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Biomedical subjects

C J Carter

Publications and source records attributed to C J Carter.

At least 19 recordsLinked to original sources
PubMed2006

Convergence of genes implicated in Alzheimer's disease on the cerebral cholesterol shuttle: APP, cholesterol, lipoproteins, and atherosclerosis.

Polymorphic genes associated with Alzheimer's disease (see ) delineate a clearly defined pathway related to cerebral and peripheral cholesterol and lipoprotein homoeostasis. They include all of the key components of a glia/neurone cholesterol shuttle including cholesterol binding lipoproteins APOA1, APOA4, APOC1, APOC2, APOC3, APOD, APOE and LPA, cholesterol transporters ABCA1, ABCA2, lipoprotein receptors LDLR, LRP1, LRP8 and VLDLR, and the cholesterol metabolising enzymes CYP46A1 and CH25H, whose oxysterol products activate the liver X receptor NR1H2 and are metabolised to esters by SOAT1. LIPA metabolises cholesterol esters, which are transported by the cholesteryl ester transport protein CETP. The transcription factor SREBF1 controls the expression of most enzymes of cholesterol synthesis. APP is involved in this shuttle as it metabolises cholesterol to 7-betahydroxycholesterol, a substrate of SOAT1 and HSD11B1, binds to APOE and is tethered to LRP1 via APPB1, APBB2 and APBB3 at the cytoplasmic domain and via LRPAP1 at the extracellular domain. APP cleavage products are also able to prevent cholesterol binding to APOE. BACE cleaves both APP and LRP1. Gamma-secretase (PSEN1, PSEN2, NCSTN) cleaves LRP1 and LRP8 as well as APP and their degradation products control transcription factor TFCP2, which regulates thymidylate synthase (TS) and GSK3B expression. GSK3B is known to phosphorylate the microtubule protein tau (MAPT). Dysfunction of this cascade, carved out by genes implicated in Alzheimer's disease, may play a major role in its pathology. Many other genes associated with Alzheimer's disease affect cholesterol or lipoprotein function and/or have also been implicated in atherosclerosis, a feature of Alzheimer's disease, and this duality may well explain the close links between vascular and cerebral pathology in Alzheimer's disease. The definition of many of these genes as risk factors is highly contested. However, when polymorphic susceptibility genes belong to the same signaling pathway, the risk associated with multigenic disease is better related to the integrated effects of multiple polymorphisms of genes within the same pathway than to variants in any single gene [Wu, X., Gu, J., Grossman, H.B., Amos, C.I., Etzel, C., Huang, M., Zhang, Q., Millikan, R.E., Lerner, S., Dinney, C.P., Spitz, M.R., 2006. Bladder cancer predisposition: a multigenic approach to DNA-repair and cell-cycle-control genes. Am. J. Hum. Genet. 78, 464-479.]. Thus, the fact that Alzheimer's disease susceptibility genes converge on a clearly defined signaling network has important implications for genetic association studies.

Alzheimer Disease↗
PubMed2006

Schizophrenia susceptibility genes converge on interlinked pathways related to glutamatergic transmission and long-term potentiation, oxidative stress and oligodendrocyte viability.

Over 130 genes have been associated with schizophrenia in genetic studies. None of these has reached a sufficient level of confidence to be accepted as a universal susceptibility gene and problems of replicability suggest that many may be false positives. Nevertheless, these genes can be grouped into distinct families related to glutamate transmission (in particular related to NMDA receptor function), the control of synaptic plasticity, dopaminergic transmission, oxidative stress, glutathione and quinone metabolism and oligodendrocyte viability. These families mirror the processes disrupted in the schizophrenic brain and certain gene families can be linked together to form a clearly defined signalling cascade involved in the phenomenon of NMDA receptor-dependent long-term potentiation and synaptic plasticity, that may be interconnected with oligodendrocyte and oxidative stress-related pathways. Many of the protein products of these genes interact with each other, forming complex integrated networks. Certain high-interest genes (for example DISC1, NRG1, COMT) may exert multiple effects on different areas of these pathways, while others exert more specific effects on certain branches. The convergence of a large number of genes on a definable signaling network raises the possibility of numerous interactions between gene candidates, and suggests that a targeted multigenic pathway approach would be useful in gene association studies.

Animals↗
PubMed2000

Oral contraceptives and thrombosis.

Oral contraceptives (OCs) are used by many millions of healthy young women. Their ease of use and efficacy against unwanted pregnancy has made them an indispensable part of modern society. Despite various changes in formulation, they are clearly associated with an increased risk of venous thromboembolism (VTE). Case-control and prospective studies have developed a range of relative risks of VTE, but the important issue is the impact of VTE relative to perceived benefits of the OC. This involves societal as well as medical judgment. The development of third-generation OCs has led to considerable concerns that these newer preparations may be associated with additional thrombotic risks over and above those of the traditional second-generation preparations. The paradoxical effect, that a change in progestogen in the combined OC could lead to increased VTE, could be explained by the induction of activated protein C resistance. In a society that is less prepared to accept unwanted side effects from medications, it is recommended that increased attention be given to patient selection, and possibly the incorporation into this process of some of the more recently discovered hypercoagulability markers.

Blood Coagulation Tests↗
PubMed2000

Surface protein variation by expression site switching in the relapsing fever agent Borrelia hermsii.

Borrelia hermsii, an agent of relapsing fever, undergoes antigenic variation of serotype-specifying membrane proteins during mammalian infections. When B. hermsii is cultivated in broth medium, one serotype, 33, eventually predominates in the population. Serotype 33 has also been found to be dominant in ticks but not in mammalian hosts. We investigated the biology and genetics of two independently derived clonal populations of serotype 33 of B. hermsii. Both isolates infected immunodeficient mice, but serotype 33 cells were limited in number and were only transiently present in the blood. Probes for vsp33, which encodes the serotype-specifying Vsp33 outer membrane protein, revealed that the gene was located on a 53-kb linear plasmid and that there was only one locus for the gene in serotype 33. The vsp33 probe and probes for other variable membrane protein genes showed that expression of Vsp33 was determined at the level of transcription and that when the vsp33 expression site was active, an expression site for other variable proteins was silent. The study confirmed that serotype 33 is distinct from other serotypes of B. hermsii in its biology and demonstrated that B. hermsii can change its major surface protein through switching between two expression sites.

Animals↗
PubMed2000

Detection of red cell aggregation by low shear rate viscometry in whole blood with elevated plasma viscosity.

The viscosity of whole blood measured at low shear rates is determined partly by shear resistance of the red cell aggregates present, stronger aggregation increasing the viscosity in the absence of other changes. Effects of cell deformability can confound interpretation and comparison in terms of aggregation, however, particularly when the plasma viscosity is high. We illustrate the problem with a comparison of hematocrit-adjusted blood from type 1 diabetes patients and controls in which it is found the apparent and relative viscosities at a true shear rate of 0.20 s-1 are lower in the patient samples than age matched controls, in spite of reports that aggregation is increased in such populations. Because the plasma viscosities of the patients were higher on average than controls, we performed a series of experiments to examine the effect of plasma protein concentration and viscosity on normal blood viscosity. Dilution or concentration by ultrafiltration of autologous plasma and viscosity measurements at low shear on constant hematocrit red cell suspensions showed (a) suspension viscosity at 0.25 and 3 s-1 increased monotonically with plasma protein concentration and viscosity but (b) the relative viscosity increased, in concert with the microscopic aggregation grade, up to a viscosity of approximately 1.25 mPa-s but above this the value the relative viscosity no longer increased as the degree of aggregation increased in concentrated plasmas. It is suggested that in order to reduce cell deformation effects in hyperviscous pathological plasmas, patient and control plasmas should be systematically diluted before hematocrit is adjusted and rheological measurements are made. True shear rates should be calculated. Comparison of relative viscosities at low true shear rates appears to allow the effects of red cell aggregation to be distinguished by variable shear rate viscometry in clinical blood samples.

Adult↗
PubMed1999

Idiopathic immune-mediated acquired von Willebrand's disease in a patient with angiodysplasia: demonstration of an unusual inhibitor causing a functional defect and rapid clearance of von Willebrand factor.

A case of idiopathic immune-mediated von Willebrand's disease (AvWD) associated angiodysplasia and recurrent lower gastrointestinal bleeding is reported. Coagulation parameters at presentation were activated partial thromboplastin time of 41 sec, bleeding time >15 min, factor VIII procoagulant activity, 5%; von Willebrand factor antigen (WF:Ag) 5%, and vWF:ristocetirn cofactor activity 11% sodium dodecyl sulfate-agarose gel electrophoresis pattern of plasma vWF showed a pattern similar to type II vWD. An in vitro inhibitor against vWF in the immunoglobulin (Ig)G fraction of the patient's plasma was demonstrated vWF parameters showed a short-lived increase after 1-deamino-8-D-arginine vasopressin (DDAVP) administration. The patient's bleeding episodes were initially managed adequately with cryoprecipitate replacement therapy and DDAVP, to which she became refractory. No significant improvement was achieved following the institution of immunosuppressive therapy in the form of high-dose steroids and cyclophosphamide. She was then treated with intravenous immunoglobulin (IvIg) to which she showed an adequate response in terms of her clinical situation and her hemostatic parameters. The patient is on maintenance treatment with repeated courses of IvIg based on vWF parameter monitoring. To our knowledge, this is the third reported association between idiopathic immune-mediated AvWD and angiodysplasia.

Aged↗
PubMed1998

Haematuria and clot retention after transurethral resection of the prostate: a pilot study.

OBJECTIVE: To determine, prospectively, the effect of clinical factors on the duration of frank haematuria and the incidence of clot retention after transurethral resection of the prostate (TURP). PATIENTS AND METHODS: Seventy-nine men who underwent TURP in a 3-month period were entered into this study, during which the time to cessation of bleeding and the occurrence of clot retention(s) were recorded over a 4-week period. The effect of other clinical factors (histology, weight of tissue resected. operative duration, grade of surgeon and resection rate) was also assessed. RESULTS: Gross haematuria ceased in 47%, 73%, 96%, and 97% of patients at the end of the first, second, third and fourth weeks, respectively. The duration of postoperative bleeding was significantly associated with the weight of tissue resected and the operation time (P<0.001 and <0.05, respectively). Furthermore, five patients were re-admitted with clot retention, but there was no significant correlation between the occurrence of this morbidity and any of the other indices. CONCLUSION: Postoperative bleeding usually stops within 3 weeks of TURP. This period, which is about half the time hitherto assumed, is directly related to the size of the gland resected and the duration of the procedure. However, the occurrence of clot retention is not significantly associated with the duration of haematuria or any of the other clinical factors evaluated. Thus, a high fluid intake is mandatory for 3 weeks after TURP, but men who continue to bleed should be advised to continue with a high-fluid regimen until their urine is clear.

Aged↗
PubMed1998

Falsely elevated INR results due to the sensitivity of a thromboplastin reagent to heparin.

The aim of this study was to determine the effect of heparin therapy on the international normalized ratio (INR). In vitro heparin sensitivity curves were created using normal and warfarinized plasma samples from patients. The INR results were measured with each of two reagents. In addition, a comparison of INR values with these two reagents was performed on plasma from patients receiving therapeutic heparin and warfarin. The INR values were measured before and after heparin removal with a heparin adsorbent system. While one of the reagents was found to be sensitive to even low levels of therapeutic heparin, the other thromboplastin was resistant up to at least 0.9 U/mL. The INR values determined for patients with one of the reagents were found to be erroneously elevated by an average of 16%. The error ranged from 2% to 55% depending on the in vivo heparin concentration. With the other reagent, the INR values were not substantially affected by heparin. Previous studies have described the effect or lack thereof of heparin on the prothrombin time. The present study demonstrates that the degree to which INR results are prolonged by heparin therapy depends on the reagent formulation. As the therapeutic index for monitoring warfarin is relatively narrow (2.0-3.0), an INR value that is falsely elevated due to reagent sensitivity may precipitate premature cessation of heparin therapy and place certain patients at risk for recurrent thrombosis in the short term.

Adsorption↗
PubMed1996

Identification of an uncultivable Borrelia species in the hard tick Amblyomma americanum: possible agent of a Lyme disease-like illness.

Bites from the hard tick Amblyomma americanum are associated with a Lyme disease-like illness in the southern United States. To identify possible etiologic agents for this disorder, A. americanum ticks were collected in Missouri, Texas, New Jersey, and New York and examined microscopically. Uncultivable spirochetes were present in approximately 2% of the ticks. Borrelia genus-specific oligonucleotides for the flagellin and 16S rRNA genes were used for amplification of DNA. Products were obtained from ticks containing spirochetes by microscopy but not from spirochete-negative ticks. Sequences of partial genes from spirochetes in Texas and New Jersey ticks differed by only 2 of 641 nucleotides for flagellin and 2 of 1336 nucleotides for 16S rRNA. Phylogenetic analysis showed that the spirochete was a Borrelia species distinct from previously characterized members of this genus, including Borrelia burgdorferi. Gene amplification could be used to detect these spirochetes in ticks and possible mammalian hosts.

Amino Acid Sequence↗
PubMed1996

The nucleotide sequence of a linear plasmid of Borrelia burgdorferi reveals similarities to those of circular plasmids of other prokaryotes.

A linear plasmid of Borrelia burgdorferi had 16,927 bp, a G+C content of 23.1%, a relative deficiency of CpG dinucleotides, and open reading frames A to O. The OrfC and OrfE proteins were similar to hypothetical proteins encoded by circular plasmids of B. burgdorferi. The OrfM and OrfN proteins were similar to replication proteins of circular plasmids of other bacteria.

Amino Acid Sequence↗
PubMed1996

New developments in acute anticoagulation therapy: what improvements over traditional heparin are on the horizon?

The quest for an orally active anticoagulant to replace warfarin sodium (Coumadin, Panwarfin, Sofarin) in long-term use has been disappointing. Most advances in oral anticoagulant therapy have involved more judicious and efficacious use of warfarin or one of its analogues. The area of heparin substitutes has experienced some exciting discoveries, with most current interest centered on low-molecular-weight heparins. Their efficacy, safety, and perhaps most important, clinical utility as a once- or twice-daily unmonitored medication have given them a meaningful role in current anticoagulation therapy. Third-generation anticoagulants, such as the direct thrombin inhibitors, are being investigated but are not ready for general clinical use. The role of ancrod (Arvin) from snake venom in patients with heparin-induced thrombocytopenic thrombosis has been clearly established. A practical issue that remains under discussion is the most suitable interaction between fiscal and clinical applications of these medications.

Ancrod↗
PubMed1995

Effect of thromboplastin and coagulometer interaction on the precision of the International Normalised Ratio.

AIMS: To examine the magnitude of thromboplastin and coagulometer interactions on the precision of International Normalised Ratio (INR) values when the manufacturers' recommended instrument specific International Sensitivity Index (ISI) values are adopted for the INR calculation. METHODS: The variability of INR values obtained from four automated phototopical coagulometers frequently used in North American laboratories was studied. When used with five commercial thromboplastins of moderate to high sensitivity (ISI values 0.92-1.97), 20 prothrombin time results were generated for each of a population of 98 patients on established warfarin treatment. RESULTS: The mean INR values of the patients ranged from 2.05 to 2.81, depending on which reagent/coagulometer combination was used. Within patient variation increased as the median INR value increased. The mean coefficient of variation of within patient INR values was 10%; the mean coefficient of variation of the prothrombin time results in seconds and prothrombin time ratio were 21 and 18%, respectively. CONCLUSIONS: There was considerable bias in the estimated ISI values of the thromboplastins compared with the manufacturers' instrument specific ISI value. Despite this apparent imperfection, our study clearly showed that the INR is preferable to other prothrombin time reporting formats for assessing the degree of anticoagulation for patients on warfarin treatment.

Adult↗
PubMed1995

Profibrinolytic and antifibrinolytic effects of platelets.

The pro- and antifibrinolytic effects of platelets have been reviewed periodically over the past 25 years. Review of the current publications indicates that the profibrinolytic and antifibrinolytic effects attributed to platelets are highly dependent upon the test system used. On balance, the antifibrinolytic effect appears to predominate; however, this conclusion awaits further experimentation, particularly through clinical studies clarifying the effects of platelets in therapeutic fibrinolysis.

Aspirin↗
PubMed1994

Reappraisal of optimal hemoglobin standards for female blood donors in Canada.

BACKGROUND: A hemoglobin (Hb) standard of 115 g per L on the copper sulfate test has been in use by the Canadian Red Cross Society Blood Services for female blood donor predonation screening since 1989. STUDY DESIGN AND METHODS: To determine if this lowered Hb standard results in increased iron deficiency in repeat blood donors, a study was conducted to evaluate the performance of the copper sulfate test and predonation capillary and venous Hb assays in a population of female blood donors most at risk of developing iron deficiency. RESULTS: Of the 174 donors who were of childbearing age, who were not taking iron supplements, and who had made at least three blood donations per year, 45 (25.9%) were iron deficient, and 64 (36.8%) had reduced iron stores; only 65 (37.3%) had normal iron stores. This study showed that capillary blood is more likely to have a higher Hb concentration (3.2 +/- 7.8 g/L) than venous blood samples, which could affect the performance of predonation screening assays that are based on capillary blood samples at a given discriminating value. With an Hb standard of 115 g per L, both the copper sulfate and capillary Hb assays were not sensitive enough to screen for iron deficiency (sensitivity, 27% and 33%; specificity, 96% and 93%, respectively) and were comparable only to the performance of a venous Hb assay with a cutoff value of 110 g per L (sensitivity, 27%; specificity, 99%). In contrast, an Hb standard of 125 g per L in the copper sulfate test could achieve a more optimal sensitivity of 79 percent and specificity of 78 percent. CONCLUSION: This study supports the use of a higher Hb cutoff value of 125 g per L for female blood donors in the predonation fingerstick copper sulfate test.

Adult↗
PubMed1994

Activation of a vmp pseudogene in Borrelia hermsii: an alternate mechanism of antigenic variation during relapsing fever.

The relapsing fever agent, Borrelia hermsii, undergoes multiphasic antigenic variation to evade its host's immune response. A frequently observed switch is serotype 7 to 26. Unlike silent vmp genes previously characterized, the transcriptionally silent vmp26 sequence was a pseudogene in lacking a start codon. In serotype 7 the location of the silent vmp26 sequence just downstream of vmp7 on the expression plasmid, as well as on the silent plasmid, was also unique. The demonstration of a predicted circular recombination product in serotype 7 but not serotype 21 populations indicates that the pseudogene was activated by an intramolecular recombination producing a deletion of DNA between 20-nucleotide direct repeats in vmp7 and psi vmp26.

Amino Acid Sequence↗
PubMed1994

A family of surface-exposed proteins of 20 kilodaltons in the genus Borrelia.

Relapsing fever and Lyme disease spirochetes of the genus Borrelia display at their surfaces abundant lipoproteins: Vmp proteins in Borrelia hermsii and Osp proteins in Borrelia burgdorferi. Vmp and Osp proteins largely determine serotype specificity, and neutralizing antibodies of infected or immunized animals are directed at them. For the present study, we examined B. hermsii serotype 33, which is unique among strain HS1 serotypes in the low frequency of switches to other serotypes during infections and in vitro cultivation. Failing to clone the complete vmp33 gene, we accomplished its further characterization by (i) determining three partial amino acid sequences, (ii) designing oligonucleotide primers based on these amino acid sequences, (iii) cloning and sequencing the central portion of vmp33, and (iv) using outwardly directed primers and the inverse PCR to clone the 5' and 3' ends of the gene and flanking regions. The transcriptional start site was identified by primer extension analysis. Vmp33 was a polypeptide of 211 amino acids; the three partial amino acid sequences were identified in the open reading frame. Vmp33 was found to be more similar to other 20-kDa Vmp proteins of B. hermsii and to OspC proteins of B. burgdorferi than it was to 35- to 39-kDa Vmp proteins of the same strain. Moreover, OspC proteins were more similar to Vmp33 than they were to OspA, -B, or -D proteins of B. burgdorferi. These sequence similarities were consistent with Western blot (immunoblot) findings of cross-reactions between Vmp33 and OspC with anti-Vmp33 and anti-OspC sera. The promoter for the expressed vmp33 gene was found to be different from the expression site for other active vmp genes characterized to date. These results indicate that Vmp33 and other small Vmp's belong with OspC to a genus-wide family of 20-kDa proteins and that expression of these proteins may be coordinated with expression of other Vmp and Osp proteins in Borrelia spp.

Amino Acid Sequence↗