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Biomedical subjects

J A Reynolds

Publications and source records attributed to J A Reynolds.

At least 19 recordsLinked to original sources
PubMed2000

Second malignant neoplasms after treatment for Hodgkin's disease in childhood or adolescence.

PURPOSE: To determine the frequency of and risk factors for second malignant neoplasms (SMNs) after treatment for Hodgkin's disease diagnosed in children and adolescents. PATIENTS AND METHODS: One hundred eighty-two consecutive, previously untreated patients with Hodgkin's disease who were younger than 20 years of age at diagnosis and who were referred to Roswell Park Cancer Institute (Buffalo, NY) for treatment between January 1, 1960, and December 31, 1989, were studied. Sex-specific standardized incidence ratios (SIRs) were calculated. Kaplan-Meier survival estimates and Cox regression analyses were performed to determine the relationship of several demographic and treatment variables to SMN incidence. RESULTS: Twenty-eight patients developed an SMN at a mean of 14.93 +/- 8.09 years (range, 2.65 to 29.88 years) after diagnosis of Hodgkin's disease. The cumulative percentage of patients who developed an SMN was 26.27 +/- 6.75% at 30 years after diagnosis. The SIR was 9.39 (95% confidence interval [CI], 4.05 to 18.49) for male patients and 10.16 (95% CI, 5.56 to 17.05) for female patients. The most frequent SMNs were thyroid cancer, breast cancer, nonmelanoma skin cancer, non-Hodgkin's lymphoma, and acute leukemia. Multivariate analysis of sex, treatment with any alkylating agent, treatment with doxorubicin, splenectomy, and relapse (as a time-dependent covariate) with time to SMN onset gave nonsignificant results. CONCLUSION: Successfully treated children and adolescents with Hodgkin's disease have a substantial risk for the occurrence of subsequent neoplasms. The most frequent SMNs (skin, thyroid, and breast) are readily detected by physical examination and available screening procedures.

Adolescent↗
PubMed1993

Effects of doxazosin on atherosclerosis in cholesterol-fed rabbits.

Doxazosin was administered to rabbits fed diets enriched in cholesterol and peanut oil for 7.5 or 12 weeks, in 2 separate experiments. Doxazosin suppressed the accumulation of cholesterol and formation of atherosclerotic plaques in the aortas of treated rabbits and prevented a diet-induced increase in aortic collagen and wall mass. Doxazosin was more effective in the thoracic and abdominal segments of the aorta than in the aortic arch. Pharmacokinetic analysis indicated that treated rabbits were exposed to concentrations of doxazosin, integrated over 24 h, which were consistent with the therapeutic range of doxazosin measured in patients treated for hypertension. Doxazosin did not alter serum levels of cholesterol or triglycerides, nor were there any consistent effects on glucose, free fatty acid or ketone levels. Hypotheses of the mechanism of action of doxazosin are discussed, including the possible involvement of alpha 1-adrenergic receptors in recruitment of smooth muscle cells by subintimal macrophages and nonadrenergic mechanisms of inhibition of lipid infiltration.

Animals↗
PubMed1992

Cytogenetic abnormalities in renal oncocytic neoplasms.

We have performed cytogenetic studies on five renal oncocytic neoplasms (three grade 2 tumors and two grade 1 tumors) identified histologically by light microscopy. One grade 1 tumor failed to produce mitotic cells. The other four tumors exhibited both normal and abnormal cell lines. Numerical abnormalities were found in both the single grade 1 and two of the grade 2 tumors whereas structural abnormalities were limited to grade 2 tumors. Aneuploidy of chromosome 12 was observed in both grade 1 and 2 tumors. Grade 2 tumors showed more extensive numerical change than the grade 1 tumors. Abnormalities of chromosome 3 characteristic of renal cell carcinoma were not found in any tumor in this series. A combination of C-banding and HaeIII endonuclease banding was used to identify an ambiguous marker. In our four cases and in the cases previously reported, loss of a sex chromosome, abnormalities of chromosomes 1 and 22, and trisomy 12 are findings most often observed in renal oncocytoma.

Adult↗
PubMed1989

Differences between the manganese- and the iron-containing superoxide dismutases of Escherichia coli detected through sedimentation equilibrium, hydrodynamic, and spectroscopic studies.

The genome of Escherichia coli codes for two superoxide dismutases that may contain either iron (FeSOD) or manganese (MnSOD) at the active site. The crystal structures of MnSODs from two bacterial sources (but not E. coli) have been completed, and structural comparisons with the crystal structure of the FeSOD from either E. coli or Pseudomonas ovalis have been made. Despite the low degree (less than 50%) of sequence homology between the E. coli enzymes, the two proteins are suggested to be structurally homologous. Nonetheless, these enzymes exhibit absolute metal cofactor specificity in conferring enzymatic activity to the inactive apoenzyme. This observation is surprising considering the identity of the active site ligands and the similarities in their geometry and surrounding environment. Using analytical ultracentrifugation, we have determined that the solution properties of these two proteins are different. Thus dialysis of FeSOD but not of MnSOD against phosphate buffer in the presence or absence of EDTA caused dissociation of the homodimer. This dissociation appeared to be related to the loss of iron from native FeSOD. Thus, apoFeSOD but not apoMnSOD existed predominantly as a monomer at protein concentrations below 150 micrograms/mL. ApoMnSOD showed no evidence for dissociation under these conditions. Fluorescence data suggest that the tryptophan environments for the two enzymes are also different. The results of these physical measurements lead us to propose that subtle differences, perhaps at the subunit contact faces, exist in the structures of these crystallographically similar proteins.

Apoenzymes↗
PubMed1988

The effects of continuous administration of murine interleukin-1 alpha in the rat.

Recombinant murine IL-1 alpha was administered continuously to rats by means of osmotic pumps implanted intraperitoneally. Continuous infusion of rIL-1 alpha in a range between 0.12 and 12.0 micrograms/day for four days was found to produce concentration-dependent weight loss. Behavioral parameters were continuously monitored and recorded at the 3.0 micrograms/day concentration in electronically-monitored activity cages during Days 2 through 5 of rIL-1 alpha administration. Parameters were separated into those affected during the dark phase (active period) or the light phase (resting period). Eating activity was found to be significantly reduced during each dark period through day 5, when compared with either untreated or PBS vehicle-infused animals. During the fourth and fifth days of infusion, however, eating behavior in animals infused with rIL-1 alpha began to increase toward control level in the latter, but not the earlier, half of the dark period. In contrast, drinking behavior was found to be significantly elevated only during the light periods. Continuous infusion of rIL-1 alpha also produced significant reductions in both horizontal locomotor activity (crossovers) and vertical locomotor activity (rears). However, in contrast to the trend toward a return of normal eating behavior, locomotor activity remained decreased through the fifth day of rIL-1 alpha infusion. These results suggest changes that could be produced by IL-1 in chronic inflammatory disease and infection.

Animals↗
PubMed1988

Overview: the oligomeric structure of the Na,K pump protein.

The purpose of this paper has not been to espouse a particular structural model for the Na,K pump protein. Rather an attempt has been made to produce an awareness of a body of scientific literature that raises some serious questions and to suggest that complacency on the subject of the oligomeric vs protomeric state of this (and perhaps other) transport proteins is inappropriate.

Macromolecular Substances↗
PubMed1987

Sarcoplasmic reticulum calcium pump: a model for Ca2+ binding and Ca2+-coupled phosphorylation.

The conventional alternating access model for Ca2+ transport by the sarcoplasmic reticulum Ca2+ pump is modified, partly on the basis of the proposed MacLennan-Green domain structure for the Ca2+-pump protein. The present model divides the uptake state (E1) of the protein into three substates, differing in the condition of the Ca2+-binding domain. The domain is an open cavity in the first substate and can bind only a single Ca2+ ion. A fast "jaw-closing" (or "hinge-bending") step then partially closes the cavity to generate the second substate that has a second Ca2+-binding site. Occupation of this site is followed by another jaw-closing step that closes the binding cavity and occludes the bound ions. The subsequent translocation step (to form E2) remains unchanged from previous models. The modified model predicts a constant transport stoichiometry of two Ca2+ per pump reaction cycle. It suggests a plausible mechanism for coupling between Ca2+ binding and ATP utilization: the model predicts (in agreement with experiment) that Ca2+ binding should be a mandatory requirement for phosphorylation of the pump protein, though ATP binding per se does not require Ca2+. The model is consistent with high cooperativity in equilibrium binding of Ca2+, both in the absence and presence of ATP.

Binding Sites↗
PubMed1986

Circular dichroism of the two major conformational states of mammalian (Na+ + K+)-ATPase.

No alteration in the circular dichroic spectrum of fully active, membrane-bound (Na+ + K+)-ATPase is observed when the protein is cycled between the two major conformational states, E1 and E2. This finding is in agreement with the infrared study by Chetverin and Brazhnikov (J. Biol. Chem. 260 (1985) 7817) and demonstrates that any difference in secondary structure between the two conformers must be less than 2%.

Animals↗
PubMed1986

Prophylaxis of Rift Valley fever with antiviral drugs, immune serum, an interferon inducer, and a macrophage activator.

Rift Valley fever virus (RVFV), a member of the family Bunyaviridae, extended its range from sub-Saharan Africa into Egypt in 1977. Its clinical spectrum is recognized to include severe manifestations such as hemorrhagic fever and encephalitis. For these reasons, as well as the limited knowledge of specific therapy for Bunyaviridae infections, we investigated several prophylactic regimens for RVF in a mouse model. Rimantadine, thiosemicarbazone, and inosiplex were ineffective. Pretreatment with glucan was of some use, but the most encouraging results were obtained with the antiviral drug ribavirin, passive antibody, or an interferon inducer polyriboinosinic-polyribocytidylic acid complexed with poly-L-lysine and carboxymethylcellulose (poly[ICLC]). Ribavirin and poly(ICLC) were also shown to be efficacious in preventing disease in hamsters. Ribavirin (loading dose of 50 mg/kg followed by 10 mg/kg at 8-h intervals for 9 days) suppressed viremia in RVF-infected rhesus monkeys. Ribavirin also reduced virus yield in infected cell cultures; sensitivity varied markedly with cell type but not with virus strain. Immune mouse ascitic fluid, with a plaque reduction neutralization titer of 1:1024, was effective in a dose of 4 ml/kg, a volume approximately equivalent to administration of a unit of convalescent plasma to a human. Poly(ICLC) may well have functioned through interferon induction, since RVFV was shown to be sensitive to interferon in cell culture, and since another macrophage activator (glucan) was only marginally effective. These studies suggest that ribavirin, poly(ICLC), and convalescent plasma may have a role in prevention or therapy of human RVF.

Animals↗
PubMed1985

Application of the principle of linked functions to ATP-driven ion pumps: kinetics of activation by ATP.

If a ligand binds with unequal affinity to two distinct states of a protein, then the equilibrium between the two states becomes a function of the concentration of the ligand. A necessary consequence is that the ligand must also affect the forward and/or reverse rate constants for transition between the two states. For an enzyme or transport protein with such a transition as a slow step in the catalytic cycle, the overall rate also becomes a function of ligand concentration. These conclusions are independent of whether or not the ligand is a direct participant in the reaction. If it is a direct participant, then the kinetic effect arising from the principle of linked functions is distinct from the direct catalytic effect. These principles suffice to account for the biphasic response of the hydrolytic activity of ATP-driven ion pumps to the concentration of ATP, without the need to invoke more than one ATP binding site per catalytic center.

Adenosine Triphosphate↗
PubMed1985

Thermodynamic and kinetic cooperativity in ligand binding to multiple sites on a protein: Ca2+ activation of an ATP-driven Ca pump.

Contrary to common belief, theoretical analysis does not predict any necessary relationship between cooperativity in the equilibrium binding of an ion to multiple binding sites on a protein and cooperativity in the kinetic activation of a reaction for which such binding is prerequisite. The sarcoplasmic reticulum Ca pump protein, for example, has two high-affinity binding sites for Ca2+, here considered to be nearly identical and independent. Equilibrium binding to these sites can be highly cooperative in spite of site-independence, as demonstrated by the well-known allosteric mechanism based on Wyman's principle of linked functions. We show in this paper that kinetic activation of the pump reaction cycle by binding of Ca2+ to these same sites can likewise be a cooperative function of Ca2+ concentration but that the criteria that determine cooperativity in the two situations are different. It is possible to observe kinetic cooperativity without concomitant cooperativity in equilibrium binding and vice versa. Application of these theoretical considerations to experimental data for the pump protein raises questions about the Ca2+ binding mechanism.

Animals↗
PubMed1985

Variable stoichiometry in active ion transport: theoretical analysis of physiological consequences.

Active ion transport systems with fixed stoichiometry are subject to a thermodynamic limit on the ion concentration gradients that they can generate and maintain, and their net rates of transport must inevitably decrease as this limit is approached. The capability to vary stoichiometry might thus be physiologically advantageous: a shift to lower stoichiometry (fewer ions pumped per reaction cycle) at increasing thermodynamic load could increase the limit on the supportable concentration gradient and could accelerate the rate of transport under high-load conditions. Here we present a theoretical and numerical analysis of this possibility, using the sarcoplasmic reticulum ATP-driven Ca pump as the example. It is easy to introduce alternate pathways into the reaction cycle for this system to shift the stoichiometry (Ca2+/ATP) from the normal value of 2:1 to 1:1, but it cannot be done without simultaneous generation of a pathway for uncoupled leak of Ca2+ across the membrane. This counteracts the advantageous effect of the change in transport stoichiometry and a physiologically useful rate acceleration cannot be obtained. This result is likely to be generally applicable to most active transport systems.

Adenosine Diphosphate↗
PubMed1985

Incorporation of membrane potential into theoretical analysis of electrogenic ion pumps.

The transport rate of an electrogenic ion pump, and therefore also the current generated by the pump, depends on the potential difference (delta psi) between the two sides of the membrane. This dependence arises from at least three sources: (i) charges carried across the membrane by the transported ions; (ii) protein charges in the ion binding sites that alternate between exposure to (and therefore electrical contact with) the two sides of the membrane; (iii) protein charges or dipoles that move within the domain of the membrane as a result of conformational changes linked to the transport cycle. Quantitative prediction of these separate effects requires presently unavailable molecular information, so that there is great freedom in assigning voltage dependence to individual steps of a transport cycle when one attempts to make theoretical calculations of physiological behavior for an ion pump for which biochemical data (mechanism, rate constants, etc.) are already established. The need to make kinetic behavior consistent with thermodynamic laws, however, limits this freedom, and in most cases two points on a curve of rate versus delta psi will be fixed points independent of how voltage dependence is assigned. Theoretical discussion of these principles is illustrated by reference to ATP-driven Na,K pumps. Physiological data for this system suggest that all three of the possible mechanisms for generating voltage dependence do in fact make significant contributions.

Biological Transport, Active↗
PubMed1984

Phospholipid vesicle formation using nonionic detergents with low monomer solubility. Kinetic factors determine vesicle size and permeability.

The method developed previously for formation of unilamellar vesicles from mixed micelles of egg lecithin and octyl glucoside [Mimms, L. T., Zampighi, G., Nozaki, Y., Tanford, C., & Reynolds, J. A. (1981) Biochemistry 20, 833-840] has been extended to allow for (1) use of nonionic detergents with much lower critical micelle concentrations and (2) variation in the time course of detergent removal. The results demonstrate the importance of kinetic factors, especially in the determination of vesicle size: initially formed vesicles are small, but the size increases slowly thereafter if detergent is not removed too quickly. Vesicle size remains fixed when the molar detergent/lipid ratio falls below about 1/1, and detergent removal becomes increasingly difficult thereafter, presumably because flip-flop of detergent from the inner to the outer leaflet of the bilayer membrane is very slow. Residual detergent (to about 25 mol %) has surprisingly little effect on anion permeability but increases cation permeability to the point where the normal discrimination between anions and cations (in pure lipid vesicles) is lost. Detergent added to initially detergent-free vesicles readily partitions into vesicular membranes (presumably only into the outer leaflet) and has a qualitatively similar effect on permeability. Vesicles produced by this method, regardless of residual detergent level, were found to be predominantly unilamellar: no multilamellar liposomes or other lipid aggregates could be detected within the accuracy of the methods employed.

Detergents↗