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Biomedical subjects

C Carter

Publications and source records attributed to C Carter.

At least 37 records · Page 2Linked to original sources
PubMed1998

Tubular antithrombin at transplantation determines subsequent renal allograft function.

BACKGROUND: Antithrombin is found in the microvasculature and tubules of normal and transplanted human kidneys. Although depletion of vascular antithrombin is associated with renal allograft dysfunction, neither the distribution nor clinical significance of tubular antithrombin is known. METHODS: Changes in tubular antithrombin in biopsy specimens (n=41) obtained from donor kidneys at transplantation were studied immunohistochemically. The relationship between these changes and subsequent graft function was analyzed. RESULTS: Granular intracellular antithrombin was found only within the proximal tubular epithelium. Allografts with depleted tubular antithrombin at transplantation (n=20) had significantly greater plasma creatinine concentrations at posttransplant days 3 (P < 0.001) and 5 (P < 0.03) than allografts with normal tubular antithrombin (n=21). Indeed, depletion of tubular antithrombin at transplantation correlated with the degree of graft dysfunction at 3 days after transplantation. CONCLUSIONS: Depleted tubular antithrombin at transplantation is associated with reduced early graft function, and this may identify patients at risk of a complicated follow-up.

Antithrombins↗
PubMed1998

Escherichia coli cytidine deaminase provides a molecular model for ApoB RNA editing and a mechanism for RNA substrate recognition.

ApoB RNA-editing enzyme (APOBEC-1) is a cytidine deaminase. Molecular modeling and mutagenesis show that APOBEC-1 is related in quaternary and tertiary structure to Escherichia coli cytidine deaminase (ECCDA). Both enzymes form a homodimer with composite active sites constructed with contributions from each monomer. Significant gaps are present in the APOBEC-1 sequence, compared to ECCDA. The combined mass of the gaps (10 kDa) matches that for the minimal RNA substrate. Their location in ECCDA suggests how APOBEC-1 can be reshaped to accommodate an RNA substrate. In this model, the asymmetrical binding to one active site of a downstream U (equivalent to the deamination product) helps target the other active site for deamination of the upstream C substrate.

APOBEC-1 Deaminase↗
PubMed1998

Molecular modelling and the biosynthesis of apolipoprotein B containing lipoproteins.

APOBEC-1 is the cytidine deaminase. We show by sequence alignment, molecular modelling and mutagenesis, that it is related in crystal structure to the cytidine deaminase of Escherichia coli (ECCDA). The two enzymes are both homodimers with composite active sites formed with loops from each monomer. In the sequence of APOBEC-1, three gaps compared to ECCDA match the size and contour of the minimal RNA substrate. We propose a model in which the asymmetric binding of one active site to the substrate cytidine which is positioned by the downstream binding of the product uridine and that this helps to target the other active site for deamination.

APOBEC-1 Deaminase↗
PubMed1998

Opioid involvement in behavior modifications of mice infected with the parasitic nematode, Nippostrongylus brasiliensis.

Several studies have documented the opiate effects of parasitic infection on experimental animals. The current study examined the relationships between infection with the intestinal nematode, Nippostrongylus brasiliensis with analgesia and activity levels. Male white mice infected with N. brasiliensis displayed a significant increase in thermal latency thresholds that rose through the duration of infection and subsided with its termination. Analgesia first became apparent on day three-post infection but did not reach statistical significance (p < 0.05) until day 7 post infection. The maximum analgesia was reached on day 8-post infection and gradually declined. By day 15 post infection, there was no significant difference in the latency times between control and infected mice. The initial significant difference in latency roughly corresponded with the onset of egg production by the parasite. The peak difference in latency times and their subsequent decline also parallels peak egg production and the decline in egg production as the infection subsided. Both naloxone and naltrindole significantly reduced the latency times (p < 0.05) of infected mice. There was also a significant difference in total ambulatory activity levels between infected and control mice. Activity levels began to decline on the second day post infection but did not reach a statistically significant difference (p < 0.05) from the controls until 9th day post infection. Infected mice that were injected with either naloxone or naltrindole had a significantly higher activity level than the infected mice injected with saline.

Animals↗
PubMed1998

The pharmacology of native N-methyl-D-aspartate receptor subtypes: different receptors control the release of different striatal and spinal transmitters.

1. N-methyl-D-aspartate (NMDA) increases the release of radiolabelled dopamine, GABA, acetylcholine and spermidine from rat striatal slices and of noradrenaline from the dorsal cervical spinal cord. 2. These five responses show differing sensitivities to NMDA and also to a variety of competitive antagonists, NMDA channel blockers, glycine antagonists and polyamine site antagonists. 3. Inhibitory activity profiles for 20 different antagonists are presented. All compounds tested showed some degree of selectivity with regard to the different responses and each response showed particular characteristics that suggested mediation by a particular native NMDA receptor subtype. 4. Receptors controlling dopamine, GABA and noradrenaline release were generally more sensitive to most antagonists compared to those controlling acetylcholine and spermidine release. 5. Receptors controlling spermidine release were furthermore insensitive to magnesium, argiotoxin, ifenprodil and eliprodil and displayed low sensitivity to memantine, dextrorphan and dextromethorphan. 6. Receptors controlling noradrenaline release could be further discriminated from those controlling dopamine and GABA release by very high sensitivity to magnesium and MK-801 and to the glycine antagonist L-689,560 but not to other glycine antagonists (CNQX, DNQX, 7-Chlorokynurenate, HA-966). 7. Many other individual drug or receptor differences were noted. The different profiles observed suggest a wide diversity of native NMDA receptors with different properties and an unexpectedly rich pharmacopeia of subtype selective antagonists of native NMDA receptors. 8. Matching subtype selectivity to particular behavioural effects may be possible and the design of subtype selective NMDA antagonists for particular clinical applications while avoiding side effect generation seems to be feasible.

Animals↗
PubMed1998

Arabidopsis thaliana contains a large family of germin-like proteins: characterization of cDNA and genomic sequences encoding 12 unique family members.

We have identified 39 Arabidopsis thaliana ESTs encoding germin-like proteins (GLPs) and have completely sequenced 25 of these cDNAs. Our analysis demonstrates that the Arabidopsis genome contains a gene family with at least 12 GLP genes. Comparisons with other known germins and germin-like proteins indicate that these Arabidopsis GLP subfamilies are unique from wheat germin. All other known GLPs fall into one of these subfamilies. The translated GLPs show approximately 35% amino acid identity with other GLPs outside of their subfamily and significantly higher levels of identity within their respective subfamily. The 3' ends of many of the GLP cDNAs are heterogeneous and several sites of polyadenylation are used. Ten of the GLPs have N-terminal signal sequences and most appear to be exported from the cell. Structurally, the GLPs are predicted to have a high content of beta-pleated sheet. Seven conserved regions of beta-sheet were found in each of the GLP proteins along with alpha-helices located at both N- and C-termini. These same structural elements are also conserved in wheat germin. With one exception, all GLP family members contain at least one N-glycosylation site. All of these sites are conserved in an unstructured loop between beta-1 and beta-2. Genes for two of these GLPs were identified in genomic sequences previously deposited in the GenBank. The GLP3b gene is physically linked to the polyubiquitin 4 gene. The 3' end of the GLP3b mRNA is only 0.5 kb from the ubq4 start of transcription. Analysis of the GLP3b promoter shows the presence of a single putative auxin-response sequence located at -124 to -111 upstream from the 5' end of the GLP3b mRNA. The GLP9 gene was identified in an Arabidopsis contig from Chromosome 4.

Amino Acid Sequence↗
PubMed1998

T cell-depleted bone marrow transplantation and delayed T cell add-back to control acute GVHD and conserve a graft-versus-leukemia effect.

Thirty-eight patients with hematological malignancies, received T cell-depleted marrow transplants (BMT) and cyclosporine to prevent acute graft-versus-host disease (aGVHD), followed by delayed add-back of donor lymphocytes to prevent leukemia relapse. In 26 patients scheduled for donor T cell add-back of 2 x 10(6) cells/kg on day 30 and 5 x 10(7) cells/kg on day 45 (schedule 1), the overall probability of grade > or = II aGVHD developing was 31.5%, with a 15.5% probability of aGVHD occurring after T cell add-back. In 12 patients receiving 10(7) donor T cells/kg on day 30 (schedule 2), the probability of grade > or = II aGVHD was 100%. The incidence of grade III-IV aGVHD was higher in schedule 2 than in schedule 1 (P=0.02). Of 24 evaluable patients, 10 (46%) developed chronic GVHD which was limited in eight and extensive in two. Current disease-free survival for 18 patients at standard risk for relapse (chronic myeloid leukemia (CML) in chronic or accelerated phase, acute myeloid leukemia in remission) vs 20 patients with more advanced leukemia or multiple myeloma were respectively 72% vs 12% (P < 0.01) with a 29% vs 69% probability of relapse (P=0.08). In 12 CML patients surviving more than 3 months, PCR analysis of the BCR/ABL transcript showed that minimal residual disease after T cell add-back was transient except in two patients who developed hematological relapse. Results indicate that the risk of acute GVHD is low following substantial T cell doses, transfused 45 days after transplant, using cyclosporine prophylaxis. Furthermore a graft-versus-leukemia effect was conserved.

Adult↗
PubMed1998

Lower moiety heminephroureterectomy in the duplex refluxing kidney: the accuracy of isotopic scintigraphy in functional assessment.

OBJECTIVE: To determine the accuracy of dimercaptosuccinic acid (DMSA) scintigraphy in assessing the differential function between upper and lower moieties of a refluxing duplex system. PATIENTS AND METHODS: Between 1990 and 1996, 20 patients underwent lower moiety heminephroureterectomy. All patients had their differential renal function assessed by DMSA scintigraphy before and after surgery, the results being assessed by comparing the predicted and actual loss of renal function. RESULTS: The mean (SD, range) function attributed to the scarred lower moiety (predicted loss of function) was 4.3 (4.9, 0-14)%, which compared with an actual mean loss of function of 6.8 (5.1, +4 to -16)%. Thus the mean (SD, range) difference between the predicted and actual loss of renal function was -2.1 (3.2, +4 to -8)%. CONCLUSION: DMSA scintigraphy provides an accurate assessment of the differential renal function between upper and lower moieties in a duplex system. The decision to proceed to lower moiety heminephroureterectomy can be logically based on the information gained from DMSA scintigraphy.

Adolescent↗
PubMed1998

Aspirin and salicylate protect against MPTP-induced dopamine depletion in mice.

The neurotoxic effects of the dopamine-selective neurotoxin MPTP (15 mg/kg, s.c.), in mice, were totally prevented by systemic administration of salicylate (ED50 = 40 mg/kg, i.p.), aspirin (ED50 = 60 mg/kg, i.p.), or the soluble lysine salt of aspirin, Aspegic (ED50 = 80 mg/kg, i.p.). The protective effects of aspirin are unlikely to be related to cyclooxygenase inhibition as paracetamol (100 mg/kg, i.p.), diclofenac (100 mg/kg, i.p.), ibuprofen (20 mg/kg, i.p.) and indomethacin (100 mg/kg, i.p.) were ineffective. Dexamethasone (3-30 mg/kg, i.p.), which, like aspirin and salicylate, has been reported to inhibit the transcription factor NF-kappaB, was also ineffective. Aspirin or salicylate (100 microM) had no effect on dopamine uptake into striatal synaptosomes or on monoamine oxidase B activity. The neuroprotective effects of salicylate derivatives could perhaps be related to hydroxyl radical scavenging. This was suggested by the fact that hydroxylated metabolites of salicylate (2,3- and 2,5-dihydrobenzoic acid) were recovered in brain tissue following the combined administration of MPTP and aspirin to a greater extent than following aspirin alone. The surprising neuroprotective effects of aspirin in an animal model of Parkinson's disease warrant further clinical investigation.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1998

Monoclonal antibody enhanced stimulation of human growth hormone action in vitro using ovine costal cartilage growth plate chondrocytes.

Investigations into the mechanism underlying antibody-mediated enhancement of growth hormone action have been hampered by the lack of an in vitro assay system. In this work, we have used isolated ovine costal cartilage growth plate chondrocytes to demonstrate, for the first time, that monoclonal antibody EB1 can enhance the proliferative actions of human growth hormone on this cell type. Chondrocytes were cultured for 14 days prior to exposure to GH+/-monoclonal antibody EB1 for a 4-day treatment period. Human growth hormone alone promoted a significant dose-dependent increase in chondrocyte proliferation; maximal stimulation was achieved at about 3.3-10 ng/ml growth hormone, and at higher doses of growth hormone, the response declined. Monoclonal antibody EB1 was shown to enhance the proliferative activity of 10 ng/ml human growth hormone in a significant dose dependent fashion. In conclusion, our results demonstrate that an antibody capable of enhancing GH activity in vivo also has the capacity to potentiate GH activity in vitro. This system may provide an important tool for investigations into the mechanism of GH action, and how this is modified by GH enhancing MAbs.

Animals↗
PubMed1998

Bilateral ruptured tubo-ovarian abscesses following bilateral tubal ligation several years earlier.

The occurrence of pelvic inflammatory disease and tubo-ovarian abscesses previously has been regarded as essentially nonexistent in the patient who has undergone tubal sterilization, although there have been isolated reports in the literature. This case describes a patient who underwent tubal ligation approximately 6 years prior to presenting with bilateral ruptured tubo-ovarian abscesses. The patient underwent emergency surgery and had an uneventful recovery. Theoretically, although bilateral tubal ligation should preclude the development of pelvic inflammatory disease, it is a diagnosis that should be considered in the patient presenting with lower pelvic and abdominal pain.

Abscess↗
PubMed1997

Calcium ionophore-treated peripheral blood monocytes and dendritic cells rapidly display characteristics of activated dendritic cells.

Human peripheral blood contains a small subpopulation of immature dendritic cells (iDC) distinguished from circulating monocytes by their low expression of CD14. We utilized leukapheresis and countercurrent centrifugal elutriation to obtain myeloid origin mononuclear cell (MOMC) fractions of monocytes and iDC for study. These subpopulations were ultrastructurally and immunophenotypically similar before culture. After a 20- to 96-h culture either alone, with recombinant human granulocyte-monocyte CSF, or with endotoxin, greater up-regulation of costimulatory molecule expression was observed among iDC than among monocytes, and only iDC expressed the activation molecule CD83. Treatment with rhIL-4 caused many MOMC to develop morphologic properties of dendritic cells within 96 h, but costimulatory molecule up-regulation and CD14 down-regulation were heterogeneous, and CD83 expression was infrequent. In contrast, calcium ionophore (CI) treatment induced rapid and consistent effects in MOMC from both healthy volunteers and cancer patients, including down-regulated CD14 expression, acquisition of dendritic cell morphologic properties, up-regulated MHC and costimulatory molecule expression, and de novo CD83 expression. Many such effects occurred within 20 h of treatment. CI treatment activated purified CD14+ monocytes and also enhanced the spontaneous activation of purified CD14-/dim iDC in culture. Unfractionated MOMC, purified monocytes, and purified iDC displayed equivalently enhanced T cell-sensitizing efficiency following CI treatment. CD4+ T cell sensitization to keyhole limpet hemocyanin and CD8+ T cell sensitization to MART-1 melanoma-associated peptide were achieved in a single culture stimulation. Therefore, circulating monocytes and iDC can be induced by CI to manifest properties of activated DC, providing large numbers of efficient, nontransformed autologous APC for T cell sensitization strategies.

Bone Marrow Cells↗
PubMed1997

Retroviral mediated gene transfer of the Fanconi anemia complementation group C gene to hematopoietic progenitors of group C patients.

Fanconi Anemia (FA) is a rare genetic disorder characterized by progress pancytopenia, congenial abnormalities, and a predisposition to malignancy. Therapy is currently limited to allogeneic marrow transplantation; patients lacking a suitable donor usually die from aplasia or acute leukemia. Recently, mutation in a novel gene named FACC (Fanconi anemia C-complementing) has been identified as causing one type of FA. FACC mutations, which introduce splicing errors or stop codons, have been identified in approximately 15% of FA patients. We have recently been successful in functional complementation of four FA cell lines using retroviral vectors to transfer a copy of the normal FACC gene. We also analyzed the ability of our viral vectors to functionally correct hematopoietic progenitor cells from a patient bearing a splice donor mutation. As for the lymphoid cell lines, these CD34-enriched cells were extremely sensitive to MMC. After infection of these progenitor cells with viral vectors bearing normal FACC, the progenitors gave rise to increased numbers of colonies both in the absence and presence of up to 5nM MMC, whereas control cells were completely destroyed by 1nM MMC. In summary, we have demonstrated that: (1) retroviral vectors can be engineered to transfer a normal FACC gene to FA(C) lymphoid cell lines and primary hematopoietic cells; (2) introduction of a normal FACC gene into CD34+ progenitors markedly enhances their growth in the absence and presence of MMC. This study is designed to determine whether hematopoietic progenitors transduced with the normal FACC gene can be reinfused safely into FA(C) patients. CD34+ cells obtained from G-CSF mobilized peripheral blood will be transduced ex vivo over a 72-hour period in the presence of IL-3, IL-6, and Stem Cell Factor with the FACC retroviral vector. These transduced cells will be reinfused into FA(C) patients. Patients will be monitored for toxicities as well as evidence of successful gene transfer and expression. The procedure will be repeated up to a total of 4 times with each treatment 2-4 months apart. Theoretically, these rescued stem cells should have a selective growth advantage within the hypoplastic FA marrow environment in vivo.

Cell Cycle Proteins↗
PubMed1997

In vitro generation of allospecific human CD8+ T cells of Tc1 and Tc2 phenotype.

We have previously shown that allospecific murine CD8+ T cells of the Tc1 and Tc2 phenotype could be generated in vitro, and that such functionally defined T-cell subsets mediated a graft-versus-leukemia (GVL) effect with reduced graft-versus-host disease (GVHD). To evaluate whether analogous Tc1 and Tc2 subsets might be generated in humans, CD8+ T cells were allostimulated in the presence of either interleukin-12 (IL-12) and transforming growth factor-beta (TGF-beta) (Tc1 culture) or IL-4 (Tc2 culture). Tc1-type CD8 cells secreted the type I cytokines IL-2 and interferon gamma (IFN-gamma), whereas Tc2-type cells primarily secreted the type II cytokines IL-4, IL-5, and IL-10. Both cytokine-secreting populations effectively lysed tumor targets when stimulated with anti-T-cell receptor (TCR) antibody; allospecificity of Tc1- and Tc2-mediated cytolytic function was demonstrated using bone marrow-derived stimulator cells as targets. In addition, both Tc1 and Tc2 subsets were capable of mediating cytolysis through the fas pathway. We therefore conclude that allospecific human CD8+ T cells of Tc1 and Tc2 phenotype can be generated in vitro, and that these T-cell populations may be important for the mediation and regulation of allogeneic transplantation responses.

Animals↗
PubMed1997

PET brain mapping study of auditory verbal supraspan memory versus visual fixation in schizophrenia.

Changes in regional cerebral blood flow (rCBF), associated with performance of an auditory verbal supraspan memory task, were studied in eight remitted DSM-III-R schizophrenic patients and eight pair-wise matched normal controls. Four positron emission tomography (PET) scans, using the [15O]-H2O technique, were acquired: two while subjects fixated a cross hair and two while performing a verbal free-recall supraspan memory task. Task performance showed typical patterns of recency and primacy effects in both groups; however, patients performed more poorly than controls on the primary (working) memory aspect of the task. Regions showing rCBF changes overlapped in both groups and were similar to those seen in previous studies of normals; however, patients had smaller increases in rCBF than controls in frontal and superior temporal cortical regions bilaterally. Our results suggest that remitted patients with schizophrenia demonstrate impairments of capacity-limited information processing, which may be related to metabolic dysfunction within a distributed network of brain structures, including the prefrontal and temporal cortical regions; however, dysfunction limited to the frontal cortex cannot be ruled out by the results of this experiment.

Adult↗
PubMed1997

The effect of time headway feedback on following behaviour.

A field study was conducted to assess the impact of continuous time headway feedback on following behaviour. An equipped vehicle was fitted with a microwave radar connected to a head-down display. The display was supplemented by an auditory tone which sounded if headway decreased below 1 second. Sixteen subjects participated in five consecutive sessions conducted on a U.K. motorway. The presence of the system and the time of the journey (i.e. rush hour vs off-peak) was manipulated across the experimental sessions. Results revealed that the presence of the system reduced the proportion of time the subjects spent at low headways (e.g. < 1 second). This effect was accentuated for: (a) subjects who habitually follow at shorter headways and (b) those scenarios characterised as following a lead vehicle at a constant velocity. The presence of the system increased time headway to a lead vehicle when an overtaking manoeuvre was initiated, but only in off-peak traffic. The system had no significant effect on speed-keeping behaviour or driver's mental workload.

Accidents, Traffic↗
PubMed1997

Enteral glutamine supplementation for very low birth weight infants decreases morbidity.

Glutamine, described as a "conditionally essential" amino acid for critically ill patients, has not been routinely added to parenteral amino acid formulations for critically ill neonates and is provided in only small quantities by the enteral route when enteral intake is low. We conducted a blinded, randomized study of enteral glutamine supplementation in 68 very low birth weight neonates randomly assigned to receive glutamine-supplemented premature formula versus premature formula alone between days 3 and 30 of life. Primary end points consisted of hospital-acquired sepsis, tolerance to subsequent enteral feedings (days with no oral intake), and duration of hospital stay. Hospital acquired sepsis was 30% (control group) and 11% (glutamine group). Logistic regression with birth weight as a covariate showed that: (1) feeding group was significant (p = 0.048) in determining the probability of developing proven sepsis over the course of hospitalization and (2) the estimated odds of developing sepsis were 3.8 times higher for infants in the control group than for those treated with glutamine. Glutamine-supplemented infants had better tolerance to enteral feedings as measured by percent of days on which feedings needed to be withheld (mean percentage of 8.8 vs 23.8, p = 0.007). Analysis of T cells demonstrated a blunting of the rise in HLA-DR+ and CD16 subsets in glutamine-supplemented infants. There were no differences in growth; in serum ammonia, urea, liver transaminase, or prealbumin concentrations; or in mean hospital stay. This study provides evidence for decreased morbidity in very-low-birth-weight neonates who receive enteral glutamine supplementation.

Diet Therapy↗