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Biomedical subjects

T Graham

Publications and source records attributed to T Graham.

At least 73 records · Page 4Linked to original sources
PubMed1992

Elevated muscle acidity and energy production during exhaustive exercise in humans.

This study examined the effect of previous intense exercise on energy production during exhaustive exercise. Subjects (n = 6) performed dynamic knee extensor exercise to exhaustion twice (Ex1 and Ex2) separated by 16 min of recovery consisting of 10 min of rest, 3.5 min of very high-intensity intermittent exercise, and a further 2.5 min of rest. This resulted in an elevated muscle lactate concentration of 13.1 mmol/kg wet wt before Ex2. Muscle lactate concentration was the same at end of Ex1 and Ex2, but the accumulation of lactate and net lactate release during Ex2 was reduced (P < 0.05) by 67 and 38%, respectively. The time to exhaustion was 3.73 and 2.98 min, respectively, and the mean rate of net lactate production for Ex2 was lower (P < 0.05) than for Ex1 (4.6 +/- 1.2 and 9.6 +/- 1.7 mmol.min-1.kg wet wt-1, respectively). Leg O2 uptake was the same for Ex1 and Ex2. Muscle pH (6.85) was lowered (P < 0.05) before Ex2, but at the end of Ex2 (6.77) it tended (P < 0.1) to be higher compared with that at the end of Ex1 (6.73). In summary, the net lactate production rate is reduced but the aerobic energy production is not significantly altered when intense exercise is repeated. Fatigue and the lowered glycolysis do not appear to be caused by the elevated acidity per se before exercise.

Acid-Base Equilibrium↗
PubMed1992

Acute and habitual caffeine ingestion and metabolic responses to steady-state exercise.

This study compared the exercise catecholamine and metabolic responses to a caffeine challenge in trained subjects before and after a 6-wk period of increased caffeine ingestion. Trained subjects (n = 6) were challenged with 500 mg of caffeine followed by prolonged exercise before and after 6 wk of increased caffeine ingestion (500 mg ingested before each daily run). A control group (n = 6) of trained subjects followed the same protocol except for caffeine ingestion. Acute caffeine ingestion resulted in increased plasma epinephrine and decreased respiratory exchange ratio (RER) during exercise. After 6 wk of caffeine supplementation, the epinephrine response to exercise or caffeine plus exercise was decreased, although the latter still resulted in a lower RER value compared with exercise without caffeine ingestion. Activity of key metabolic enzymes (hexokinase, citrate synthase, phosphorylase, and 3-hydroxyacyl-coenzyme A dehydrogenase) from biopsies of the gastrocnemius showed no response to 6 wk of this increased adrenergic receptor stimulation and, on the basis of the lower RER, enhanced fat metabolism. This study suggests that caffeine ingestion by trained subjects causes increases in plasma epinephrine and reduces the RER during exercise. However, habitual stimulation results in a general dampening of the epinephrine response to caffeine or exercise. There was no indication that increased adrenergic stimulation and fat oxidation caused any adaptation in the activity of metabolic enzymes.

Adult↗
PubMed1992

Characterization of B-cell phenotypic changes during ileal and jejunal Peyer's patch development in sheep.

Changes in B-cell phenotype during development of ileal and jejunal Peyer's patches (PP) of sheep were investigated using flow cytometry and immunoperoxidase-stained cryosections. On Day 104 of gestation (term at 150 days) B-cell clusters were identified in the lamina propria of the ileum. These clusters were composed of cells that expressed surface IgM (sIgM), lambda or kappa light chain, and BAQ44A, a B-cell differentiation molecule. No cells in the clusters stained for terminal deoxynucleotide transferase. On Day 132 gestation, a change was evident in the phenotype of ileal PP B cells. Most B cells expressed a reduced level of sIgM and 20% were BAQ44A-. The B cells in the dome region were BAQ44A+ but few BAQ44A+ cells were present in the follicles. At 6-8 weeks of age BAQ44A+ cells were restricted to the dome region of the ileal PP; flow cytometric analysis confirmed that 25% of B cells isolated from the dome/follicle complex were BAQ44A+. Thus, the primordial PP was populated with B cells that were phenotypically similar to circulating B cells (sIgMhigh, BAQ44A+). After 132 days gestation, the predominant B-cell phenotype in the ileal PP changed to sIgMlow and BAQ44A-. This phenotypic change could be the result of either early immigrant B-cell differentiation or subsequent colonization by sIgMlow BAQ44A- B cells. The phenotypic changes of ileal PP follicular B cells were not complete until after birth and different phenotypic changes were observed in follicles of the jejunal PP of young lambs.

Animals↗
PubMed1992

Guidelines for cardiac monitoring of children during and after anthracycline therapy: report of the Cardiology Committee of the Childrens Cancer Study Group.

The anthracycline antibiotics, daunorubicin, doxorubicin, and the newer derivatives, are important components of many antineoplastic chemotherapeutic regimens. Their usefulness is limited by their cardiotoxicity. Sequential monitoring of cardiac function of patients undergoing chemotherapy allows identification of subclinical cardiotoxicity. In many patients monitoring can thus guide the modification of the chemotherapy to minimize cumulative cardiotoxicity, reducing acute and long-term clinical and subclinical sequelae. Such monitoring also aids in the comparison of cardiotoxicity produced by different drugs and different methods and schedules of drug administration. The considerable variability of monitoring regimens between institutions and in the literature has detracted from its usefulness. The Cardiology Committee of the Childrens Cancer Study Group has, therefore, reviewed the field and has formulated recommendations for standardized noninvasive monitoring of children during and immediately after chemotherapy and for the modification of the chemotherapy where indicated.

Antibiotics, Antineoplastic↗
PubMed1991

Prevention of transfusion-induced sensitization to minor histocompatibility antigens on DLA-identical canine marrow grafts by gamma irradiation of marrow donor blood.

Dogs given total-body irradiation and marrow transplants from DLA-identical littermates exhibit prompt and sustained hematopoietic engraftment. However, animals given three preceding blood transfusions from the marrow donor before transplant become sensitized and reject the marrow graft. Rejection is due to exposure to polymorphic minor non-DLA histocompatibility antigens expressed on blood mononuclear cells. We sought to determine whether heat treatment would prevent blood from sensitizing recipients in this model since heating blood to 45 degrees C for 45 min abrogates the ability of blood mononuclear cells to stimulate in mixed lymphocyte culture. Three of 4 evaluable dogs given heat-treated blood before transplant rejected their marrow grafts. To prevent possible reexpression/reacquisition of mononuclear cell functional activity in vivo after transfusion, subsequent dogs were given heated blood that was additionally exposed to 2000 cGy gamma irradiation. Eight of 10 evaluable dogs given blood treated in this fashion engrafted. Unexpectedly, 9 out of 10 evaluable dogs transfused with blood treated only with gamma irradiation also engrafted. These results demonstrate that treatment of blood with gamma irradiation alone or in combination with heat prevents transfusion-induced sensitization to minor histocompatibility antigens. Results from this canine model suggest that blood products be gamma irradiated before transfusion in patients who are transplant candidates in order to prevent sensitization to minor histocompatibility antigens and reduce the risk of marrow graft rejection.

Animals↗
PubMed1990

Bone marrow transplantation in canine GM1 gangliosidosis.

Allogeneic bone marrow transplantation was carried out in an 81-day-old Portuguese water dog with GM1 gangliosidosis using a DLA identical sibling as donor. Engraftment was complete and beta-galactosidase activity in leukocytes of the transplanted dog were similar to those in the donor. Over the next 2.5 months neurological deterioration in the transplanted dog was similar to that in untreated dogs with GM1 gangliosidosis. Cerebral ganglioside GM1 concentrations were not diminished by bone marrow transplantation and cerebral beta-galactosidase activity was negligible. We conclude that allogeneic bone marrow transplantation early in life is ineffective in canine GM1 gangliosidosis.

Animals↗
PubMed1990

Lactate and potassium fluxes from human skeletal muscle during and after intense, dynamic, knee extensor exercise.

This study examines lactate and K+ fluxes from muscle to blood during and after intense exercise. Ten men performed exhaustive dynamic exercise (mean load 65 W, mean duration 3.18 min) with the knee extensors of one leg. The mean lactate efflux was 15.5 (range 8.9-24.0) mmol min-1 at exhaustion, and it was linearly related to the lactate gradient. A linear relationship was also obtained if the H+ gradient was taken into account. Muscle pH decreased from 7.14 at rest to 6.71 (range 6.50-6.87) at exhaustion. At rest and during late recovery blood lactate was distributed across the erythrocyte membrane according to the membrane potential (intra-/extracellular ratio of 0.5), but during rapid lactate release this ratio decreased to 0.2. In-vitro experiments demonstrated a time constant of 1.2 min for lactate efflux from the erythrocytes. Approximately 70% of the K+ ions released from the muscle to the blood accumulated in the plasma; the rest were taken up by other tissues. However, erythrocytes were not involved as a dilution space. The small change in erythrocyte K+ concentration was due to cellular volume changes. During recovery the kinetics of K+ reuptake by the muscle were described by a very fast (less than 1 min) and a slow component (greater than 1 min): the magnitude of the former was equivalent to what had accumulated in the plasma. Individuals displayed a wide range of intramuscular lactate concentrations and pH values at exhaustion. Further, the pH changes were not as extreme as previously reported, suggesting that pH may not be the only factor involved in the fatigue process. A possible role for the potassium shifts as a limiting factor for muscle function is discussed.

Adult↗
PubMed1990

Failure of anti-MHC antibodies to prevent GVHD in DLA mismatched unrelated canine marrow recipients.

Gene products of the major histocompatibility complex (MHC) have been shown to elicit lethal graft-versus-host disease (GVHD) in experimental animals. Antibodies specific for MHC cell surface determinants might therefore be expected to overcome histocompatibility barriers and influence survival of marrow graft recipients. GVHD can be consistently induced in dogs by transplanting donor marrow cells into lethally irradiated, unrelated, mismatched recipients. Three anti-Ia monoclonal antibodies were administered to five canine recipients, each at a dose of 0.2 mg/kg body weight per day intravenously for 10 days, beginning on day 0, the day of transplantation. Eight canine recipients were treated with antidog alloantiserum 10 ml/kg body weight per day intravenously on days -2 to day +20, in addition to receiving postgrafting methotrexate. The antiserum was generated by immunizing a matched littermate of the donor with peripheral blood cells of the recipient before transplantation. Survival was no different in the two groups of dogs, compared with historical controls without antibody treatment. A possible explanation for the failure of anti-MHC antibodies to modify acute GVHD in the dog is the inability of antibody to reach critical tissue sites targeted in GVHD.

Animals↗
PubMed1989

Bone marrow toxicity of total-body irradiation combined with radiosensitizers.

The effect of the addition of radiosensitizers to low-dose total-body irradiation was studied. SR2508 (1 g/kg) or misonidazole (0.35 g/kg) was given 30 min prior to single-dose total-body irradiation, delivered at 0.1 Gy/min. Six dogs received either SR2508 or misonidazole and 2 Gy irradiation, and 14 dogs served as controls, receiving no drug and either 2 or 3 Gy of total-body irradiation. All dogs had a decline in their white blood cell and platelet counts and were supported with prophylactic antibiotics and platelet transfusions. High plasma levels of both radiosensitizers were achieved. The degree of cytopenia with 2 Gy total-body irradiation when combined with either radiosensitizer was not significantly greater than that seen with 2 Gy alone, and the neutropenia was significantly less than that seen with 3 Gy alone. The only observed toxicity of the drugs was vomiting, which started shortly after the infusion of SR2508 and before the radiation treatment. A single high-dose infusion of a radiosensitizer combined with total-body irradiation appears to cause a mild increase in bone marrow toxicity but is otherwise well tolerated.

Animals↗
PubMed1989

Antibody-radionuclide conjugates as part of a myeloablative preparative regimen for marrow transplantation.

The behaviors of an anti-Ia antibody (7.2) and an antibody directed at a lymphocyte adhesion molecule (S.5) radiolabeled with 131I were studied in normal dogs. Antibody 7.2 localized to spleen and, to a lesser extent, to marrow and lymph nodes. Antibody S.5 rapidly localized to marrow and spleen, achieving tissue/blood ratios greater than 6:1 within three hours of injection that were maintained for at least 48 hours. Prior treatment with cyclophosphamide (CY) markedly altered the distribution of S.5 but had much less effect on the distribution of 7.2 and almost no effect on the distribution of a control antibody. When animals were treated with increasing doses of 131I labeled to S.5, lethal myelosuppression occurred when a dose of 6 mCi/kg was reached. At this dose, the otherwise lethal effects of 131I could be reversed with autologous marrow transplant support.

Animals↗
PubMed1988

L-leucyl-L-leucine methyl ester treatment of canine marrow and peripheral blood cells. Inhibition of proliferative responses with maintenance of the capacity for autologous marrow engraftment.

Incubation of canine marrow and peripheral blood mononuclear cells with L-leucyl-L-leucine methyl ester resulted in the inhibition of mitogen- and alloantigen-induced blastogenesis, the elimination of allosensitized CTL and NK activity, and prevented the development of CTL from pCTL. The effects of these incubations were similar to those described in mice and humans. Additionally, in vitro CFU-GM growth from treated canine marrow was reduced, but could be regained when the Leu-Leu-OMe-treated marrow was cocultured with either untreated autologous peripheral blood mononuclear cells or monocyte-enriched PBMC but not with untreated monocyte-depleted PBMC. Six of seven dogs conditioned with 920 cGy total-body irradiation engrafted successfully after receiving autologous marrow that was incubated with Leu-Leu-OMe prior to infusion. These cumulative results indicate that incubation with Leu-Leu-OMe is a feasible method to deplete canine marrows of alloreactive and cytotoxic T cells prior to transplantation.

Animals↗
PubMed1988

Toxicity trial of prophylactic 9-[2-hydroxy-1-(hydroxymethyl)ethoxymethyl]guanine (ganciclovir) after marrow transplantation in dogs.

The effects of 9-[2-hydroxy-1-(hydroxymethyl)ethoxymethyl]guanine, or ganciclovir, administered during the immediate posttransplant period to dogs given total-body irradiation and autologous marrow transplants were studied. Doses of ganciclovir of 3.0 mg/kg (body weight) per day were well tolerated without detectable delay in hematopoietic recovery, whereas doses of 5.0 mg/kg per day were associated with delayed platelet recovery.

Acyclovir↗
PubMed1987

Engraftment of dogs with Ia-positive marrow cells isolated by avidin-biotin immunoadsorption.

Previous work has shown failure of engraftment in lethally irradiated dogs when autologous marrow was depleted of Ia-positive cells with an anti-Ia antibody and complement before infusion. In the current study, we have utilized an avidin-biotin immunoadsorption procedure to obtain a population of highly enriched Ia-positive cells for autologous bone marrow transplantation in dogs given lethal irradiation. Dog marrow cells (2.4 to 7.0 X 10(9) cells) that contained 8.6% to 19.9% Ia-positive cells were treated successively with monoclonal antibody 7.2, which reacts with a framework determinant of Ia-antigen, and biotin-conjugated goat antimouse immunoglobulin. These treated cells were passed over a column of avidin-Biogel (polyacrylamide) and the adherent cells removed by mechanical agitation. Seven lethally irradiated dogs were transplanted with 5.9 to 33.4 X 10(6) recovered adherent cells per kilogram of which 69.0% to 88.0% were Ia-positive. All dogs had hematologic recovery; six are alive and well with durable engraftment and one died on day 15 posttransplant. They are immunologically normal as determined by lymph node and bone marrow biopsies, lymphocyte function, and immunophenotyping of peripheral blood and bone marrow cells. These data provide further evidence that canine hematopoietic stem cells express Ia-like antigens and that these cells are capable of complete hematopoietic and immunologic reconstitution in an autologous model.

Animals↗