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Biomedical subjects

M A Smith

Publications and source records attributed to M A Smith.

At least 217 records · Page 12Linked to original sources
PubMed1999

Regulatory function of human CD4+ cytolytic T lymphocytes.

Allograft rejection is mediated by both CD4+ and CD8+ T cells. The lytic function of the classic CD8+ cytolytic T lymphocytes (CTL) occurs through recognition of allogeneic major histocompatibility complex (MHC) class I on the surface of the graft. CD4+ CTL recognize MHC class II through a direct recognition pathway or an indirect pathway where MHC peptides are presented in the context of self MHC class II. Lytic CD4+ cells may destroy graft tissue or, we hypothesize, the indirect CD4+ T cell may down regulate CD8+ CTL by recognition of donor MHC peptides presented by self MHC class II expressed on CD8+ T cells. To define the role of CD4+ CTL in allograft outcome we used a CD4+ CTL that is MHC class II restricted, recognizing human leucocyte antigen (HLA)-A1 and HLA-B8 peptides in the context of HLA-DR4. This line (MDSxA1/B8) will lyse DR4+ B lymphoblastoid cells (LCL) pulsed with HLA-A1/B8 peptides (amino acids 60-84 of the alpha1 domain of the MHC class I molecule). These T cells will also lyse peptide-pulsed antigen-specific T cell clones, both CD4+ and CD8+, that express HLA-DR4. These clones must process and present the MHC class I peptides for recognition and lysis to occur. These results suggest a possible mechanism to explain allograft tolerance. Lytic CD4+ T cells, that recognize donor HLA peptides through an indirect antigen presentation pathway, down-regulate donor-specific CTL through peptide-specific lysis resulting in graft tolerance.

Antigen Presentation↗
PubMed1999

Fumarate metabolism and the microaerophily of Campylobacter species.

(1) The role of fumarate metabolism in the microaerophily of the Campylobacter genus and the effects of therapeutic agents against it were investigated. (2) NMR spectroscopy was employed to determine the properties of Campylobacter fumarase (Fum) and fumarate reductase (Frd). Radiotracer analysis was used to determine the production of carbon dioxide by Campylobacter cells. Standard microbiological techniques were used to measure the effects of environmental conditions and inhibitors on bacterial growth. (3) All Campylobacter species tested showed both Fum and Frd activities. Frd activity was observed with or without the addition of an exogenous electron donor in the particulate fractions obtained from lysates. Fumarate was oxidized to carbon dioxide via the acetyl-CoA cleavage pathway. The genes encoding proteins involved in fumarate metabolism were identified in the Campylobacter jejuni genome. Cells grew better in atmospheres with 5 and 10% oxygen levels. Fum activity was the same in cultures grown under different oxygen tensions and did not vary with the age of cultures. Frd activity was higher in cultures which grew at faster rates and decreased with the age of cultures. Four Frd inhibitors showed bactericidal effects against Campylobacter spp. with different potencies. The relative strengths of inhibition of the compounds followed the same order as the bactericidal effects. (4) The results suggested that Frd and Fum are constitutive and play a fundamental role in these microaerophiles which show characteristics of anaerobic metabolism, and that the Frd inhibitors tested would not be of therapeutic use.

Animals↗
PubMed1999

Redox metals and neurodegenerative disease.

Multiple lines of evidence implicate redox-active transition metals as mediators of oxidative stress in neurodegenerative diseases. Among the recent research discoveries is the finding that transition metals bind to proteins associated with neurodegeneration, including the prion protein. Whereas binding in the latter case may serve an antioxidant function, adventitious binding of metals to other proteins appears to preserve their catalytic redox activity in a manner that disturbs free radical homeostasis. Alterations in the levels of copper- and iron-containing metalloenzymes, involved in processing partially reduced oxygen species, are also likely to contribute to altered redox balance in neurodegenerative diseases. Nonetheless, even in familial forms of amyotrophic lateral sclerosis linked to mutations in superoxide dismutase, it is unclear whether an altered enzyme activity or, indirectly, a disturbance in transition-metal homeostasis is involved in the disease pathogenesis.

Amyloid beta-Peptides↗
PubMed1999

Comparison of six dose-response models for use with food-borne pathogens.

Food-related illness in the United States is estimated to affect over six million people per year and cost the economy several billion dollars. These illnesses and costs could be reduced if minimum infectious doses were established and used as the basis of regulations and monitoring. However, standard methodologies for dose-response assessment are not yet formulated for microbial risk assessment. The objective of this study was to compare dose-response models for food-borne pathogens and determine which models were most appropriate for a range of pathogens. The statistical models proposed in the literature and chosen for comparison purposes were log-normal, long-logistic, exponential, beta-Poisson and Weibull-Gamma. These were fit to four data sets also taken from published literature, Shigella flexneri, Shigella dysenteriae, Campylobacter jejuni, and Salmonella typhosa, using the method of maximum likelihood. The Weibull-gamma, the only model with three parameters, was also the only model capable of fitting all the data sets examined using the maximum likelihood estimation for comparisons. Infectious doses were also calculated using each model. Within any given data set, the infectious dose estimated to affect one percent of the population ranged from one order of magnitude to as much as nine orders of magnitude, illustrating the differences in extrapolation of the dose response models. More data are needed to compare models and examine extrapolation from high to low doses for food-borne pathogens.

Food Microbiology↗
PubMed1999

Prospective evaluation of soft tissue masses and sarcomas using fluorodeoxyglucose positron emission tomography.

BACKGROUND: The differentiation of soft tissue sarcoma (STS) from benign masses is difficult owing to their clinical and radiological similarities. Accurate staging is hindered by the large number of sites at which metastases may be found. This study examined the value of whole-body [18F]2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) in patients presenting with soft tissue masses. METHODS: Thirty patients with a soft tissue mass suspected to be malignant were evaluated with FDG PET. The images were evaluated qualitatively and quantitatively for uptake of FDG to determine whether benign lesions could be differentiated from malignant tumours, and for the presence of metastases. RESULTS: Thirty-one masses were removed from 30 patients; 12 were benign and 19 were malignant STSs. Using qualitative assessment of the FDG PET images, all the high-grade STSs (n = 12) were correctly identified, but low-grade STS (n = 7) could not be differentiated from a benign lesion. Using a quantification assessment, there was a 95 per cent sensitivity and a 75 per cent specificity in diagnosing STS. Three patients had metastases at presentation; two were correctly identified by FDG PET. CONCLUSION: FDG PET has a role in distinguishing high-grade STS from low-grade or benign STS and may have a role in staging malignant tumours.

Adolescent↗
PubMed1999

Primary juxtaarticular soft tissue lymphoma arising in the vicinity of inflamed joints in patients with rheumatoid arthritis.

AIMS: Primary soft tissue lymphoma is uncommon and little is known regarding its aetiology and pathogenesis. In a review of 37 soft tissue lymphomas we uncovered three cases associated with rheumatoid arthritis which we report herein. METHODS AND RESULTS: The clinical records and pathology of the cases are described together with the results of in situ hybridization studies with oligonucleotide probes to Epstein-Barr virus (EBV) encoded RNA (EBER). All three patients were females with a long-standing history of rheumatoid arthritis ranging from 9 to 17 years. Each presented with a soft tissue mass in the vicinity of a joint affected by rheumatoid disease. All had received prior treatment with nonsteroidal anti-inflammatory drugs and one also received gold, penicillamine and intra-articular steroids to affected joints. None had received methotrexate. Histologically, the juxtaarticular soft tissue masses were all B-cell lymphomas. None were associated with EBV as determined by in situ hybridization. CONCLUSIONS: These cases document an association between rheumatoid arthritis and soft tissue lymphoma of B-cell type, arising in the vicinity of an affected joint. Chronic local immune stimulation may have played a significant role in the genesis of these lymphomas, unlike the frequently reversible and EBV-positive lymphomas that occur in rheumatoid patients on immunosuppressive therapy.

Adult↗
PubMed1999

The role of cell cycle-mediated events in Alzheimer's disease.

The mechanism(s) underlying selective neuronal death in Alzheimer's disease remain unresolved. However, recently, we and others showed that susceptible hippocampal neurones in Alzheimer's disease express markers common to cells in various phases of the cell cycle. Since neuronal maturation is associated with effective escape from the cell division cycle, emergence out of quiescence may be deleterious. Here, we review a number of current findings indicating that disregulated ectopic re-activation of cell cycle-mediated events, akin to neoplasia, represent an important early pathway associated with neuronal death and, more importantly, one that involves virtually the entire spectrum of the pathological events described in Alzheimer's disease.

Alzheimer Disease↗
PubMed1999

Re-entry into the cell cycle: a mechanism for neurodegeneration in Alzheimer disease.

Several recent findings demonstrated increased expression of cell cycle-related proteins in the degenerating neurons found in Alzheimer disease. We hypothesize that this apparent attempt to re-enter the cell cycle is a neuronal response to external growth stimuli that leads to an abortive re-entry into the cell cycle. However, since neurons of adults apparently lack the capacity both to divide in vivo and in vitro, it is possible that they lack the components necessary to complete the cell division process. Nonetheless, the importance of these findings is that they provide an explanation for the increased phosphorylation of cytoskeletal proteins such as tau and neurofilaments that represent the most striking intracellular changes in the disease. Further, it is our contention that inappropriate reentry into the cell cycle and interrupted mitotic processes are significant factors not only in the cytoskeletal pathology but also in the neuronal degeneration that characterizes the pathology of Alzheimer disease.

Adult↗
PubMed1999

An examination of the interactions between the antinociceptive effects of morphine and various mu-opioids: the role of intrinsic efficacy and stimulus intensity.

UNLABELLED: We examined the effects of several opioids that vary in intrinsic efficacy at the mu-opioid receptor alone and in combination with morphine in a rat warm water tail withdrawal procedure using 50 degrees C and 52 degrees C water (i.e., low- and high-stimulus intensities). Morphine, levorphanol, dezocine, and buprenorphine produced dose-dependent increases in antinociception using both stimulus intensities. Butorphanol produced maximal levels of antinociception at the low, but not at the high, stimulus intensity, whereas nalbuphine failed to produce antinociception at either stimulus intensity. For cases in which butorphanol and nalbuphine failed to produce antinociception alone, these opioids dose-dependently antagonized the effects of morphine. When levorphanol, dezocine, and buprenorphine were combined with morphine, there was a dose-dependent enhancement of morphine's effects. Similar effects were obtained at the low-stimulus intensity when butorphanol was administered with morphine. In most cases, the effects of these combinations could be predicted by summating the effects of the drugs when administered alone. These results indicate that the level of antinociception produced by an opioid is dependent on the intrinsic efficacy of the drug and the stimulus intensity. Furthermore, the level of antinociception produced by the opioid, not necessarily the opioids' intrinsic efficacy, determines the type of interaction among opioids. IMPLICATIONS: Compared with high-efficacy opioids, lower efficacy opioids produce lower levels of pain relief, especially in situations of moderate to severe pain. When opioids are given in combination, the effects can only be predicted on the basis of the antinociception obtained when the drugs are administered alone.

Analgesics, Opioid↗
PubMed1999

HMO membership and patient age and the use of specialty care for hospitalized patients with acute stroke: The Minnesota Stroke Survey.

BACKGROUND: The number of older patients enrolling in health maintenance organizations (HMOs) is increasing. Concerns have been raised that older patients may be targeted by HMOs for more stringent cost-containment mechanisms, including reduced access to expensive specialty care. OBJECTIVES: We investigated the relationship between membership in an HMO and the decision to consult with a neurologist or admit to a neurology ward for patients hospitalized with acute stroke. We then compared 1-year mortality of patients who received neurology care to the 1-year mortality of those who did not receive neurology care. DESIGN: Retrospective medical record review. SUBJECTS: A sample of hospitalized acute stroke patients (age range, 30-79 years) who were discharged from Minneapolis-St. Paul metropolitan hospitals with a diagnosis code of acute cerebrovascular disease from 1991 to 1993. MEASURES: Trained nurses abstracted the medical records. Stroke events (n = 2,320) were validated using clinical criteria and neuroimaging reports. Mortality data were obtained from the Minnesota Death Index. RESULTS: Among patients enrolled in HMOs, 30% of validated stroke patients did not receive neurology care in comparison with 19% of patients not enrolled in HMOs. After adjusting for patient mix and hospital characteristics, the odds of receiving neurology care were half as great for patients enrolled in HMOs as compared with patients not enrolled in HMOs (odds ratio [OR] = 0.52, 95% confidence interval [CI] 0.36-0.74). The association of membership in HMOs with lower use of neurology care was concentrated in older patients. Within each age group, the odds ratios and 95% CI of receiving neurology care for patients enrolled in HMOs versus patients not enrolled in HMOs were: < 55 years (1.06, 0.42-2.67), 55 to 64 years (0.54, 0.34-0.87), 65 to 74 years (0.51, 0.36-0.71), and >75 years (0.40, 0.24-0.68). Using Cox regression, 30-day mortality did not differ between patients who received neurology care and those who did not. Among 30-day survivors, the mortality hazards ratio (HR) during the next 11 months for patients who received neurology care was 71% of the hazard for patients who did not receive neurology care (HR = 0.71, 95% CI = 0.55-0.91). CONCLUSIONS: These data suggest that membership in an HMO was associated with reduced access to neurology care for older patients with acute stroke and that patients who received neurology care had a lower risk of death during the year after their stroke. It remains to be determined if these differences in outcome are caused by true differences in stroke management or by unmeasured characteristics.

Acute Disease↗
PubMed1999

Fluorodeoxyglucose PET in the evaluation of amputations for soft tissue sarcoma.

The aims of this study were to evaluate the uptake of fluorodeoxyglucose (FDG) in the stumps of patients who have had amputations for soft tissue sarcoma and assess its utility in identifying local recurrence of disease. Sixteen patients who had either an upper or a lower limb amputation were evaluated. FDG PET scans (half body scans to the stump +/- local emission transmission views of the stump) were performed as part of their routine follow-up for evidence of metastases over a number of years (mean = 2.6 years; range 0.25-8 years). Diffuse uptake was found in 10 stumps for up to 18 months post-surgery without any evidence of disease recurrence. Focal areas of uptake were associated with known pressure areas with skin breakdown that could be seen clinically. In the absence of localized clinical changes, these areas represented a recurrence and needed a biopsy.

Adolescent↗
PubMed1999

Etiology of outpatient pediatric nondysenteric diarrhea: a multicenter study in the United States.

BACKGROUND: Few data have been published recently on the etiology of outpatient pediatric diarrhea in the US. METHODS: We determined the etiology of acute, nondysenteric diarrhea among 147 children between 2 and 11 years old presenting to 9 outpatient clinics in various regions of the US between August, 1991, and August, 1993. Enteropathogens were sought by conventional laboratory methods. The various diarrheagenic Escherichia coli were sought. RESULTS: A recognized etiologic agent was detected in the stools of 89 (60.5%) children and 15 (10) patients had multiple agents detected. Rotavirus was found in 43 (29.3%) of the children, with a spring and winter peak in occurrence. Giardia lamblia was identified in 22 (15%) cases with a spring peak. HEp-2 cell-adherent E. coli were found in 15 (10.2%). Other agents found included: enteric adenovirus in 7 (4.8%); Salmonella in 5 (3.4%); enterohemorrhagic E. coli in 5 (3.4%); enteropathogenic E. coli in 2 (1.4%); enterotoxigenic E. coli in 2 (1.4%); Entamoeba histolytica in 1 (0.70%); and Campylobacter jejuni in 1 (0.7%). CONCLUSIONS: In addition to the presence of conventional enteropathogens, diarrheagenic E. coli (HEp-2 cell-adherent E. coli, enterohemorrhagic E. coli, enteropathogenic E. coli and enterotoxigenic E. coli) were associated with endemic pediatric diarrhea in the US.

Acute Disease↗
PubMed1999

Regional bone mineral density after orthotopic liver transplantation.

OBJECTIVES: Although there is a fall in lumbar spine bone mineral density (BMD) after liver transplantation, little is known about femoral neck or total body BMD. Therefore we determined: (a) the proportion of patients with preexisting hepatic osteopenia before transplantation and (b) the effects of transplantation on global and regional BMD. DESIGN: Retrospective analysis of BMD measurements of patients before and up to 2 years after liver transplantation. METHODS: BMD was assessed by dual energy X-ray absorptiometry in 56 patients, before and at regular intervals after liver transplantation, for up to 24 months, to measure total body, lumbar spine (L2-L4) and femoral neck BMDs. RESULTS: Pre-transplant, 23% of patients had osteoporosis (a negative Z score > 2). Paired data before and after transplantation revealed no change in total body BMD. However, there was a fall in lumbar spine BMD (1.04+/-0.03 to 1.02+/-0.03 g/cm2; P < 0.04) at 1 month after transplantation. The reduction in lumbar spine BMD was seen up to 12 months, BMD at 18-24 months being similar to pre-transplant values. Femoral neck BMD also fell (0.96+/-0.06 to 0.83+/-0.04 g/cm2; P < 0.03), but only after 6-9 months, thereafter remaining below pre-transplant values until the end of the follow-up period. CONCLUSIONS: Although osteopenia is common in patients with liver disease, total bone density does not fall after transplantation. Nonetheless regional lumbar spine and femoral neck bone density does fall after transplantation with a risk period for femoral neck fracture which may extend for up to 2 years.

Absorptiometry, Photon↗
PubMed1999

Risk factors for asthma deaths: a population-based, case-control study.

OBJECTIVES: To investigate risk factors for death from asthma using a case-control study design with two control groups. METHODS: Cases (n = 42) comprised subjects aged 10-59 years who died from asthma. Two control groups were selected: a random sample of asthmatics from the community (n = 132) and age and sex matched patients recently admitted to hospital for asthma (n = 89). We obtained information from proxies of cases and controls, and their general practitioners, by a structured telephone survey. Matched and unmatched logistic regression analyses were used to determine odds ratios for risk factors for asthma deaths. RESULTS: Compared to community controls, important risk factors for asthma deaths included indicators of asthma severity, use of three or more groups of asthma medications, more extensive use of health services for asthma, poor compliance with asthma medications and regularly missing hospital and general practitioner appointments for asthma. Compared to hospital controls, risk factors for asthma deaths were previous visits to emergency department for asthma, knowledge about asthma medications and regularly missing general practitioner appointments. CONCLUSIONS: In this study, severity of asthma, increased health service utilisation and suboptimal asthma self-management were associated with increased risks for asthma death. IMPLICATIONS: People with severe asthma or poorly controlled asthma have a greater risk of dying from their asthma. Both clinicians and non-clinicians managing asthma should regularly assess the appropriateness of management to prevent deaths.

Adolescent↗
PubMed1999

Stepping-table gadolinium-enhanced digital subtraction MR angiography of the aorta and lower extremity arteries: preliminary experience.

PURPOSE: To compare stepping-table digital subtraction gadolinium-enhanced magnetic resonance (MR) angiography of the distal aorta and lower extremity arteries with conventional catheter digital subtraction x-ray angiography in patients with arterio-occlusive disease. MATERIALS AND METHODS: Twenty patients underwent both conventional catheter angiography and fast three-dimensional gadolinium-enhanced MR angiography of the aorta and outflow vessels at 1.5 T; the images were acquired in three consecutive imaging locations during a single infusion of a gadolinium chelate. RESULTS: Compared with catheter angiography, according to the findings of two blinded independent reviewers, MR angiography had sensitivities of 81% and 89% and specificities of 91% and 95%, respectively, for demonstration of insignificant (< or = 50%) stenosis versus significant (51%-100%) stenosis. For demonstration of occlusion, the sensitivity and specificity were 94% and 97%, respectively, by consensus. There was good interobserver correlation between the two readers overall (kappa = 0.65 for reporting the degree of narrowing in all lesions; 0.86, for reporting of insignificant versus significant stenoses; and 0.928, for reporting of occluded versus patient segments). CONCLUSION: Stepping-table digital subtraction contrast material-enhanced MR angiography has high accuracy compared with catheter angiography in patients with arterio-occlusive disease of the aorta and outflow vessels. These preliminary study results suggest that this technique may ultimately provide a safe, noninvasive, and cost-effective alternative to catheter angiography.

Aged↗
PubMed1999

GABA(A) receptor-mediated miniature postsynaptic currents and alpha-subunit expression in developing cortical neurons.

Previous studies have described maturational changes in GABAergic inhibitory synaptic transmission in the rodent somatosensory cortex during the early postnatal period. To determine whether alterations in the functional properties of synaptically localized GABA(A) receptors (GABA(A)Rs) contribute to development of inhibitory transmission, we used the whole cell recording technique to examine GABAergic miniature postsynaptic currents (mPSCs) in developing cortical neurons. Neurons harvested from somatosensory cortices of newborn mice showed a progressive, eightfold increase in GABAergic mPSC frequency during the first 4 wk of development in dissociated cell culture. A twofold decrease in the decay time of the GABAergic mPSCs, between 1 and 4 wk, demonstrates a functional change in the properties of GABA(A)Rs mediating synaptic transmission in cortical neurons during development in culture. A similar maturational profile observed in GABAergic mPSC frequency and decay time in cortical neurons developing in vivo (assessed in slices), suggests that these changes in synaptically localized GABA(A)Rs contribute to development of inhibition in the rodent neocortex. Pharmacological and reverse transcription-polymerase chain reaction (RT-PCR) studies were conducted to determine whether changes in subunit expression might contribute to the observed developmental alterations in synaptic GABA(A)Rs. Zolpidem (300 nM), a subunit-selective benzodiazepine agonist with high affinity for alpha1-subunits, caused a reversible slowing of the mPSC decay kinetics in cultured cortical neurons. Development was characterized by an increase in the potency of zolpidem in modulating the mPSC decay, suggesting a maturational increase in percentage of functionally active GABA(A)Rs containing alpha1 subunits. The relative expression of alpha1 versus alpha5 GABA(A)R subunit mRNA in cortical tissue, both in vivo and in vitro, also increased during this same period. Furthermore, single-cell RT-multiplex PCR analysis revealed more rapidly decaying mPSCs in individual neurons in which alpha1 versus alpha5 mRNA was amplified. Together these data suggest that changes in alpha-subunit composition of GABA(A)Rs contribute to the maturation of GABAergic mPSCs mediating inhibition in developing cortical neurons.

Animals↗