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Biomedical subjects

A G Smith

Publications and source records attributed to A G Smith.

At least 91 records · Page 5Linked to original sources

The use of "clinic room" presentation as an educational tool in the ambulatory care setting.

OBJECTIVE: To evaluate the utility of "clinic room" case presentation in the ambulatory care setting. BACKGROUND: Neurology is increasingly an outpatient specialty. The transition from ward to clinic presents challenges for student and resident education. Interaction between attending physician and trainee is limited by busy patient schedules. New educational strategies must be developed to address the particular challenges of the outpatient clinic. One strategy to increase the quality and length of attending-trainee interaction is case presentation in the patient's presence. METHODS: The authors randomized 100 patients seen in an academic neuromuscular clinic to presentation in a conference room or clinic room. In the latter, all interaction between the trainee and attending occurred in the patient's presence. The attending recorded the time spent with the trainee and patient. The patient was asked to complete a survey and provide certain demographic information. RESULTS: The two groups were similar demographically. Time spent by the attending physician was similar between the two settings. Although there was no difference in patient satisfaction, those randomized to clinic room presentation were significantly more likely (p < 0.002) to feel their questions were answered adequately. There were trends toward these patients feeling less embarrassed, feeling that they were treated respectfully, and feeling that adequate time was spent with them. CONCLUSIONS: Although clinic room presentation does not save attending time, it allows for a more dynamic and intensive interaction among teacher, student, and patient.

Ambulatory Care↗

A comparison of two commercial quantitative electromyographic algorithms with manual analysis.

Quantitative EMG (QEMG) is a useful technique in the evaluation of neuromuscular disease. Manual waveform measurements have been replaced by automated computer-based measurements, but there is no uniformity in computer algorithms used to make waveform measurements. We compared QEMG measurements made by algorithms in two commercially available EMG machines with manual measurements. Motor unit action potentials (MUAPs) were simultaneously fed into the two machines and analyzed using QEMG default settings and automatic waveform marking. The averaged MUAPs were also manually marked. The two algorithms and manual marking did not differ significantly for MUAP amplitude. There were significant differences between algorithms for duration and number of phases. Our study indicates that, although automated algorithms make QEMG more practical, visual inspection, and remarking of each MUAP if needed, is necessary before making clinical judgments from the data.

Action Potentials↗

Single H2Kb, H2Db and double H2KbDb knockout mice: peripheral CD8+ T cell repertoire and anti-lymphocytic choriomeningitis virus cytolytic responses.

Single H2Kb, H2Db and double H2KbDb homozygous knockout (KO) mice were generated and their peripheral CD8+ T cell repertoires compared to that of C57BL/6 (B6) mice. Limited (10-20%, H2Db), substantial (30-50%, H2Kb) and profound (90%, H2KbDb) reduction of peripheral CD8+ T cells was observed in KO mice, without Vbeta diversity alteration. Classical class Ia molecules therefore ensure most but not all of the peripheral CD8+ T cell repertoire education. As expected, H2Kb but also H2Db KO mice developed choriomeningitis following intracranial infection by lymphocytic choriomeningitis virus with the same kinetics, lethality and CD8+ cell implication as wild-type B6 mice. By contrast, H2KbDb (class Ia-Ib+) KO mice survived. Choriomeningitis of H2Db KO mice was linked to the development of a subdominant (in normal B6 mice) H2Kb-restricted cytotoxic T lymphocyte response. Mice expressing a restricted set of histocompatibility class I molecules should represent useful tools to evaluate the immunological potentials of individual MHC class I molecules.

Animals↗

Persistent health effects of dioxin contamination in herbicide production.

A total of 159 cases of chloracne reported in 1969-1975 in TCDD-contaminated production of the herbicide 2,4,5-T have been followed for mortality and morbidity up to 1996 when blood and urine tests were performed on 50 survivors of these exposed chemical workers and matched controls. In exposed, the most frequent cause of sick leave was chloracne which persisted in 32%. Neurological symptoms were reported frequently (44% sleep disturbance, 32% headache, 30% neuralgia). BSR, leucocytes, gamma-GT, SGOT, and SGPT were significantly higher in exposed than in controls. The effects of exposure (P= 0.002) and alcohol (P= 0.002) on gamma-GT were found to be independent of each other. Comparisons within the chloracne cohort showed significantly exposed TCDD per gram blood lipid in patients with a history of liver disease (mean 801 pg/g) than without (mean 407 pg/g). Other congeners were not found elevated but some higher chlorinated furans and PCBs were found reduced in patients with liver disease. In multiple regression analysis with the factors age, alcohol, and log TCDD, the effects of TCDD and its interaction with age were found significant, indicative of chronic liver damage after high TCDD exposure at a young age. The prevalence of neurological symptoms and signs of chronic liver disease were related to TCDD in blood and abnormal poryphyrins in urine. In 48% coproporphyrin I > III ratio was elevated, this group showing increased TCDD (mean 719 pg/g). These results contribute to the evidence that chloracne is not the only chronic disease which can be related to TCDD exposure, even 23 years after exposure and despite high intersubject variability of TCDD half-life and other exposures.

2,4,5-Trichlorophenoxyacetic Acid↗

The dopamine D3/D2 receptor agonist 7-OH-DPAT induces cognitive impairment in the marmoset.

Previous work has shown that dopaminergic systems are involved in cognitive function in the common marmoset. The present study investigated the role of dopamine D3 receptors in cognitive performance in the marmoset. The effects of the putative dopamine D3 receptor agonist, 7-OH-DPAT, on performance of a same-day reversal visual object discrimination task were assessed using a miniature Wisconsin General Test Apparatus (WGTA). Within the same test session marmosets acquired a two-choice object discrimination initial task and a reversal task to criterion. 7-OH-DPAT (6-10 microg/kg) significantly impaired reversal task performance only, without affecting acquisition of the initial task. A higher dose of 25 microg/kg 7-OH-DPAT impaired initial task acquisition as well as reversal task acquisition, possibly as a consequence of a nonspecific influence on motor function. The dopamine D2 receptor antagonist (-)sulpiride (5-10 microg/kg) and the alpha2-receptor antagonist yohimbine (50 microg/kg) failed to attenuate the effects of 7-OH-DPAT (6 microg/kg) in this task. In contrast, the dopamine D2/D3 receptor antagonist raclopride (50 microg/kg) significantly attenuated the 7-OH-DPAT-induced impairment of reversal task performance. These results suggest that activation of dopamine D3 receptors produces a selective impairment of aspects of cognitive function in the marmoset.

Adrenergic alpha-Antagonists↗

New prospects for human stem-cell therapy in the nervous system.

It would be of enormous benefit if human neural tissue could be generated in vitro as this would allow screening for neuroactive compounds, and provide a source of tissue for testing cellular and gene therapies for CNS disorders. It is now well established that pluripotent embryonic stem cells (ES cells) from the mouse can be propagated in culture and differentiated into a range of tissues, including neuronal and glial cells. In other studies, more-restricted neural stem cells have been isolated from both the developing and adult rodent brain. Current reports now describe similar pluripotent and neural stem cells cultured from human embryos. While the exact nature of these cells continues to be explored, they can be grown for extended periods of time while retaining the capacity for neuronal and glial differentiation. In some cases, they have been shown to integrate into the developing or damaged adult brain. This article reviews their biology, with a focus on the possible links between ES-cell and neural stem-cell technologies, and the strategies used to isolate and expand defined cell populations.

Animals↗

Response to cladribine in previously treated patients with chronic lymphocytic leukaemia identified by ex vivo assessment of drug sensitivity by DiSC assay.

The ability to identify non-responders to cytotoxic chemotherapy has significant clinical and economic benefits. Differential staining cytotoxicity (DiSC) assays were performed in 34 previously treated patients with chronic lymphocytic leukaemia prior to treatment with cladribine. Of the 28 identified as ex vivo sensitive, 26 achieved a complete (CR) or partial response (PR) (median length of response 1. 5 years, median survival 3.37 years) and two had a >70% fall in lymphocytes: six identified as ex vivo resistant failed to respond. The DiSC assay can accurately identify a subgroup of patients resistant to cladribine.

Aged↗

Erythema nodosum secondary to meningococcal septicaemia.

We report a case of erythema nodosum (EN) secondary to Neisseria meningitidis infection in a 77-year-old woman. Histology of two biopsy specimens from two different lesions showed characteristic features of EN. Blood culture showed Neisseria meningitidis group C.

Aged↗

Multiple basal cell carcinomas in a patient with acute myeloid leukaemia and chronic lymphocytic leukaemia.

Skin cancer is a well-recognized risk of prolonged immunosuppression, for example, following renal transplantation. These tumours contrast with idiopathic lesions in that squamous cell, rather than basal cell carcinomas usually predominate. We report a Caucasian female who developed multiple basal cell carcinomas following protracted cytotoxic therapy for acute myeloid leukaemia and subsequently chronic lymphocytic leukaemia. No other clinical risk factors nor relevant polymorphisms of genes encoding for detoxifying enzymes were identified. Immune suppression is a well-recognized cause of multiple skin tumours, the most striking increase usually being of squamous cell carcinomas. We believe this woman is representative of a subgroup of immunosuppressed patients who, for as yet poorly understood reasons, have a predisposition to basal cell, rather than squamous cell carcinoma accrual.

Acute Disease↗

Association of NAD(P)H:quinone oxidoreductase (NQO1) null with numbers of basal cell carcinomas: use of a multivariate model to rank the relative importance of this polymorphism and those at other relevant loci.

Glutathione S-transferase GSTM1 B and GSTT1 null, and cytochrome P450 CYP2D6 EM have been associated with cutaneous basal cell carcinoma (BCC) numbers, although their quantitative effects show that predisposition to many BCC is determined by an unknown number of further loci. We speculate that other loci that determine response to oxidative stress, such as NAD(H):quinone oxidoreductase (NQO1) are candidates. Accordingly, we assessed the association between NQO1 null and BCC numbers primarily to rank NQO1 null in a model that included genotypes already associated with BCC numbers. We found that only 14 out of 457 cases (3.1%) were NQO1 null. This frequency did not increase in cases with characteristics linked with BCC numbers including gender, skin type, a truncal lesion or more than one new BCC at any presentation (MPP). However, the mean number of BCC in NQO1*0 homozygotes was greater than in wild-type allele homozygotes and heterozygotes, although the difference was not quite significant (P = 0.06). These data reflect the link between NQO1 null and BCC numbers in the 42 MPP cases rather than the whole case group. We identified an interaction between NQO1 null and GSTT1 null that was associated with more BCC (P = 0.04), although only four cases had this combination. The relative influence of NQO1 null was studied in a multivariate model that included: (i) 241 patients in whom GSTM1 B, GSTT1 null and CYP2D6 EM genotype data were available, and (ii) 101 patients in whom these genotypes, as well as data on GSTM3, CYP1A1 and melanocyte-stimulating hormone receptor (MC1R) genotypes were available. NQO1 null (P = 0.001) and MC1R asp294/asp294 (P = 0.03) were linked with BCC numbers, and the association with CYP2D6 EM approached significance (P = 0.08). In a stepwise regression model only these genotypes were significantly associated with BCC numbers with NQO1 null being the most powerful predictor.

Age Factors↗

Adaptive responses to environmental chemicals.

Adaption to chemical agents in the environment is a fundamental part of the evolutionary process and a large number of genes have evolved to specifically detoxify potentially harmful chemical agents. These genes can act at various levels within cells and determine circulating chemical or toxin concentrations, and uptake and efflux rates as well as intracellular detoxification enzymes, such as the cytochrome P-450-dependent mono-oxygenases and glutathione S-transferases. These multigene families of proteins play a central role in chemical and drug detoxification and their polymorphic expression may well be a factor in disease susceptibility.

Adaptation, Physiological↗

Low levels of p53 are associated with resistance to tetrachlorodibenzo-p-dioxin toxicity in DBA/2 mice.

We show here that DBA/2 strain mice have a complex mutation/polymorphism in the promoter region of the Trp53 locus (the mouse p53 locus). This region has previously been shown to be essential for p53 expression. We further show that the DBA/2 mutation is associated with approximately fourfold lower p53 levels in thymocytes treated with the DNA-damaging agent etoposide in-vitro, and with relative resistance of these thymocytes to apoptosis induced by the DNA-damaging agent etoposide compared with C57BL/6 mice. When part of the promoter containing this mutation was inserted into a plasmid containing a luciferase reporter gene but lacking eukaryote promoter sequences and transfected into MCF-7 human breast cell line cells, the mean luciferase activity was slightly less with the DBA/2 than with the C57BL/6 promoter-reporter construct (p < 0.01). We found that DBA/2xC57BL/6 F2 hybrid mice with the DBA/2 genotype at the Trp53 locus were relatively resistant to tetrachlorodibenzo-p-dioxin toxicity, and this resistance was additive with resistance associated with the Ahr locus. DBA/2 mice are long-lived and do not have particularly high levels of cancer, suggesting either that they carry other compensatory tumour resistance alleles (such as Ahr(d)), or that, while there may be a p53 protein dosage effect for acute toxicity, lower than normal levels of p53 may still be sufficient to protect against cancer. In evolutionary terms, it may be better to maintain low levels of p53 in order to avoid death from acute toxicity, even at the expense of a higher incidence of cancer in later life.

Animals↗

Cytochrome P450 CYP2D6 genotypes: association with hair colour, Breslow thickness and melanocyte stimulating hormone receptor alleles in patients with malignant melanoma.

We previously identified associations between polymorphism in the cytochrome P450 CYP2D6 gene and outcome in several cancers. We have now examined the hypothesis that homozygosity for the mutant alleles, CYP2D6*4 and CYP2D6*3, is associated with susceptibility and outcome in malignant melanoma. Outcome was assessed by Breslow thickness. We first confirmed previous reports that these mutant alleles are associated with increased susceptibility to malignant melanoma. For example, the frequency of homozygosity for CYP2D6*4 was significantly greater (P = 0.006, chi-squared 1 d.f. = 7.4, odds ratio 2.2, 95% confidence interval 1.2, 3.9) in cases (9.1%) than in control individuals (4.3%). The frequency of homozygosity for the mutant alleles was next examined in the malignant melanoma cases grouped on the basis of characteristics associated with malignant melanoma risk. Homozygosity was significantly more common (P = 0.038) in cases with red/blonde hair than in those with brown/black hair. We found no associations between the CYP2D6 genotype and sex, skin type or eye colour. The possible association of CYP2D6 with outcome was assessed by comparing genotype frequencies in patients with tumours of Breslow thickness < 1.5 mm with those whose tumours were > or = 1.5 mm. In patients with red/blonde, but not brown or black hair, homozygosity for CYP2D6*4 was significantly associated with thicker lesions in a multivariate model (P = 0.036). We further examined the association of CYP2D6*4 homozygosity with red/blonde hair by classifying patients on the basis of homo- or heterozygosity for wild-type or val92met, asp294his or asp84glu melanocyte stimulating hormone receptor (MC1R) alleles. None of the nine patients with brown/black hair with the asp294his allele were homozygotes for CYP2D6*4. By contrast, in the patients with red/blonde hair, three of five cases with asp294his were homozygotes for the mutant CYP2D6 allele. The difference in the frequency of CYP2D6*4 homozygotes in the red/blonde cases with wild-type MC1R alleles compared with those with asp294his was significant (exact P = 0.029). No associations between val92his or asp84glu and CYP2D6 alleles were identified.

Cytochrome P-450 CYP2D6↗

Analysis of amplified variable number tandem repeat loci for evaluation of engraftment after hematopoietic stem cell transplantation.

Many methods have been used to evaluate engraftment of donor cells after hematopoietic stem cell transplantation in allogeneic recipients. The identification of variable number tandem repeat loci in the human genome and the development of methods for testing amplified DNA segments containing these polymorphic loci have provided a novel and highly convenient approach for assessing the success of hematopoietic stem cell transplantation. We discuss the advantages and limitations of this approach as it has been implemented in our laboratory. We summarize the reasons for testing genetic markers after hematopoietic stem cell transplantation, using illustrations from our own experience. This information is designed to help disseminate similar methods in laboratories that do not yet provide such services, to assist laboratory personnel in understanding the clinical and research needs of physicians who request such services and to assist clinicians who interpret the results of genetic marker studies.

Graft Survival↗

Presentation with multiple cutaneous basal cell carcinomas: association of glutathione S-transferase and cytochrome P450 genotypes with clinical phenotype.

We previously reported associations between numbers of basal cell carcinomas (BCCs) and glutathione S-transferase (GSTM1 and GSTT1) and cytochrome P450 (CYP2D6) genotypes. Thus, although GSTM1 AB is protective, GSTM1 null, GSTT1 null, and CYP2D6 EM are associated with increased numbers of lesions. Here, we examine the hypothesis that these genotypes are associated with high-risk subgroups. The subgroup studied comprised 119 patients with more than one previously unidentified BCC at first or later presentations [multiple presentation phenotype (MPP)]. These patients were part of a group of 773 BCC patients that also included 567 patients with one BCC and 87 patients with only one lesion at each presentation [single presentation phenotype (SPP)] but who developed multiple BCCs. The number of tumors in the MPP was significantly greater than that in the SPP groups. In the MPP but not SPP patients, GSTM1 AB, GSTT1 null, and CYP2D6 EM were significantly associated with BCC numbers, suggesting that previously observed associations reflect the influence of these genes only in the MPP cases. There was no evidence that MPP patients had received more UV exposure. We also determined whether the increased numbers of BCC in the MPP cases reflects an association with the truncal tumor phenotype. The values of the rate ratios indicated that the MPP is a marker for the risk of many BCCs, although the combination of MPP and a truncal tumor is a higher-risk phenotype. The data demonstrate the heterogeneity in BCC patients, which reflects differences in genetic factors that determine skin response to UV.

Adult↗

Optimizing outcome after unrelated marrow transplantation by comprehensive matching of HLA class I and II alleles in the donor and recipient.

In unrelated marrow transplantation, the benefit of matching class II HLA-DRB1 and DQB1 alleles of the donor and recipient is well documented. Little is known about the clinical relevance of matching for class I HLA-A, B, and C alleles. We used DNA-amplification methods to identify the HLA-A, B, and C alleles of 300 patients and their donors. The incidence of graft failure was correlated with multiple class I mismatching in the donor. The risk of grades III-IV acute graft-versus-host disease was highest with class II mismatching in the recipient. Mismatching for a single class I or class II allele had no effect on survival, but mortality was increased by mismatching for more than one class I allele and by simultaneous mismatching for class I and class II alleles. We conclude that matching HLA class I and class II alleles of the donor and recipient can improve outcome after unrelated marrow transplantation.

Alleles↗