriction have on this measure.

Animals↗