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Biomedical subjects

D Barnes

Publications and source records attributed to D Barnes.

At least 19 recordsLinked to original sources
PubMed2001

Diminished frequency of interleukin-10-secreting, T-cell receptor peptide-reactive T cells in multiple sclerosis patients might allow expansion of activated memory T cells bearing the cognate BV gene.

T cells responsive to T-cell receptor (TCR) determinants may regulate pathogenic Th1 responses in patients with multiple sclerosis (MS) through interleukin (IL)-10-dependent bystander suppression. In this study, innate IL-10- and interferon (IFN)-gamma-secreting T cells responsive to TCR peptides were quantified in peripheral blood mononuclear cells of MS patients and healthy controls (HC) using the ELISPOT assay. Most HC had vigorous IL-10 but low IFN-gamma frequencies to BV5S2 and BV6S1 peptides. In contrast, MS patients had significantly lower IL-10 frequency responses to the TCR peptides but normal responses to concanavalin A. Patients undergoing TCR-peptide vaccination had moderate responses that fluctuated in concert with vaccination. In an MS patient and HC, expression of BV6S1 by activated memory T cells was inversely associated with the presence of IL-10-secreting BV6S1-reactive T cells. These results suggest that MS patients have diminished frequencies of innate TCR-reactive T cells that may allow oligoclonal expansion of activated autoreactive Th1 effector cells expressing cognate V genes.

Adult↗
PubMed2001

A prospective study of physical activity and cognitive decline in elderly women: women who walk.

BACKGROUND: Several studies have suggested that physical activity is positively associated with cognitive function in elderly persons. Evidence about this association has been limited by the cross-sectional design of most studies and by the frequent lack of adjustment for potential confounding variables. We determined whether physical activity is associated with cognitive decline in a prospective study of older women. METHODS: We studied 5925 predominantly white community-dwelling women (aged > or =65 years) who were recruited at 4 clinical centers and were without baseline cognitive impairment or physical limitations. We measured cognitive performance using a modified Mini-Mental State Examination at baseline and 6 to 8 years later. Physical activity was measured by self-reported blocks (1 block approximately 160 m) walked per week and by total kilocalories (energy) expended per week in recreation, blocks walked, and stairs climbed. Cognitive decline was defined as a 3-point decline or greater on repeated modified Mini-Mental State Examination. RESULTS: Women with a greater physical activity level at baseline were less likely to experience cognitive decline during the 6 to 8 years of follow-up: cognitive decline occurred in 17%, 18%, 22%, and 24% of those in the highest, third, second, and lowest quartile of blocks walked per week (P< .001 for trend). Almost identical results were obtained by quartile of total kilocalories expended per week. After adjustment for age, educational level, comorbid conditions, smoking status, estrogen use, and functional limitation, women in the highest quartile remained less likely than women in the lowest quartile to develop cognitive decline (for blocks walked: odds ratio, 0.66 [95% confidence interval, 0.54-0.82]; for total kilocalories: odds ratio, 0.74 [95% confidence interval, 0.60-0.90]). CONCLUSIONS: Women with higher levels of baseline physical activity were less likely to develop cognitive decline. This association was not explained by differences in baseline function or health status. This finding supports the hypothesis that physical activity prevents cognitive decline in older community-dwelling women.

Aged↗
PubMed2001

Excluding pulmonary embolism at the bedside without diagnostic imaging: management of patients with suspected pulmonary embolism presenting to the emergency department by using a simple clinical model and d-dimer.

BACKGROUND: The limitations of the current diagnostic standard, ventilation-perfusion lung scanning, complicate the management of patients with suspected pulmonary embolism. We previously demonstrated that determining the pretest probability can assist with management and that the high negative predictive value of certain D -dimer assays may simplify the diagnostic process. OBJECTIVE: To determine the safety of using a simple clinical model combined with D -dimer assay to manage patients presenting to the emergency department with suspected pulmonary embolism. DESIGN: Prospective cohort study. SETTING: Emergency departments at four tertiary care hospitals in Canada. PATIENTS: 930 consecutive patients with suspected pulmonary embolism. INTERVENTIONS: Physicians first used a clinical model to determine patients' pretest probability of pulmonary embolism and then performed a D -dimer test. Patients with low pretest probability and a negative D -dimer result had no further tests and were considered to have a diagnosis of pulmonary embolism excluded. All other patients underwent ventilation-perfusion lung scanning. If the scan was nondiagnostic, bilateral deep venous ultrasonography was done. Whether further testing (by serial ultrasonography or angiography) was done depended on the patients' pretest probability and the lung scanning results. MEASUREMENTS: Patients received a diagnosis of pulmonary embolism if they had a high-probability ventilation-perfusion scan, an abnormal result on ultrasonography or pulmonary angiography, or a venous thromboembolic event during follow-up. Patients for whom the diagnosis was considered excluded were followed up for 3 months for the development of thromboembolic events. RESULTS: The pretest probability of pulmonary embolism was low, moderate, and high in 527, 339, and 64 patients (1.3%, 16.2%, and 37.5% had pulmonary embolism), respectively. Of 849 patients in whom a diagnosis of pulmonary-embolism had initially been excluded, 5 (0.6% [95% CI, 0.2% to 1.4%]) developed pulmonary embolism or deep venous thrombosis during follow-up. However, 4 of these patients had not undergone the proper diagnostic testing protocol. In 7 of the patients who received a diagnosis of pulmonary embolism, the physician had performed more diagnostic tests than were called for by the algorithm. In 759 of the 849 patients in whom pulmonary embolism was not found on initial evaluation, the diagnostic protocol was followed correctly. Only 1 (0.1% [CI, 0.0% to 0.7%]) of these 759 patients developed thromboembolic events during follow-up. Of the 437 patients with a negative D -dimer result and low clinical probability, only 1 developed pulmonary embolism during follow-up; thus, the negative predictive value for the combined strategy of using the clinical model with D -dimer testing in these patients was 99.5% (CI, 99.1% to 100%). CONCLUSION: Managing patients for suspected pulmonary embolism on the basis of pretest probability and D -dimer result is safe and decreases the need for diagnostic imaging.

Adolescent↗
PubMed2001

Cystic fibrosis pathogens activate Ca2+-dependent mitogen-activated protein kinase signaling pathways in airway epithelial cells.

Much of the pulmonary disease in cystic fibrosis is associated with polymorphonuclear leukocyte-dominated airway inflammation caused by bacterial infection. Respiratory epithelial cells express the polymorphonuclear chemokine interleukin-8 (IL-8) in response to ligation of asialylated glycolipid receptors, which are increased on damaged or regenerating cells and those with cystic fibrosis transmembrane conductance regulator mutations. Because both Pseudomonas aeruginosa and Staphylococcus aureus, the most common pathogens in cystic fibrosis, bind asialylated glycolipid receptors such as asialoGM1, we postulated that diverse bacteria can activate a common epithelial signaling pathway to elicit IL-8 expression. P. aeruginosa PAO1 but not pil mutants and S. aureus RN6390 but not the agr mutant RN6911 stimulated increases in [Ca(2+)](i) in 1HAEo- airway epithelial cells. This response stimulated p38 and ERK1/2 mitogen-activated protein kinase (MAPK) signaling cascades resulting in NF-kappaB activation and IL-8 expression. Ligation of the asialoGM1 receptor or thapsigargin-elicited Ca(2+) release activated this pathway, whereas P. aeruginosa lipopolysaccharide did not. The rapid kinetics of epithelial activation precluded bacterial invasion of the epithelium. Recognition of asialylated glycolipid receptors on airway epithelial cells provides a common pathway for Gram-positive and Gram-negative organisms to initiate an epithelial inflammatory response.

Adhesins, Bacterial↗
PubMed2001

Loss of heterozygosity mapping at chromosome arm 16q in 712 breast tumors reveals factors that influence delineation of candidate regions.

Loss of heterozygosity (LOH) at the long arm of chromosome 16 occurs in at least half of all breast tumors and is considered to target one or more tumor suppressor genes. Despite extensive studies by us and by others, a clear consensus of the boundaries of the smallest region of overlap (SRO) could not be identified. To find more solid evidence for SROs, we tested a large series of 712 breast tumors for LOH at 16q using a dense map of polymorphic markers. Strict criteria for LOH and retention were applied, and results that did not meet these criteria were excluded from the analysis. We compared LOH results obtained from samples with different DNA isolation methods, ie., from microdissected tissue versus total tissue blocks. In the latter group, 16% of the cases were excluded because of noninterpretable LOH results. The selection of polymorphic markers is clearly influencing the LOH pattern because a chromosomal region seems more frequently involved in LOH when many markers from this region are used. The LOH detection method, i.e., radioactive versus fluorescence detection, has no marked effect on the results. Increasing the threshold window for retention of heterozygosity resulted in significantly more cases with complex LOH, i.e., several alternating regions of loss and retention, than seen in tumors with a small window for retention. Tumors with complex LOH do not provide evidence for clear-cut SROs that are repeatedly found in other samples. On disregarding these complex cases, we could identify three different SROs, two at band 16q24.3 and one at 16q22.1. In all three tumor series, we found cases with single LOH regions that designated the distal region at 16q24.3 and the region at 16q22.1. Comparing histological data on these tumors did not result in the identification of a particular subtype with LOH at 16q or a specific region involved in LOH. Only the rare mucinous tumors had no 16q LOH at all. Furthermore, a positive estrogen content is prevalent in tumors with 16q LOH, but not in tumors with LOH at 16q24.3 only.

Breast Neoplasms↗
PubMed2001

The role of liver biopsy in chronic hepatitis C.

Hepatitis C virus (HCV) is a major cause of chronic liver disease worldwide, affecting 175 million people globally. Over 80% of acutely infected patients go on to develop chronicity, but only 20% to 25% will develop end-stage liver disease and its complications. The sequelae of HCV-induced chronic liver disease accounts for 8,000 to 10,000 deaths annually in the United States and is currently the leading indication for liver transplantation. To date, there are no accurate noninvasive markers of disease activity and fibrosis. Liver biopsy is indicated to exclude other forms of liver pathologies and to establish the stage of liver disease. In this study, the role of liver biopsy in chronic hepatitis C was evaluated. Additionally, we calculated a discriminant score to predict cirrhosis in chronic hepatitis C infection. Our results showed that additional diagnoses or unsuspected diagnoses are less frequent than clinicians' suspected. We confirmed that the discriminant score for predicting cirrhosis is inferior to liver biopsy. In conclusion, the majority of patients with chronic hepatitis C will require a liver biopsy, which has an important implication on staging of the liver disease, prognosis, and possibly further management options.

Adult↗
PubMed2001

A multi-laboratory evaluation of an enzyme-linked immunoassay quantitating human antibodies to Streptococcus pneumoniae polysaccharides.

An enzyme-linked immunoassay (EIA) is described and evaluated which quantitates human antibodies to serotype specific S. pneumoniae polysaccharide (PnPs) in human sera. Based on the observations previously described by Koskela (1), native PnPs are used as coating antigens and sera are absorbed with a soluble pneumococcal absorbant material containing C-polysaccharide (CPs) to ensure measurement of serotype specific anti-PnPs antibodies. The robustness of this method was evaluated by ten laboratories using the same reagents, protocol, and five human serum samples. Reproducible antibody values were obtained for IgM, IgG, and IgA antibodies to five different PnPs serotypes, 3, 6B, 14, 19F, and 23F. The overall mean percent coefficients of variation in this interlaboratory study for all five selotype specific anti-PnPs determinations with the five coded sera were 30% for IgG, 3/% for IgM, and 36% for IgA. This assay can be standardized for quantitation of serotype specific anti-PnPs antibodies, allowing comparison of antibody values in vaccine trials evaluating pneumococcal vaccines.

Enzyme-Linked Immunosorbent Assay↗
PubMed2001

Neuronal apoptosis inhibitory protein expression after traumatic brain injury in the mouse.

Apoptosis of brain cells is triggered by traumatic brain injury (TBI) and is blocked by caspase inhibitors. The neuronal apoptosis inhibitor protein (NAIP), which has been shown to inhibit apoptosis by both caspase-dependant and caspase-independent mechanisms, is neuroprotective in rat models of cerebral ischemia and axotomy. In order to gain a better appreciation of CNS apoptosis following head injury in general and the possible involvement of NAIP specifically, we have configured a mouse model of TBI. In addition to demonstrating apoptosis, the spatiotemporal expression or levels of a number of proteins with apoptosis modulating effects have been determined. Apoptosis of neurons and oligodendrocytes following TBI was observed in brain sections which were triple-stained with in situ end labeling, bisbenzimide and immunofluorescent stain for neuron specific nuclear protein and myelin-associated glycoprotein, respectively. Further evidence for apoptosis following TBI in this model was obtained in brain samples using ligation-mediated PCR amplification of DNA fragments and gel electrophoresis. The temporal profile of apoptosis was similar to the temporal profile of microglial activation determined by CD11b staining and TNFa expression induced by TBI. NAIP staining in sections of cerebral cortex and subcortical white matter increased at 6 h and decreased towards control levels at 24 h post-TBI. Temporal changes in the expression of NAIP were also observed using Western blot analysis of brain samples removed from injured cortex and sub-cortical white matter. At the time that NAIP expression decreased markedly (24 h post-TBI), procaspase-3 levels also decreased, PARP cleavage increased, and the highest levels of apoptosis were observed. These findings have implications in our understanding of traumatically induced programmed cell death and may be useful in the configuration of therapies for this common injury state.

Animals↗
PubMed2001

Myocardial scintigraphy correlates poorly with coronary angiography in the screening of transplant arteriosclerosis.

BACKGROUND: Coronary angiography remains an important screening tool for transplant coronary arteriosclerosis (TxCAD) after heart transplantation despite criticism that it underestimates the incidence of TxCAD. In an effort to improve TxCAD incidence estimation, several methods of screening have been proposed. In the present study, the incidence of TxCAD assessed by both yearly coronary angiography and stress myocardial scintigraphy imaging was reviewed. PATIENTS AND METHODS: Ninety-nine consecutive primary heart transplantations were performed from 1988 to 1999. The standard immunosuppression protocol consisted of the introduction of antilymphocyte globulin and steroids, while maintenance therapy was with cyclosporine, imuran and steroids. Coronary angiography and a stress 2-methoxyisobutyl-isonitrile perfusion scan were performed yearly. TxCAD was defined by angiographic evidence of luminal abnormality by catheterization, or a perfusion abnormality at rest or after stress on myocardial scintigraphy. RESULTS: The mean recipient age was 49+/-12 years and the mean donor age was 33+/-13 years. The etiology of heart failure was ischemic cardiomyopathy (50%), dilated cardiomyopathy (41%) and congenital heart disease (9%). The freedom from angiographic TxCAD was 92% at one year, 64% at five years and 35% at eight years. The freedom from nuclear imaging TxCAD was 92% at one year, 69% at five years and 44% at eight years. However, a diagnosis of TxCAD by angiography only correlated with a diagnosis of TxCAD by nuclear imaging 52.8% of the time in the same patient, with a median time between studies of one month. CONCLUSION: The overall incidence of TxCAD diagnosed by angiography and nuclear imaging appears similar but correlates poorly in patients, casting doubt on the routine use of myocardial scintigraphy for screening TxCAD.

Adolescent↗
PubMed2000

The frequency of germ-line mutations in the breast cancer predisposition genes BRCA1 and BRCA2 in familial prostate cancer. The Cancer Research Campaign/British Prostate Group United Kingdom Familial Prostate Cancer Study Collaborators.

Predisposition to prostate cancer has a genetic component, and there are reports of familial clustering of breast and prostate cancer. Two highly penetrant genes that predispose individuals to breast cancer (BRCA1 and BRCA2) are known to confer an increased risk of prostate cancer of about 3-fold and 7-fold, respectively, in breast cancer families. Blood DNA from affected individuals in 38 prostate cancer clusters was analyzed for germ-line mutations in BRCA1 and BRCA2 to assess the contribution of each of these genes to familial prostate cancer. Seventeen DNA samples were each from an affected individual in families with three or more cases of prostate cancer at any age; 20 samples were from one of affected sibling pairs where one was < or = 67 years at diagnosis. No germ-line mutations were found in BRCA1. Two germ-line mutations in BRCA2 were found, and both were seen in individuals whose age at diagnosis was very young (< or = 56 years) and who were members of an affected sibling pair. One is a 4-bp deletion at base 6710 (exon 11) in a man who had prostate cancer at 54 years, and the other is a 2-bp deletion at base 5531 (exon 11) in a man who had prostate cancer at 56 years. In both cases, the wild-type allele was lost in the patient's prostate tumor at the BRCA2 locus. However, intriguingly, in neither case did the affected brother also carry the mutation. Germ-line mutations in BRCA2 may therefore account for about 5% of prostate cancer in familial clusters.

Adult↗
PubMed2000

Cortical myoclonus and cerebellar pathology.

OBJECTIVE: To study the electrophysiologic and pathologic findings in three patients with cortical myoclonus. In two patients the myoclonic ataxic syndrome was associated with proven celiac disease. BACKGROUND: The pathologic findings in conditions associated with cortical myoclonus commonly involve the cerebellar system, but there has only been one report of cerebellar pathology in a patient in whom cortical myoclonus was physiologically characterized antemortem. METHODS: Cortical somatosensory evoked potentials (SEPs) were recorded and EEG activity was averaged preceding myoclonic electromyographic activity. In one patient cortico-cortical inhibition was tested using two paired ipsilateral magnetic stimuli over the motor strip. Neuropathologic examination was carried out, including linear Purkinje cell densities/millimeter calculations for different regions of the cerebellum. RESULTS: The electrophysiology showed evidence of dysfunction of the sensorimotor cortex with enlarged SEPs and a time-locked cortical potential preceding the action myoclonus. In addition, motor cortical inhibition was abnormal in one case. Pathology showed unremarkable primary sensory, motor, and premotor cerebral cortices, except for unilateral gliosis of the motor cortex in one case. The cerebellum showed patchy atrophy and ongoing degeneration. A striking feature was the greater severity of Purkinje cell loss and Bergmann gliosis in the outer aspects than in the depths of the folia. CONCLUSIONS: Pathologic abnormalities are paradoxically mainly located in the cerebellum in some patients with cortical myoclonus, despite clear electrophysiologic evidence of cortical dysfunction. This observation suggests that enhanced excitability of the sensorimotor cortex may arise as a distant effect of cerebellar pathology.

Adult↗
PubMed2000

Enkephalins are transported by a novel eukaryotic peptide uptake system.

We have identified an oligopeptide transporter in the yeast Saccharomyces cerevisiae which mediates the uptake of tetra- and pentapeptides, including the endogenous opioids leucine enkephalin (Tyr-Gly-Gly-Phe-Leu) and methionine enkephalin (Tyr-Gly-Gly-Phe-Met). The transporter is encoded by the gene OPT1. Yeast expressing OPT1 can utilize enkephalins to satisfy amino acid auxotrophic requirements for growth. The transport of radiolabeled leucine enkephalin exhibits saturable kinetics, with a K(m) of 310 microM. Transport activity is optimum at acidic pH and sensitive to reagents which uncouple oxidative phosphorylation, suggesting an energy dependence on the proton gradient. Growth, transport, and chromatographic data indicate that leucine enkephalin is not hydrolyzed in the extracellular medium and as such is translocated intact across the cell membrane. The system is specific for tetra- and pentapeptides and can be inhibited by the opioid receptor antagonists naloxone and naltrexone. To date, this is the first example of a eukaryotic transport system which can use enkephalins as a substrate, opening the possibility that a homologue exists in higher eukaryotes.

Animals↗
PubMed2000

The effect of oral and intravenous methylprednisolone treatment on subsequent relapse rate in multiple sclerosis.

We investigated the effect of oral and intravenous methylprednisolone treatment on subsequent relapse rate in patients with multiple sclerosis. Following a double blind trial designed to compare the effect of oral and intravenous methylprednisolone treatment on promoting recovery from acute relapses of multiple sclerosis, 80 patients were followed for two years with six-monthly assessments during which all subsequent relapses were recorded. The annual relapse rate was slightly higher in the oral compared with the intravenous methylprednisolone-treated patients (1.06 vs. 0.78), but the adjusted difference between the two groups was not statistically significant (0.18; 95% CI -0.19 to 0.55, P=0.3). The time to onset and the severity of the first relapse after treatment, the number of relapse free patients at the end of the follow-up period, and the severity of the relapses during the follow-up period were similar in the two groups. This trial did not show a statistically significant difference in relapse rate during the first two years following oral compared with intravenous methylprednisolone treatment.

Administration, Oral↗
PubMed2000

Immunohistochemical expression of uPA, uPAR, and PAI-1 in breast carcinoma. Fibroblastic expression has strong associations with tumor pathology.

The urokinase-type plasminogen activator (uPA) system has been implicated in tumor spread. We have used immunohistochemistry to examine three components of this system, ie, uPA, uPA receptor (uPAR), and plasminogen activator inhibitor-1 (PAI-1), in a pilot study on 142 cases of breast carcinoma. We wished to determine whether there were any relationships between expression of the proteins in either tumor cells or fibroblasts and clinical and pathological features. Strong uPA expression in each cell type was significantly related to high tumor grade (P = 0.013 and 0.008, respectively), and was more common in invasive than in in situ carcinomas (P < 0.0001). Fibroblastic expression of uPAR was only related to the presence of invasion (P < 0.0001). Strong PAI-1 expression in both cell types was seen in high-grade tumors (tumor cells, P = 0.012; fibroblasts, P < 0.001), but only fibroblastic expression was related to the presence of invasion (P = 0.042). Fibroblastic expression of both uPA and uPAR were positively correlated with tumor size. Although patients with strong fibroblastic expression of uPA showed a tendency toward a shorter time to relapse, none of the plasminogen activator proteins were significantly associated with relapse-free survival. These results suggest that strong expression of uPA, uPAR, and PAI-1 in fibroblasts rather than in tumor cells have the most impact on the clinical behavior of breast cancer. Larger prospective studies are needed to confirm these findings.

Adult↗
PubMed2000

Cancer screening in the elderly population.

This article reviews the current state of knowledge regarding cancer screening in the geriatric population. Care of the elderly requires knowledge of underlying physiologic changes, comorbidities, quality-of-life factors, and life expectancies. There is always the danger that ageism may prevent elderly cancer patients from receiving the proper treatment. On the other hand, overzealous treatment can lead to adverse results if elderly patients are not properly targeted based on current evidence of the benefits and risks of specific screening practices.

Age Factors↗
PubMed2000

Surgical shunts and TIPS for variceal decompression in the 1990s.

BACKGROUND: In the 1990s, liver transplantations and transjugular intrahepatic portosystemic shunts (TIPS) have become the most common methods to decompress portal hypertension. This center has continued to use surgical shunts for variceal bleeding in good-risk patients who continue to bleed through endoscopic and pharmacologic treatment. This article reports this center's experience with surgical shunts and TIPS shunts from 1992 through 1999. METHODS: Sixty-three patients (Child A, 43 patients; Child B, 20 patients) received surgical shunts: distal splenorenal, 54 patients; splenocaval, 4 patients; coronary caval, 1 patient; and mesocaval, 4 patients. Sixty-two patients had refractory variceal bleeding, and 1 patient had ascites with Budd-Chiari syndrome. Two hundred patients (Child A, 24 patients; Child B, 62 patients; Child C, 114 patients) received TIPS shunts. One hundred forty-nine patients had refractory variceal bleeding, and 51 patients had ascites, hydrothorax, or hepatorenal syndrome. Data were collected by prospective databases, protocol follow-up, and phone contact. RESULTS: The 30-day mortality rate was 0% for surgical shunts and 26% for TIPS shunts; the overall survival rate was 86% (median follow-up, 36 months) for surgical shunts and 53% (median follow-up, 40 months) for TIPS shunts. For surgical shunts, the portal hypertensive rebleeding rate was 6.3%; the overall rebleeding rate was 14.3%. For TIPS shunts, the overall rebleeding rate was 25.5% (30-day, 9.4%; late, 22.4%). There were 4 reinterventions for surgical shunts (6.3%); the reintervention rate for TIPS shunts in the bleeding group was 33%, and the reintervention rate in the ascites group was 9.5%. Encephalopathy was severe in 3.1% of the shunt group and mild in 17.5%; this was not systematically evaluated in the TIPS shunts patients. CONCLUSIONS: Surgical shunts still have a role for patients whose condition was classified as Child A and B with refractory bleeding, who achieve excellent outcomes with low morbidity and mortality rates. TIPS shunts have been used in high-risk patients with significant early and late mortality rates and have been useful in the control of refractory bleeding and as a bridge to transplantation. The comparative role of TIPS shunts versus surgical shunt in patients whose condition was classified as Child A and B is under study in a randomized controlled trial.

Adult↗