Single kidney transplants from donors with low estimated creatinine clearance.
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Creatinine↗
Biomedical subjects
C Carter
Publications and source records attributed to C Carter.
The pill and thrombosis: epidemiological considerations.
The oral contraceptive is one of the most widely taken medications in the healthy population. The clinically important side-effects are venous and arterial thrombosis. Accurate estimates of incidence of these side-effects have proven to be difficult. Diagnostic modalities for thrombosis are sub-optimal and the problems of study methodology, primarily a reliance on non-experimental studies, have limited the ability to define the attributable risk of thrombosis from oral contraception. Pharmacological attempts to further decrease venous thrombotic side-effects by the use of third-generation oral contraceptives have failed. This places a greater emphasis on the selection of patients to help avoid giving medication to those patients with underlying thrombotic risk factors. An example of this approach has been the clear confirmation of the adverse effects of cigarette smoking and arterial thrombosis in oral contraceptive users. At the biochemical level, hypercoagulability testing may be useful. Screening for high-frequency prothrombotic abnormalities, such as the Factor V Leiden genotype, represents an important addition to the process by which patients are selected, and may be prototypic of further advances.
Adult↗
The use of low-dose aprotinin, epsilon-aminocaproic acid or tranexamic acid for prevention of mediastinal bleeding in patients receiving aspirin before coronary artery bypass operations.
Patients undergoing primary myocardial revascularization were randomized to one of three drug regimens (low-dose aprotinin, epsilon-aminocaproic Acid or tranexamic Acid) to determine which drug regimen would most effectively reduce post-operative bleeding and the need for blood products. All patients had received 325 mg of aspirin within 48 h before operation. All three drug regimens reduced the requirements for blood products and postoperative bleeding after coronary artery bypass operations. There was, however, no significant difference between drug regimens.
Aminocaproic Acid↗
False-positive WBC imaging secondary to a distended bladder and fecal retention.
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Colon, Sigmoid↗
Prospective evaluation of neutrophil autoantibodies in 500 consecutive patients with inflammatory bowel disease.
Previous studies have shown antineutrophil cytoplasmic autoantibodies (ANCA) in patients with inflammatory bowel disease (IBD). A particular subclass, the so-called 'atypical' (perinuclear) p-ANCA type, occurs in the majority of patients with ulcerative colitis. The purpose of this prospective study was to assess, in a blinded fashion, this 'subclinical' serological marker in a consecutive series of IBD patients. Five hundred patients were evaluated, including 247 patients with ulcerative colitis and 253 with Crohn's disease involving the small and/or large intestine. Overall, 194 (38.8%) of all patients with IBD were positive, including 164 (66.3%) with ulcerative colitis and 30 (11.9%) with Crohn's disease. Except for coexistent sclerosing cholangitis, no other clinical or laboratory variable had an effect on the rate of ANCA detection. This is the largest single study of ANCA in patients with IBD and the only study to provide data solely from a single Canadian centre. Results emphasize the immunopathological differences between ulcerative colitis and Crohn's disease, and indicate that both disorders are heterogeneous inflammatory disease processes.
Adult↗
Health care construction will continue to build.
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Aged↗
Neurochemical characteristics of amisulpride, an atypical dopamine D2/D3 receptor antagonist with both presynaptic and limbic selectivity.
The benzamide derivative amisulpride shows a unique therapeutic profile being antipsychotic, at high doses, and disinhibitory, at low doses, while giving rise to only a low incidence of extrapyramidal side effects. In vitro, amisulpride has high affinity and selectivity for the human dopamine D2 (Ki = 2.8 nM) and D3 (Ki = 3.2 nM) receptors. Amisulpride shows antagonist properties toward D3 and both pre- and postsynaptic D2-like dopamine receptors of the rat striatum or nucleus accumbens in vitro. At low doses (< or = 10 mg/kg) amisulpride preferentially blocks presynaptic dopamine autoreceptors that control dopamine synthesis and release in the rat, whereas at higher doses (40-80 mg/kg) postsynaptic dopamine D2 receptor occupancy and antagonism is apparent. In contrast, haloperidol is active in all of these paradigms within the same dose range. Amisulpride preferentially inhibits in vivo binding of the D2/D3 antagonist [3H]raclopride to the limbic system (ID50 = 17 mg/kg) in comparison to the striatum (ID50 = 44 mg/kg) of the rat, increases striatal and limbic tissue 3,4-dihydroxyphenylacetic acid levels with similar potency and efficacy, and preferentially increases extracellular 3,4-dihydroxyphenylacetic acid levels in the nucleus accumbens when compared to the striatum. Haloperidol shows similar potency for the displacement of in vivo [3H]raclopride binding in striatal and limbic regions and preferentially increases striatal tissue 3,4-dihydroxyphenylacetic acid levels. The present data characterize amisulpride as a specific dopamine receptor antagonist with high and similar affinity for the dopamine D2 and D3 receptor. In vivo, it displays a degree of limbic selectivity and a preferential effect, at low doses, on dopamine D2/D3 autoreceptors. This atypical profile may explain the therapeutic efficacy of amisulpride in the treatment of both positive and negative symptoms of schizophrenia.
Acetylcholine↗
Challenges of the residential hospice caregiver. First hospice residential care center in Kansas.
A hospice residential care center reflects exciting grassroots community effort. Neither bureaucracy nor the opinions of medical of health care experts have shaped the facility, but the needs of the clients, and their families were determinative. The residence extends the concept of quality of life and hospice work as it offers total care to dying clients and their families.
Health Planning↗
Etiology, natural history, management and molecular genetics of hereditary nonpolyposis colorectal cancer (Lynch syndromes): genetic counseling implications.
We estimate that 5-10% of virtually all forms of cancer are due to a primary hereditary etiology. However, a hereditary cancer diagnosis is often missed because the family history of cancer is given short shrift in medical practice. Hereditary nonpolyposis colorectal cancer (HNPCC) certainly fits this estimate, although some studies suggest that a minimum of 2% with a range as high as 10% of the total colorectal cancer burden is due to HNPCC. Mutations in one of the four mismatch repair genes, i.e., hMSH2, hMLH1, hPMS1, and hPMS2, account for about 70% of HNPCC kindreds. Other germ-line mutations are likely to be identified to account for the remainder of HNPCC patients. By far the most common HNPCC mutations involve hMSH2 and hMLH1, with hPMS1 and hPMS2 accounting for only about 3% of such families. Prior to these molecular genetic discoveries, the genetic counselor could only provide the patient with an estimate of a 50% likelihood of manifesting HNPCC based on the counselee having one or more first-degree relatives manifesting syndrome cancers in their direct genetic lineage. Because DNA testing has become available in families with known mutations, we have provided pretest group education in the form of a family information service with intensive education about the natural history, genetic risk, surveillance, and options for management of HNPCC, as well as discussion of the potential for fear, anxiety, apprehension, and insurance or employer discrimination that might impact on this DNA testing. Following informed consent, these relatives were then counseled on a one-to-one basis. Using DNA-based genetic counseling involving hMSH2 or hMLH1, we have provided this service to four extended HNPCC kindreds. Details of this genetic counseling experience on these four kindreds will be discussed.
Adaptor Proteins, Signal Transducing↗
Inhibition of synaptosomal veratridine-induced sodium influx by antidepressants and neuroleptics used in chronic pain.
Veratridine-induced (10 microM) increases in intracellular sodium ([Na+]int) or calcium ([Ca2+]int) in rat cortical synaptosomes, measured with the fluorescent dyes SBFI or FLUO-3 were blocked by tetrodotoxin (IC50 Na+ 14 nM; Ca2+ 20 nM) and by a series of reference sodium channel blockers with neuroprotective (riluzole, lifarizine IC50 approximately 1-5 microM), anticonvulsant (lamotrigine, phenytoin IC50 approximately 70-140 micro M), local anaesthetic (lidocaine, procaine IC50 approximately 60-200 microM) or antiarrhythmic properties (quinidine, disopyramide, amiodarone, mexiletene, propafenone, fleicainide IC50, approximately 2-200 microM). Potencies for inhibition of veratridine-induced sodium and calcium entry were closely matched. These agents did not, or only weakly blocked, potassium evoked (50 mM) increases in [Ca2+]int. A number of antidepressant monoamine uptake inhibitors (amitriptyline, fluoxetine, clomipramine, desipramine, imipramine) or neuroleptics (pimozide, cinnarizine, haloperidol) were also potent inhibitors of veratridine-induced increases in [Na+]int or [Ca2+]int with affinities ranging from approximately 1-10 microM. A number of these drugs, from diverse chemical and pharmacological classes, are used for the treatment of chronic pain and their mechanism of action could perhaps be related to their common effects on a particular species of neuronal sodium channel.
Analgesics↗
Spatial working memory deficits and their relationship to negative symptoms in unmedicated schizophrenia patients.
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Adult↗
Identification and function of type-2 and type-3 ryanodine receptors in gut epithelial cells.
Reverse transcription-PCR (RT-PCR) techniques were used to identify the expression of ryanodine receptor (RyR) isoforms in gut epithelial cells. Restriction digest and sequence analysis of the PCR product showed the presence of RyR 2 and RyR 3. [3H]Ry binding studies on a microsome preparation, in a high-salt buffer, showed specific binding with an EC50 of 15 microM. In order to determine a potential functional role for these RyRs, we first characterized the response of the cells to acetylcholine. At all concentrations used acetylcholine induced sinusoidal cytosolic Ca2+ concentration ([Ca2+]i) oscillations. In response to 10(-4) M acetylcholine, levels of inositol 1,4,5-trisphosphate (InsP3) showed a peak of six times the basal level, at 30 s after stimulation. Application of caffeine alone failed to elicit a rise in cytosolic Ca2+. However, caffeine (5-50 mM) did rapidly and reversibly inhibit the acetylcholine-induced [Ca2+]i oscillations. The effects of Ry were more complex. Applied alone, Ry had no effect on the [Ca2+]i signal. When applied during agonist-evoked [Ca2+]i oscillations, Ry (10 microM) slowly blocked the response. In the continuous presence of Ry (10 microM) a short application of acetylcholine elicited a [Ca2+]i response that continued as oscillations even when the agonist was removed. The oscillations, in the presence of Ry (10 microM) but absence of agonist, were blocked either by removal of extracellular Ca2+ or by an application of a higher concentration of Ry (100 microM). These effects are consistent with the known use-dependence and dose-dependence for Ry action at the RyR. We conclude that the RyR 2 and RyR 3, identified by RT-PCR, play a central role in [Ca2+]i oscillations in gut epithelial cells.
Acetylcholine↗
CD34+ cell dose predicts survival, posttransplant morbidity, and rate of hematologic recovery after allogeneic marrow transplants for hematologic malignancies.
After autologous or allogeneic transplants of peripheral blood stem cells (PBSC), an adequate dose of CD34+ cells is necessary to ensure early and sustained hematopoietic engraftment and favorable clinical outcome. There are no comparable data on the relationship between CD34+ cell dose and recovery after allogeneic bone marrow transplants (BMT). Twenty-eight patients with hematologic malignancies received a BMT from an HLA-identical sibling, using T-cell depletion and cyclosporin for graft-versus-host disease prophylaxis and delayed donor lymphocyte transfusions in an attempt to prevent leukemia relapse. The treatment-related mortality (TRM), primarily due to infections and cytopenias, was significantly higher for 13 patients receiving less than 1 x 10(6) CD34+ cells/kg (64.9% +/- 12.8% v 6.9% +/- 6.4%, P = .003). Survival at a median follow-up of 1 year was also lower in the group receiving less than 1 x 10(6) CD34+ cells/kg (30.8% +/- 12.8 v 74.3% +/- 13.7%, P = .005). The CD34+ cell dose was the only variable significantly associated with TRM. The dose of CD34+ cells also correlated with speed of hematopoistic recovery. Patients receiving more than 2 x 10(6) CD34+ cells/kg showed significantly earlier recovery of monocytes and a trend for earlier recovery of lymphocytes. They achieved platelet and red blood cell transfusion independence earlier, required less granulocyte colony-stimulating factor support during ganciclovir treatment, and spent fewer days in the hospital after transplantation. These results suggest that, for allogeneic T-cell-depleted BMT, the higher CD34+ cell doses may improve outcome in engrafting patients.
Adult↗
Growth hormone stimulates the secretion of insulin-like growth factor binding protein-2 (IGFBP-2) by monolayer cultures of sheep costal growth plate chondrocytes.
Using monolayer cultures of costal chondrocytes established from four week old Clun Forest lambs, we have demonstrated that, under serum free conditions the cells release three IGFBPs (32, 29 and 21 kDa) into the medium. The most abundant of these--the 32 kDa BP--was shown to be IGFBP-2 by Western blotting. Furthermore we demonstrate that the levels of IGFBP-2 in conditioned medium are acutely increased (6, 12 and 24 h time points) following treatment of cells with bovine GH (1-100 ng/ml). In a parallel set of experiments, using ovine fibroblasts (derived from dermis) we show that IGFBPs of Mr 32, 29 and 21 kDa are also secreted by this cell type. However the relative abundance of these BPs differed from that seen in the chondrocyte cultures, with the 21 kDa species now the most abundant. In addition, prolonged exposure of autoradiographs indicated that fibroblasts secreted a higher Mr IGFBP (most probably ovine BP-3) that was not detected in any of our chondrocyte cultures. Most significant however was the demonstration that bGH did not dramatically affect the levels of IGFBPs in fibroblast cell cultures. We conclude that GH stimulates BP-2 production from chondrocytes and this is a cell-type specific effect in as much as it is not replicated in cultures of dermal fibroblasts.
Animals↗
Pharmacology of N-methyl-D-aspartate-evoked [3H]noradrenaline release in adult rat spinal cord.
N-Methyl-D-aspartate (NMDA) produced a concentration-related increase in [3H]noradrenaline release from adult rat cervical spinal cord slices. Its potency was relatively low and the response concentrated in dorsal spinal regions although also observed in ventral slices. NMDA did not increase the release of radiolabelled glutamate, aspartate, gamma-aminobutyric acid (GABA), acetylcholine or serotonin. In comparison with previously characterised NMDA responses in the striatum, (release of dopamine, GABA, acetylcholine or spermidine) the spinal response was particularly sensitive to MK-801 and magnesium and to L-689,560 but not to other glycine receptor antagonists (7-chlorokynurenate, CNQX (6-cyano-7-nitroquinoxaline-2,3-dione), DNQX (6,7-dichloroquinoxaline-2,3-dione), (+)-HA966). Dextrorphan and dextromethorphan produced partial or biphasic inhibition curves suggesting a subdivision of NMDA receptors. NMDA-evoked [3H]noradrenaline release was moderately sensitive to CPP and CGP37849 but insensitive to arcaine. These characteristics distinguish the native spinal NMDA receptor subtype(s) from those so far characterised in the striatum suggesting a unique spinal NMDA receptor subtype.
Animals↗
Partitioning of HIV-1 Gag and Gag-related proteins to membranes.
The binding of HIV-1 Gag and Gag-related proteins to model membranes was examined using three experimental systems: (i) large unilamellar phospholipid vesicles (LUVs) and recombinant Gag purified from Escherichia coli; (ii) LUVs added to a mammalian cell extract in which Gag proteins were expressed by a coupled transcription/translation system; and (iii) inside-out plasma membrane vesicles purified from human red blood cells (RBC) and recombinant, purified Gag from E. coli. Several novel aspects of HIV-1 Gag membrane interactions were observed: (i) Gag proteins bound with high affinity to both model membranes with a negatively charged surface and to RBC membranes. (ii) Binding of the Gag precursor and mature Gag proteins exhibited different sensitivities to ionic strength indicating that the precursor directed membrane binding through interactions that were qualitatively and quantitatively distinct from those of any of its individual domains. Studies using energy transfer between tryptophan residues in the proteins and anthroyloxy-containing probes inserted in the LUVs indicated that the orientation of the precursor and of the mature proteins on the membrane surface were distinct; (iii) Gag oligomers appear to have facilitated high-affinity binding under high salt conditions, suggesting that protein-protein interactions led to formation of stronger electrostatic or new hydrophobic membrane binding determinants. Since binding studies with model membranes permit quantitative analysis, these experimental approaches may permit identification of interactions that drive Gag assembly on the membrane.
Cloning, Molecular↗
Escherichia coli tryptophanyl-tRNA synthetase mutants selected for tryptophan auxotrophy implicate the dimer interface in optimizing amino acid binding.
Tryptophan auxotrophs of Escherichia coli in which mutations were mapped to the trpS locus (encoding tryptophanyl-tRNA synthetase) have been previously isolated. We have investigated the tryptophanyl-tRNA synthetase (TrpRS) purified from six auxotrophic strains for changes in amino acid activation and aminoacylation. Steady-state kinetic analyses show that these mutant TrpRS proteins have increases in the apparent KM for tryptophan, decreases in turnover number, or both, without significant changes in the apparent KM for ATP or tRNA(Trp). The crystal structure of a highly homologous tryptophanyl-tRNA synthetase from Bacillus stearothermophilus in a complex with the cognate aminoacyl adenylate allowed us to place the mutations in a structural context. The mutations in the enzymes are located in the KMSKS loop (M196I), in or near the active site (D112E, P129S, A133E) or far from the active site. The last three mutants (T60R, L91F, G329S) could not be predicted by examination of the protein structure as they line an interface between the C-terminal alpha-helix of one subunit and the Rossmann folds of both subunits, thus affecting a specific region of the dimer interface. These results support a role for dimerization in properly configuring the two active sites of the dimeric enzymes in the Trp/Tyr subclass of class I aminoacyl-tRNA synthetases in order to achieve optimal catalysis.
Amino Acid Sequence↗
Evidence for native NMDA receptor subtype pharmacology as revealed by differential effects on the NMDA-evoked release of striatal neuromodulators: eliprodil, ifenprodil and other native NMDA receptor subtype selective compounds.
NMDA increases the release of [14C]acetylcholine and [3H]spermidine or of [14C]GABA and [3H]dopamine from rat striatal slices. The pharmacology of these responses suggests that release of dopamine and GABA, acetylcholine, and spermidine is mediated, respectively, by three distinct NMDA receptor subtypes. IC50 values of compounds for the inhibition of dopamine and GABA release were closely matched, suggesting mediation by the same subtype. This receptor was generally more sensitive to all NMDA antagonists tested relative to that controlling acetylcholine or spermidine release (channel blockers, glycine antagonists, competitive antagonists and polyamine antagonists). The receptors controlling acetylcholine and spermidine release were characterised by lower antagonist sensitivity in general, and that controlling spermidine release was further defined by a marked insensitivity to ifenprodil, eliprodil, magnesium, dextromethorphan, dextrorphan, memantine, desipramine and polyamine spider toxins. In binding studies in which the displacement of 2 nM [3H]MK801 was studied in membranes prepared from a number of brain regions (in the presence of saturating concentrations of glutamate, glycine and spermidine) small regional differences in IC50 values were observed for a number of channel blockers, but no compound generated biphasic displacement curves that would allow masking of a particular subtype and it was not possible to detect binding components that were insensitive to memantine, dextrorphan dextromethorphan or desipramine. Ifenprodil produced biphasic displacement curves in the 1-day-old rat cortex and midbrain (with IC50 values of approximately 2 and 70 microM) and both ifenprodil and eliprodil displaced a small proportion (18%) of [3H]MK-801 with high affinity in the adult rat spinal cord. Displacement of [3H]MK801 by these compounds in all other adult brain regions (cortex, striatum, hippocampus, thalamus, pons, medulla, cerebellum) was monophasic and of low affinity. In general the subtype selectivity suggested by the release studies was not mirrored in the binding experiments, probably because of excessive heterogeneity of sites in the membrane preparations and to the subtype selectivity of [3H]MK801 itself.
Animals↗