Biomedical subjects

M M Meyer

Publications and source records attributed to M M Meyer.

8 recordsLinked to original sources

PubMed1992

The amino acid substrate of bovine tyrosine hydroxylase.

Tyrosine hydroxylase catalyzes the tetrahydropterin-dependent hydroxylation of tyrosine to form 3,4-dihydroxyphenylalanine. Several nonphysiological aromatic amino acids have been examined as inhibitors and substrates for bovine adrenal tyrosine hydroxylase. The Ki values for para-substituted phenylalanines increase as the size of the substituent increases. For each A2 increase in surface area of the substituent, the free energy of binding becomes 50 cal more positive. Replacement of the phenyl ring with a pyridyl ring decreases the affinity about one order of magnitude. A number of these aromatic amino acids are also substrates for the enzyme. The KM values again increase in size with increasing size of the substituent, but the Vmax value is independent of the reactivity of the amino acid. The effect of size on binding is consistent with a tight interaction between the para position region of the substrate and the enzyme. The lack of a change in the Vmax value is consistent with the rate-limiting step in catalysis by bovine tyrosine hydroxylase being formation of the hydroxylating intermediate rather than hydroxylation of the amino acid. These results will be useful in designing mechanism-based inhibitors of catecholamine biosynthesis and establish that the mechanisms of rat and bovine tyrosine hydroxylase do not differ significantly.

Adrenal Glands↗

PubMed1991

Can recognition of living things be selectively impaired?

Brain damage sometimes seems to impair recognition of living things, despite relatively preserved recognition of nonliving things. The most straightforward interpretation of this dissociation is that the recognition of living things depends on some specialized mechanisms that are not needed for the recognition of nonliving things. However, there are alternative interpretations of the dissociation in terms of the greater complexity or inter-item similarity of living things, or the more specific, within-category identifications that are usually required for living things. Surprisingly, the relevant tests to discriminate among these rival hypotheses have never been performed. We took the factors of visual complexity, inter-item similarity, specificity of identification, as well as others, into account in analyzing the visual recognition performance of two head-injured visual agnosic patients. In each case we found that recognition of living things was still disproportionately impaired when the effects of the other factors were accounted for.

Adult↗

PubMed1991

T-cell receptor variable beta genes show differential expression in CD4 and CD8 T cells.

Studies in transgenic and inbred strains of mice have shown that the critical molecular interactions controlling positive selection involve major histocompatibility complex (MHC), T-cell receptor (TCR), and CD4 or CD8 coreceptor molecules. Correlations have been established between MHC gene products and the percentage of CD4 or CD8 T cells that express specific variable (V) beta-gene products as part of the alpha beta heterodimer. These studies have important implications regarding potential mechanisms of HLA-linked autoimmune diseases in humans. If similar interactions are required for positive selection in humans, one would predict that the TCR repertoire expressed by mature, peripheral blood CD4 and CD8 T cells would vary. To test this hypothesis the expression of specific TCR V beta-region genes by CD4 and CD8 T cells from healthy individuals was compared using both triple-color flow cytometry and polymerase chain reaction based experimental approaches. The results show that the TCR repertoire does vary as a function of CD4 and CD8 T-cell subsets. Among unrelated individuals certain V beta genes were consistently overrepresented in the CD4 population (V beta-5.1, -6.7a, and -18); some were skewed to the CD8 population (V beta-14) while others showed variable patterns (V beta-12 and -17). Deletion of entire V beta gene families was not observed suggesting that this is a rare event in humans. Attempts to correlate the expressed TCR repertoire in humans with HLA alleles will require consideration of these differences in expression as a function of subset.

Antibodies, Monoclonal↗

PubMed1991

A note on randomization and selection bias in maintenance therapy clinical trials.

In this article we demonstrate that even in randomized controlled clinical trials, unobserved confounding variables can bias the outcome of a study. For the case of a two-phase maintenance therapy trial where patients who respond to treatment during the acute phase are then randomized to a maintenance therapy, we show explicitly the role that confounding may play in biasing the interpretation of the results of such a trial. We suggest an alternative design to deal with the problem of a selection effect for treatment responders in the acute phase of the trial by randomizing patients at the outset of the study to both an acute and maintenance therapy.

Bias↗

PubMed1991

Outcome of renal transplantation at Oregon Health Sciences University: 1982 to 1990.

1. Graft survival increased over the 4 periods between 1982 and 1990 (82-84, 85-86, 87-88, 89-90). The largest increase was in the 89-90 period. 2. Immunosuppression was the key to improved outcome. Cadaveric graft recipients given OKT3 induction plus triple therapy with cyclosporine, azathioprine, and prednisone had significantly better graft survival compared with all other drug combinations. Other factors were improved patient selection, donor management, and outpatient care. 3. Mean serum creatinine levels did not change after cyclosporine was introduced for immunosuppression. The mean serum creatinine level was approximately 1.7 mg/dl at 3 months, 6 months, and 12 months post-transplantation in all 4 periods. 4. Living-related donor outcome was significantly better than cadaveric donor outcome. Half-life for 2-haplotype-matched kidneys was 37 years compared with 12 years for 1-haplotype matches and 6.5 years for cadaveric kidneys. 5. Immediate function and a rejection-free first month were both associated with significantly improved graft survival. 6. Neither peak PRA nor graft number (1st vs regraft) correlated with graft survival. Highly sensitized (PRA greater than 50%) patients and regrafted patients fared as well as less sensitized (PRA less than or equal to 50%) and first graft recipients. This outcome was attributed to a sensitive crossmatch. Because of the crossmatch, highly sensitized patients received much better HLA matches. 7. The incidence of early rejection and delayed function declined significantly between the earliest and latest periods. Improved immunosuppression, donor management, and renal preservation were cited as contributing factors.

Actuarial Analysis↗

PubMed1987

Evidence for water channels in renal proximal tubule cell membranes.

Water transport mechanisms in rabbit proximal convoluted cell membranes were examined by measurement of: osmotic (Pf) and diffusional (Pd) water permeabilities, inhibition of Pf by mercurials, and activation energies (Ea) for Pf. Pf was measured in PCT brush border (BBMV) and basolateral membrane (BLMV) vesicles, and in viable PCT cells by stopped-flow light scattering; Pd was measured in PCT cells by proton NMR T1 relaxation times using Mn as a paramagnetic quencher. In BLMV, Pf (0.019 cm/sec, 23 degrees C) was inhibited 65% by 5 mM pCMBS and 75% by 300 microM HgCl2 (KI = 42 microM); Ea increased from 3.6 to 7.6 kcal/mole (15-40 degrees C) with 300 microM HgCl2. In BBMV, Pf (0.073 cm/sec, 23 degrees C, Ea = 2.8 kcal/mole, less than 33 degrees C and 13.7 kcal/mole, greater than 33 degrees C) was inhibited 65% with HgCl2 with Ea = 9.4 kcal/mole (15-45 degrees C). Mercurial inhibition in BLMV and BBMV was reversed with 10 microM mercaptoethanol. Viable PCT cells were isolated from renal cortex by Dounce homogenization and differential seiving. Impedence sizing studies show that PCT cells are perfect osmometers (100-1000 mOsm). Assuming a cell surface-to-volume ratio of 25,000 cm-1, Pf was 0.010 +/- 0.002 cm/sec (37 degrees C) and Pd was 0.0032 cm/sec. Pf was independent of osmotic gradient size (25-1000 mOsm) with Ea 2.5 kcal/mole (less than 27 degrees C) and 12.7 kcal/mole (greater than 27 degrees C). Cell Pf was inhibited 53% by 300 microM HgCl2 (23 degrees C) with Ea 6.2 kcal/mole. These findings indicate that cell Pf is not restricted by extracellular or cytoplasmic unstirred layers and that cell Pf is not flow-dependent. The high BLMV and BBMV Pf, inhibition by HgCl2, low Ea which increases with inhibition, and the measured Pf/Pd greater than 1 in cells in the absence of unstirred layers provide strong evidence for the existence of water channels in proximal tubule brush border and basolateral membranes. These channels are similar to those found in erythrocytes and are likely required for rapid PCT transcellular water flow.

Animals↗

PubMed1986

Human platelet osmotic water and nonelectrolyte transport.

The osmotic water (Pf) and nonelectrolyte permeability (Ps) properties of human platelets were characterized using the stopped-flow light-scattering technique. At 37 degrees C, Pf = 0.007 +/- 0.001 cm/s, the urea reflection coefficient (sigma urea) = 0.95 +/- 0.04, and Ps for a series of permeant nonelectrolytes was (in cm X s-1 X 10(-6)) 2.1 (urea), 3.5 (glycerol), 3.8 (thiourea), 17 (ethylene glycol), 18 (acetamide), 23 (formamide), and 24 (butyramide). Pf did not depend on the size of the osmotic gradient or on the direction of volume flow. Mercurial sulfhydryl reagents did not inhibit osmotic water transport, and phloretin and phenylurea did not inhibit urea transport. There was a discontinuity in the temperature dependence for both Pf and urea permeability (P urea) at 36 degrees C; enthalpy (delta H) = 25 (greater than 36 degrees C) and 4.4 kcal/mol (less than 36 degrees C) for Pf, and delta H = 26 (greater than 36 degrees C) and 7 kcal/mol (less than 36 degrees C) for P urea. In contrast to the facilitated water and urea transport systems in the red blood cell, these results suggest that the mechanism for water and urea transport in the platelet is primarily by diffusion through membrane phospholipid. A computer-simulated model of platelet circulation through the renal medulla, based on the measured values for Pf, P urea, and sigma urea, indicated that platelets undergo an approximately 40% decrease in volume in the inner medulla and an approximately 20% overshoot in volume as they return to the external isosmotic environment.

Amides↗

PubMed1985

A solid start.

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Humans↗