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Biomedical subjects

K Cox

Publications and source records attributed to K Cox.

At least 37 records · Page 2Linked to original sources
PubMed2000

Significance of detecting Epstein-Barr-specific sequences in the peripheral blood of asymptomatic pediatric liver transplant recipients.

Pediatric allograft recipients are at increased risk for Epstein-Barr virus (EBV)-associated illnesses. The early identification and diagnosis of EBV-associated disorders is critical because disease progression can often be curtailed by modification of immunosuppression. We have previously shown that detection of EBV-specific sequences in the circulation by polymerase chain reaction (PCR) correlated well with the clinical symptoms of EBV infection. The purpose of the current study is to determine the significance of detecting EBV-specific sequences by PCR in asymptomatic pediatric liver transplant recipients. Peripheral-blood DNA was analyzed for the EBV genes, coding from the nuclear antigen 1 (EBNA-1) and the viral capsid antigen (gp220) by PCR. Samples from asymptomatic pediatric liver transplant recipients were analyzed from the immediate postoperative period and at 2- to 4-month intervals thereafter. We followed up 13 of these asymptomatic recipients who tested positive for EBV compared with 7 asymptomatic recipients who tested negative for EBV during the early posttransplantation period. Follow-up ranged from 1.5 to 4 years posttransplantation. Nine patients (69%) initially positive for EBV and asymptomatic ultimately developed symptoms of EBV infection, including fever, lymphadenopathy, rash, respiratory and gastrointestinal symptoms, and/or hepatitis. Five of these patients (56%) went on to develop posttransplant lymphoproliferative disorder based on histological examination of biopsied tissue and immunohistochemical identification of the EBV antigen/DNA in tissue. This is the first report suggesting that detection of EBV-specific sequences in the absence of symptoms may herald impending EBV-associated disorders. Thus, routine monitoring for circulating EBV sequences in asymptomatic recipients may be useful in the early identification of those at risk for developing EBV-associated disease and its ultimate prevention.

Child, Preschool↗
PubMed2000

Endotracheal lidocaine administration via an esophageal combitube.

The purpose of this study was to test the hypothesis that lidocaine is systemically absorbed after administration via a Combitube placed in the esophagus, and that therapeutically significant plasma lidocaine concentrations can be attained using this route with standard endotracheal doses (2.0 mg/kg). During general anesthesia, 27 elective surgical patients received 2.0 mg/kg lidocaine (diluted as necessary with 0.9% saline to a minimum total volume of 10 mL) via a Combitube (study group, n = 13) or an endotracheal tube (control group, n = 14). Venous blood samples were drawn for 3 h after lidocaine administration and plasma concentrations determined by gas chromatography using a nitrogen-phosphorus detector (NPD). Overall, average lidocaine concentrations were maximal after 5 min, reaching 0.8+/-0.7 and 1.7+/-0.7 microg/mL in the Combitube and endotracheal tube groups, respectively. Individual patient peak concentrations averaged 1.0+/-0.7 and 2.2+/-1.1 microg/mL in the same two groups, 19+/-16 and 10+/-15 min after lidocaine administration, respectively. No patients reported chest discomfort or dyspnea upon awakening, and no other side effects were noted. In support of the hypothesis, administration of lidocaine via an esophageal Combitube results in systemic drug uptake; however, at conventional endotracheal doses, plasma concentrations are subtherapeutic. It remains to be determined whether higher doses of lidocaine administered via an esophageal Combitube will result in therapeutic plasma concentrations.

Adolescent↗
PubMed2000

Setting the context for research: exploring the philosophy and environment of a cancer clinical trials unit.

This paper describes a process of context setting that was undertaken prior to designing a study to assess the psychosocial impact of participation in phase I and II anticancer drug trials from the patient's perspective. The paper outlines how and why this context setting was undertaken and highlights important aspects of the culture and organization of cancer clinical trials that may influence patients' experiences in trial recruitment and participation. In this way, the context setting proved to be an invaluable tool for providing an orientation to the environment where patients received their care and treatment as well as identifying issues that would need to be taken into consideration later in the research study design.

Adaptation, Psychological↗
PubMed2000

Examining and recording clinical performance: a critique and some recommendations.

Clinical performance is too complex and interactive for measurement. Judgment is always necessary for its assessment. Experienced clinicians judge trainee performance on many small details. This clinical judgment turns on the trainee's handling of important details in the patient and the malady. But the recording of performance retreats to categories and checklists that contain nothing of those critical details or the trainee's judgment. Checklists are incapable of identifying what actually happened, and 'could do' categories have no predictive accuracy in asserting what cases a trainee can actually manage. Clinical examinations have even been subverted by the naive, pseudorational error that competence is defined by obedience to doing exactly what someone else expects you to do in every case, as in an OSCE examination. Cases are the unit of clinical practice. The clinical curriculum should be comprised of the critical core cases the trainee must be able to handle in each discipline. Case management, procedural skills and professional behavior can be assessed accurately only in the context of daily clinical work. Formal examinations lack the range of cases and open-ended time that allow examiners to explore a trainee's case knowledge and judgment. Habitual behavior can be assessed only by observing habitual behavior in everyday practice. Assessment and recording should take place only in real world settings, focused on performance on the core cases trainees must be competent to manage.

Journal Article↗
PubMed2000

The heat-stable antigen determines pathogenicity of self-reactive T cells in experimental autoimmune encephalomyelitis.

Induction of myelin-specific CD4 T cells is a pivotal event in the development of experimental autoimmune encephalomyelitis (EAE). Other checkpoints in EAE pathogenesis have not been clearly defined, although multiple genetic loci are known to influence EAE development. We report here that targeted mutation of the heat-stable antigen (HSA) abrogates development of EAE despite a complete lack of effect on induction of autoimmune T cells. To test whether T-cell expression of HSA is sufficient, we created transgenic mice in which HSA is expressed exclusively in the T-cell lineage. We found that these mice remain resistant to EAE induction. Adoptive transfer studies demonstrate that both T cells and non-T cells must express HSA in order for the pathogenic T cells to execute their effector function. Moreover, HSAIg, a fusion protein consisting of the extracellular domain of the HSA and the Fc portion of immunoglobulin, drastically ameliorates the clinical sign of EAE even when administrated after self-reactive T cells had been expanded. Thus, identification of HSA as a novel checkpoint, even after activation and expansion of self-reactive T cells, provides a novel approach for immunotherapy of autoimmune neurologic diseases, such as multiple sclerosis.

Adoptive Transfer↗
PubMed1999

Development of an automated mass spectrometry system for the quantitative analysis of liver microsomal incubation samples: a tool for rapid screening of new compounds for metabolic stability.

There is a continuing need for increased throughput in the evaluation of new drug entities in terms of their pharmacokinetic parameters. One useful parameter that can be measured in vitro using liver microsomal preparations is metabolic stability. In this report, we describe an automated system that can be used for unattended quantitative analysis of liver microsomal samples for a series of compounds. This system is based on the Sciex API 150 (single quadrupole) liquid chromatography/mass spectrometry system and utilizes 96-well plate autosampler technology as well as a custom-designed AppleScript which executes the on-line data processing and report generation. It has the capability of analyzing at least 75 compounds per week or 300 compounds per month in an automated fashion.

Autoanalysis↗
PubMed1999

Mapping and expression of a bifunctional thymidylate synthase, dihydrofolate reductase gene from maize.

A bifunctional gene (ZmDHFR-TS) encoding dihydrofolate reductase (DHFR) and thymidylate synthase (TS) was cloned from a Zea mays cDNA library. Both of these enzymes are involved in nucleotide biosynthesis, specifically in the formation of thymidine monophosphate (TMP). Comparison of the deduced amino acid sequence with DHFR-TS sequences from three other plant sources revealed over 75% similarity and motifs typical of DHFR-TS proteins. Two copies of the gene were mapped to chromosomes 2 and 4. This represents the first DHFR-TS gene cloned from a monocotyledonous plant. Expression of ZmDHFR-TS was examined in developing kernels and various tissues of maize by RNA gel blot hybridization analysis in order to determine the relationship between expression of this gene and DNA synthesis. RNA transcripts for ZmDHFR-TS accumulated to high levels in developing maize kernels when endosperm cells were undergoing endoreduplication and cell division. Meristematic maize tissues had high levels of ZmDHFR-TS mRNA, but transcripts were barely detectable in RNA isolated from the root elongation zone and from mature leaf tissues.

Amino Acid Sequence↗
PubMed1999

Clinical isoflurane metabolism by cytochrome P450 2E1.

BACKGROUND: Some evidence suggests that isoflurane metabolism to trifluoroacetic acid and inorganic fluoride by human liver microsomes in vitro is catalyzed by cytochrome P450 2E1 (CYP2E1). This investigation tested the hypothesis that P450 2E1 predominantly catalyzes human isoflurane metabolism in vivo. Disulfiram, which is converted in vivo to a selective inhibitor of P450 2E1, was used as a metabolic probe for P450 2E1. METHODS: Twenty-two elective surgery patients who provided institutionally-approved written informed consent were randomized to receive disulfiram (500 mg orally, N = 12) or nothing (controls, N = 10) the evening before surgery. All patients received a standard isoflurane anesthetic (1.5% end-tidal in oxygen) for 8 hr. Urine and plasma trifluoroacetic acid and fluoride concentrations were quantitated in samples obtained for 4 days postoperatively. RESULTS: Patient groups were similar with respect to age, weight, gender, duration of surgery, blood loss, and delivered isoflurane dose, measured by cumulative end-tidal isoflurane concentrations (9.7-10.2 MAC-hr). Postoperative urine excretion of trifluoroacetic acid (days 1-4) and fluoride (days 1-3) was significantly (P<0.05) diminished in disulfiram-treated patients. Cumulative 0-96 hr excretion of trifluoroacetic acid and fluoride in disulfiram-treated patients was 34+/-72 and 270+/-70 micromoles (mean +/- SD), respectively, compared to 440+/-360 and 1500+/-800 micromoles in controls (P<0.05 for both). Disulfiram also abolished the rise in plasma metabolite concentrations. CONCLUSIONS: Disulfiram, a selective inhibitor of human hepatic P450 2E1, prevented 80-90% of isoflurane metabolism. These results suggest that P450 2E1 is the predominant P450 isoform responsible for human clinical isoflurane metabolism in vivo.

Administration, Oral↗
PubMed1999

Menstrual cycle variability in midazolam pharmacokinetics.

Activity of cytochrome P450 3A4 (CYP3A4), the most abundant human P450 isoform and responsible for metabolizing approximately half of all therapeutic agents, has been speculated to vary during the menstrual cycle. This investigation evaluated CYP3A4 activity during the menstrual cycle, using midazolam clearance as a metabolic probe. Midazolam (1 mg i.v.) was administered to nonsmoking, nonpregnant female volunteers (N = 11, age 26 +/- 5 years) with normal menstrual cycles on three separate occasions during the same cycle: days 2 (menstrual phase), 13 (estradiol peak), and 21 (progesterone peak). Venous plasma midazolam concentrations were determined by gas chromatography-mass spectrometry. Midazolam clearance was determined by noncompartmental and compartmental analysis. Midazolam plasma disposition did not differ between phases of the menstrual cycle. There was no significant difference in any measure of midazolam clearance. Noncompartmental clearances (mean +/- SD) were 7.36 +/- 2.73, 6.34 +/- 3.59, and 6.23 +/- 2.04 ml/kg/min, respectively, on days 2, 13, and 21 of the menstrual cycle. These results suggest no difference in hepatic CYP3A4 activity on menstrual cycle days 2, 13, and 21. Consideration of menstrual cycle variability in the metabolism of CYP3A4 substrates does not appear indicated in the dosing or design of clinical trials.

Adolescent↗
PubMed1998

Posttransplant lymphoproliferative disorders and gastrointestinal manifestations of Epstein-Barr virus infection in children following liver transplantation.

BACKGROUND: Epstein-Barr virus (EBV) infection is common after liver transplantation in children and is associated with the risk of posttransplant lymphoproliferative disorders (PTLD). METHODS: This retrospective study examined the frequency of gastrointestinal (GI) symptoms and the risk of PTLD in pediatric liver recipients who developed symptomatic EBV infection. We reviewed 172 children who received orthotopic liver transplants between March 1988 to December 1994. Twenty-two cases were retransplants. The mean age at transplantation was 3.7 years (range, 0.1-17 years). The immunosuppressive regimens consisted of induction therapy with Minnesota antilymphocyte globulin/antithymocyte globulin/OKT3 in most cases and maintenance therapy with prednisone and either cyclosporine or tacrolimus (FK506). RESULTS: After 1 year of minimum follow-up, 54 of 172 patients had symptomatic EBV infections (confirmed by serology, histology, or whole blood polymerase chain reaction. At the time of infection, 38.5% (21/54) had either diarrhea or GI bleeding or both. PTLD developed in 11 patients (6.4%). The incidence of PTLD was 42.9% (9/21) when GI bleeding or diarrhea was associated with EBV infections, compared with 6.1% (2/33) when EBV infection was not associated with GI symptoms. Seven of 10 (70%) patients with GI bleeding and 2 of 11 (18.2%) with diarrhea developed PTLD. Of seven patients examined by endoscopy for GI bleeding, two had biopsy-proven PTLD of the GI tract, whereas one of two patients examined by endoscopy for diarrhea had biopsy-proven PTLD. DISCUSSION: In summary, a high incidence of PTLD was found in patients who developed GI bleeding or diarrhea associated with EBV infection after pediatric liver transplantation. In these patients, endoscopy and biopsy may lead to early diagnosis of PTLD.

Adolescent↗
PubMed1998

Bottlebrush dendritic endings and large dendritic fields: motion-detecting neurons in the tectofugal pathway.

In avian and mammalian brains, visual information from the retina is conveyed to the telencephalon via two separate pathways: the thalamofugal and the tectofugal pathways. Recently, Karten et al. ([1997] J. Comp. Neurol. 387:449-465) examined a portion of the tectofugal pathway, the projection from the optic tectum to the nucleus rotundus thalami, in pigeons. They defined two distinct subpopulations of tectal neurons projecting from the stratum griseum centrale (SGC; tectal layer 13) to specific divisions of the rotundus. The goal of this study in chick was to verify the existence of the type I and type II SGC neurons, as defined by Karten et al., and then examine in greater detail the connectivity and morphology of these SGC neurons. Furthermore, our results suggest how the unique morphological characteristics of SGC neurons contribute to the large receptive fields (20-50 degrees) found in physiological recordings and the SGC neuronal response to extremely small (ca. 0.05 degree), fast-moving (100 degrees/second) stimuli. By injecting retrograde tracer into various divisions of the chick rotundus, we verified that, indeed, the chick did possess type I and type II SGC neurons, as well as a "new" type of SGC neuron, type III, that is not found in the pigeon. We then used intracellular cell-filling techniques to define further these three types of SGC neurons. Our examination revealed the following: Type I SGC neurons had large, circular dendritic fields (average diameter, 1,725 microns) composed of smooth dendrites and ending in spine-rich, bottlebrush endings located in retinorecipient tectal layer 5b; type II SGC neurons had elliptical dendritic fields (average 1,447 microns) and dendritic endings located never more superficially than tectal layer 8; and type III SGC neurons had large dendritic fields (average 1,800 microns) of unknown shape and bottlebrush dendritic endings located in retinorecipient tectal layer 4. We suggest that the neuronal features of the SGC neurons (i.e., bottlebrush dendritic endings and large dendritic fields) are key morphological characteristics for the detection of motion within the tectofugal pathway. Furthermore, because neurons with similar morphology have also been found in the tecta of both mammals and reptiles, we suggest that these neuronal features are fundamental components of a phylogenetically conserved system used for the "extrastriate" detection of motion in vertebrates.

Animals↗
PubMed1998

Effects of oral tolerance induction by myelin basic protein on Vbeta8+ Lewis rat T cells.

Encephalitogenic T cells from Lewis rats use a restricted T cell receptor (TCR) gene combination, Vbeta8.2 and Valpha2. The oral administration of myelin basic protein (MBP) to Lewis rats prior to encephalitogenic challenge results in a marked inhibition of clinical neurologic signs of encephalitis, reduced central nervous system pathology, suppressed T cell reactivity to MBP, and decreased serum anti-MBP antibody responses. The present study determined the TCR Vbeta8 gene usage in rats rendered orally tolerant to MBP as compared with vehicle-fed or unfed controls. Total RNA was extracted from lymph node cells (LNC), Northern blots run, and hybridizations performed using a rat beta chain V region probe positive for Vbeta8.2. The results indicate that feeding MBP results in a decrease in Vbeta8+ TCR RNA expression in lymph nodes draining the site of encephalitogenic challenge. T cell proliferation was reduced in LNC of tolerized rats relative to control rats. No change in the Vbeta8+ TCR RNA expression or MBP reactivity was observed in the mesenteric lymph nodes (MLN) of vehicle-fed or MBP-fed rats, although an increase in cell number was found in the MLN of both groups. These results suggest that the mechanisms of orally induced tolerance involve local clonal deletion or migration of Vbeta8+ T cells, of which MBP-specific T cells are a part.

Administration, Oral↗
PubMed1998

Endotracheal flumazenil: a new route of administration for benzodiazepine antagonism.

The purpose of this study was to determine if flumazenil is absorbed from broncho-pulmonary tissue after intratracheal administration and whether therapeutically significant plasma concentrations can be obtained. Six elective surgical patients received a dose of 1.0 mg flumazenil in 10 mL saline intratracheally during general anesthesia. Blood samples were drawn for 6 hours after administration and plasma concentrations were determined by gas chromatography-mass spectrometry (GC-MS). An average peak plasma flumazenil concentration of 65.9 +/- 43.1 ng/mL was attained within 1 minute after administration. No patients reported chest discomfort or dyspnea upon awakening and there were no other side effects noted. Administration of flumazenil via an endotracheal tube results in rapid attainment of therapeutic blood levels.

Absorption↗
PubMed1998

Investigating psychosocial aspects of participation in early anti-cancer drug trials: towards a choice of methodology.

This paper presents the methodological approach and research methods chosen to explore psychosocial aspects of participation in early anti-cancer drug trials from the perspective of those actually involved. The paper describes how an appropriate methodology, or principles of reasoning behind the choice of research methods, emerged. The choice of methodology was based on three elements: first, an understanding of the competing philosophies about how research can be approached and conducted; second, the author's view of the subject area; and third, a consideration of previous research approaches which have investigated psychosocial aspects of cancer clinical trials. A qualitative methodology situated within an interpretative paradigm was eventually chosen as the most appropriate means of exploring trial participants' experiences and the aim and objectives of the research were developed within this methodological framework.

Antineoplastic Agents↗
PubMed1997

Integrin alpha v beta 6 enhances coxsackievirus B1 lytic infection of human colon cancer cells.

Viral entry into host cells depends upon specific interactions between virus attachment proteins and cell surface receptors that enable virus binding and internalization of virus and/or the virus-receptor complex. We have recently reported that the ubiquitous cell surface molecule, decay-accelerating factor (DAF), is a major cell attachment receptor for Coxsackieviruses B1, B3, and B5. However, DAF permits only virus binding and not virus internalization, invoking the presence of secondary or accessory receptors. Among the known receptors for enteroviruses are members of the cell adhesion molecule family known as integrins. In the present study, we found that expression of the epithelial-restricted integrin, alpha v beta 6, on colonic epithelial cells significantly enhanced Coxsackievirus B1-mediated cell lysis. Importantly, the viral-mediated cell killing required the presence of the 11-amino-acid C-terminal cytoplasmic extension unique to the beta 6 subunit, providing the first evidence of regulation of viral infectivity by integrin cytoplasmic domains. These results indicate that alpha v beta 6 expression on intestinal epithelial cells critically affects Coxsackievirus B1 infectivity. This may be essential in the conversion of asymptomatic enterovirus infection into clinically apparent disease.

Antigens, Neoplasm↗