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Biomedical subjects

M A Smith

Publications and source records attributed to M A Smith.

At least 109 records · Page 6Linked to original sources
PubMed2001

Increased levels of oxidative stress markers detected in the brains of mice devoid of prion protein.

Although minor abnormalities have been reported in prion protein (PrP) knock-out (Prnp-/-) mice, the normal physiological function of PrP, the causative agent implicated in transmissible spongiform encephalopathies (TSE), remains unresolved. Since there are increasing correlations between oxidative stress and amyloidoses, we decided to investigate whether PrP plays a role in oxidative modulation. We found higher levels of oxidative damage to proteins and lipids in the brain lysates of Prnp-/- as compared to wild-type (WT) mice of the same genetic background. These two indicators, protein oxidation and lipid peroxidation, are hallmarks of cellular oxidative damage. Elevated levels of ubiquitin-protein conjugates were also observed in Prnp-/- mice, a probable consequence of cellular attempts to remove the damaged proteins as indicated by increased proteasome activity. Taken together, these findings are indicative of a role for PrP in oxidative homeostasis in vivo.

Aldehydes↗
PubMed2001

Activation and redistribution of c-jun N-terminal kinase/stress activated protein kinase in degenerating neurons in Alzheimer's disease.

Cellular responses to increased oxidative stress appear to be a mechanism that contributes to the varied cytopathology of Alzheimer's disease (AD). In this regard, we suspect that c-Jun N-terminal kinase/Stress activated protein kinase (JNK/SAPK), a major cellular stress response protein induced by oxidative stress, plays an important role in Alzheimer disease in susceptible neurons facing the dilemma of proliferation or death. We found that JNK2/SAPK-alpha and JNK3/SAPK-beta were related to neurofibrillary pathology and JNK1/SAP-Kgamma related to Hirano bodies in cases of AD but were only weakly diffuse in the cytoplasm in all neurons in control cases and in non-involved neurons in diseased brain. In this regard, in hippocampal and cortical regions of individuals with severe AD, the activated phospho-JNK/SAPK was localized exclusively in association with neurofibrillar alterations including neurofibrillary tangles, senile plaque neurites, neuropil threads and granulovacuolar degeneration structures (GVD), completely overlapping with tau-positive neurofibrillary pathology, but was virtually absent in these brain regions in younger and age-matched controls without pathology. However, in control patients with some pathology, as well as in mild AD cases, there was nuclear phospho-JNK/SAPK and translocation of phospho-JNK/SAPK from nuclei to cytoplasm, respectively, indicating that the activation and re-distribution of JNK/SAPK correlates with the progress of the disease. By immunoblot analysis, phospho-JNK/SAPK is significantly increased in AD over control cases. Together, these findings suggest that JNK/SAPK dysregulation, probably resulting from oxidative stress, plays an important role in the increased phosphorylation of cytoskeletal proteins found in AD.

Adolescent↗
PubMed2001

Induction of NADPH cytochrome P450 reductase by the Alzheimer beta-protein. Amyloid as a "foreign body".

A large body of data suggests that the Alzheimer's amyloid peptide (Abeta) causes degeneration and death of neurons by mechanisms that involve reactive oxygen species. The pathways involved in Abeta-mediated oxidative injury are only partially understood. We theorized that abnormal microaggregates and/or pathological conformations of Abeta peptides may behave as xenobiotics and trigger the induction of NADPH cytochrome P450 reductase (CP450r), an enzyme which, if induced by non-physiological substrates (such as xenobiotics like drugs or other 'foreign molecules'), is known to cause oxidative stress. In order to test this hypothesis, i.e. that Abeta can increase the expression of CP450r, SK-N-SH human neuroblastoma cells were exposed to Abeta25-35 and Abeta1-42 and then examined for induction of this enzyme in immunoblots, using specific antibodies. Following exposure to Abeta peptides, neuroblastoma cells showed a clear-cut induction of CP450r. To determine whether this mechanism is operational in vivo, we investigated the expression of CP450r in a transgenic mouse model of Alzheimer's disease (AD) and in brains from patients afflicted with AD, using an immunocytochemical approach. Tissue sections from brains of transgenic mice exhibited strong immunoreactivity for CP450r, surrounding amyloid deposits. The pattern of expression of CP450r was similar to that exhibited by neuritic and oxidative stress markers. Sections from non-transgenic mice showed no detectable immunoreactivity. Immunostaining of sections from four brains with neuropathologically confirmed AD showed a pattern of abnormality different from transgenic mice that was characterized by abnormal immunoreactivity for CP450r within the cytoplasm of cortical neurons. No labeling was seen in sections from aged-matched control brains. The data showed that CP450r is induced by Alzheimer amyloid peptide and that such a response must be considered as one possible mechanism whereby Abeta causes oxidative stress.

Alzheimer Disease↗
PubMed2001

Activation of MKK6, an upstream activator of p38, in Alzheimer's disease.

Mitogen-activated protein kinase (MAPK) p38 has been implicated in the pathogenesis of Alzheimer's disease, but the upstream cascade leading to p38 activation has not been elucidated in the disease. In the present study, we focused on mitogen-activated protein kinase kinase 6 (MKK6), one of the upstream activators of p38 MAPK. We found that MKK6 was not only increased but also specifically associated with granular structures in the susceptible neurons in the hippocampus and cortex of Alzheimer's disease patients, but was only weakly diffuse in the cytoplasm in neurons in control cases. Immunoblot analysis demonstrated a significant increase of MKK6 level in Alzheimer's disease compared with age-matched controls. In this regard, in hippocampal and cortical regions of individuals with Alzheimer's disease, the activated phospho-MKK6 was localized exclusively in association with pathological alterations including neurofibrillary tangles, senile plaques, neuropil threads and granular structures, overlapping with activated p38 MAPK suggesting both a functional and mechanic link. By immunoblot analysis, phospho-MKK6 is also significantly increased in AD compared with control cases. Together, these findings lend further credence to the notion that the p38 MAPK pathway is dysregulated in Alzheimer's disease and also indicates an active role for this pathway in disease pathogenesis.

Adolescent↗
PubMed2001

Stem cell factor: laboratory and clinical aspects.

Stem cell factor is an essential haemopoietic progenitor cell growth factor with proliferative and anti-apoptotic functions. Molecular biologists have now dissected some of the various pathways through which this cytokine signals to the nucleus. At the same time, new molecules have become available which can inhibit SCF signalling. This provides an exciting prospect for the treatment of Kit+ malignancies such as acute myeloblastic leukaemia. The capacity of SCF to synergize with other cytokines has been exploited in the ex vivo expansion of haemopoietic progenitors and dendritic cells, which may also hold therapeutic promise. In this review the last 5 years' literature on these issues is reviewed and collated.

Antineoplastic Agents↗
PubMed2001

Seven cases of surgical native valve endocarditis caused by coagulase-negative staphylococci: An underappreciated disease.

BACKGROUND: Native valve endocarditis caused by coagulase-negative staphylococci is uncommon and the diagnosis is infrequently considered. The disease, however, appears to be increasing in frequency and can pursue an aggressive clinical course. We report the clinical features of 7 cases of coagulase-negative staphylococcal native valve endocarditis (CNS-NVE) seen at 1 institution with a large cardiovascular referral base over a 10-month period. All cases required valve replacement surgery. METHODS: Clinical history, echocardiograms, and microbiologic and histopathologic data were reviewed for 7 patients with surgical CNS-NVE. RESULTS: Four patients had intravenous central catheters, and 1 had recent surgery, whereas the remaining 2 had no identifiable risk factors. Presentations ranged from subacute (4 cases) to acute with complications (3 cases). Complications included congestive heart failure, stroke, and heart block. Echocardiography demonstrated valvular lesions in all 7 cases. Valve pathologic study demonstrated gram-positive cocci in all 7 cases; blood cultures grew coagulase-negative staphylococci in 6 cases and valve cultures grew Staphylococcus epidermidis in 5 cases. CONCLUSIONS: Coagulase-negative staphylococci, including S epidermidis, can cause severe native valve endocarditis requiring valve replacement. The increasing use of intravascular access devices in the community may herald an increase in the incidence of CNS-NVE. A high index of diagnostic suspicion in the appropriate clinical setting is critical for optimal management.

Adult↗
PubMed2001

Oxidative damage is the earliest event in Alzheimer disease.

Recently, we demonstrated a significant increase of an oxidized nucleoside derived from RNA, 8-hydroxyguanosine (8OHG), and an oxidized amino acid, nitrotyrosine in vulnerable neurons of patients with Alzheimer disease (AD). To determine whether oxidative damage is an early- or end-stage event in the process of neurodegeneration in AD, we investigated the relationship between neuronal 8OHG and nitrotyrosine and histological and clinical variables, i.e. amyloid-beta (A beta) plaques and neurofibrillary tangles (NFT), as well as duration of dementia and apolipoprotein E (ApoE) genotype. Our findings show that oxidative damage is quantitatively greatest early in the disease and reduces with disease progression. Surprisingly, we found that increases in A beta deposition are associated with decreased oxidative damage. These relationships are more significant in ApoE epsilon4 carriers. Moreover, neurons with NFT show a 40%-56% decrease in relative 8OHG levels compared with neurons free of NFT. Our observations indicate that increased oxidative damage is an early event in AD that decreases with disease progression and lesion formation. These findings suggest that AD is associated with compensatory changes that reduce damage from reactive oxygen.

Aged↗
PubMed2001

Measuring the direct costs of graduate medical education training in Minnesota.

PURPOSE: To demonstrate the usefulness of self-reported cost-accounting data from the sponsors of training programs for estimating the direct costs of graduate medical education (GME). The study also assesses the relative contributions of resident, faculty, and administrative costs to primary care, surgery, and the combined programs of radiology, emergency medicine, anesthesiology, and pathology (REAP). METHOD: The data were the FY97 direct costs of clinical education reported to Minnesota's Department of Health by eight sponsors of 117 accredited medical education programs, representing 394 sites of training (both hospital- and community-based) and 2,084 full-time-equivalent trainees (both residents and fellows). Average costs of clinical training were calculated as residency, faculty, and administrative costs. Preliminary analysis showed average costs by type of training programs, comparing the cost components for surgery, primary care, and REAP. RESULTS: The average direct cost of clinical training in FY97 was $130,843. Faculty costs were 52%, resident costs were 26%, and administrative costs were 20% of the total. Primary care programs' average costs were lower than were those of either surgery or REAP programs, but proportionally they included more administrative costs. CONCLUSIONS: As policymakers assess government subsidies for GME, more detailed cost information will be required. Self-reported data are more cost-effective and efficient than are the more detailed and costly time-and-motion studies. This data-collection study also revealed that faculty costs, driven by faculty hours and base salaries, represent a higher proportion of direct costs of GME than studies have shown in the past.

Accounting↗
PubMed2001

To help or hinder: Which is more important in explaining a physician's willingness to recommend a health plan?

PURPOSE: To examine how specific health plan practices contribute to physicians' willingness to recommend a health plan to a patient, and whether the relative importance of plan practices is viewed differently when patients are seriously ill. METHODS: The Physician's Evaluation of Health Plans Project has surveyed 1,757 generalist physicians in 16 health plans in 5 areas nationwide. Each physician reported on one plan. Three multi-item scales assessed physicians' perceptions of health plan activities that facilitated or impeded high-quality care in the plans and the clinical capabilities of plan physicians. Regression analyses were used to explore relations between facilitators, barriers, and clinical capabilities, and two global physician judgments (the physician's willingness to recommend a plan and their judgment that a plan provided lower quality for sicker patients). RESULTS: A physician's willingness to recommend a health plan is more highly related to what plans do to facilitate care than to the barriers created by plans in managing care. However, barriers to care were substantially more important when evaluating health plan quality for sicker patients. CONCLUSIONS: From the physician's perspective, the relative importance of plan strategies to manage care is different for typical patients and patients who are more seriously ill. Efforts to collect information on health plan quality should separately evaluate care for sicker patients, in addition to evaluating the overall performance of the health plan.

Attitude of Health Personnel↗
PubMed2001

Sensitivity to the effects of sedative-hypnotics on motor performance: influence of task difficulty and chronic phenobarbital administration.

The present investigation examined sensitivity to the effects of various sedative-hypnotics on motor performance in rats treated chronically with phenobarbital. Eight rats were trained to walk on a rotorod treadmill at low (8 r.p.m.) and high (24 r.p.m.) rotational speeds. Prior to the chronic regimen, phenobarbital, pentobarbital, amobarbital, diazepam and clonazepam produced dose-dependent impairments in motor performance at both speeds. During chronic treatment with phenobarbital (100 mg/kg/day), tolerance was conferred to the effects of all the drugs examined, as evidenced by rightward shifts in their dose-effect curves. For all drugs, the magnitude of this tolerance was generally consistent across the two speeds. Following a 6-week washout period, during which no drugs were administered, dose-effect curves for each drug shifted back toward their original (i.e. pre-chronic) positions. Under all conditions, the doses required for each drug to impair motor performance at the low speed were higher than those required to impair motor performance at the high speed. These data suggest that sensitivity to the motor-impairing effects of sedative-hypnotics is influenced by the difficulty of the behavioral task, but that task difficulty does not modulate the maximal extent to which tolerance and cross-tolerance are expressed.

Amobarbital↗
PubMed2001

The use of granulocyte colony-stimulating factor for treatment of autoimmune neutropenia.

The advent of better diagnostic tools, molecular techniques, and cytokine therapies have come together at the end of the 20th century to provide an improved outlook for patients with autoimmune neutropenia. Severe chronic neutropenia is no longer idiopathic in most cases, and growth factor therapy can be safely offered to selected patient groups. Previously unsuccessful and even dangerous forms of treatment are no longer appropriate, and G-CSF treatment appears to be safe when administered long term. Fears about transformation of these disorders into acute myeloblastic leukemia probably relate to the underlying natural history of these disorders rather than to their treatment.

Autoantibodies↗
PubMed2001

Use of two-dimensional gel electrophoresis to measure changes in synovial fluid proteins from patients with rheumatoid arthritis treated with antibody to CD4.

Synovial fluid proteins from microliter volumes of synovial fluid were resolved by two-dimensional polyacrylamide gel electrophoresis and detected by silver staining to investigate the feasibility of using two-dimensional (2D) electrophoresis in the clinical research setting and provide global disease information of disease progression. Several hundred proteins could be resolved as spots, many of which displayed the characteristic pattern of plasma-derived glycoproteins. The lowest level of detection was approximately 0.2 ng from a total of 50 microg of protein loaded. Most of the proteins could be identified on the basis of pI and molecular weight when compared with plasma protein maps on the World Wide Web. Unknown proteins were characterized by mass spectrometry of tryptic digests and by comparison with peptide databases. Synovial fluids from patients with rheumatoid arthritis were analyzed using this technique. Each subject received a fixed dose of antibody to CD4 as part of a phase II clinical trial to determine the efficacy of this immunosuppressive treatment in modifying disease activity. Synovial fluid was removed at day 0, followed by administration of antibody. Subsequent removal of synovial fluid and additional administration of antibody were carried out at different times thereafter. Changes in levels of acute-phase proteins were quantified by densitometry of silver-stained 2D polyacrylamide gels. Other parameters of disease progression such as serum C-reactive protein and physician's global assessment of clinical condition were used for comparison. In this way, changes in acute-phase proteins towards normal levels, as measured by 2D polyacrylamide gel electrophoresis, could be correlated with clinical improvement and conventional clinical chemistry measurements. Thus, the system can be used for quantitative analysis of protein expression in sites of autoimmune disease activity such as the synovial fluid of rheumatoid arthritis patients.

Acute-Phase Proteins↗
PubMed2001

A systematic review of the staging performance of endoscopic ultrasound in gastro-oesophageal carcinoma.

BACKGROUND: Endoscopic ultrasound (EUS) may be used for preoperative staging of gastro-oesophageal carcinoma but performance values given in the literature differ. AIMS: To identify and synthesise findings from all articles on the performance of EUS in tumour, node, metastasis (TNM) staging of gastro-oesophageal carcinoma. SOURCE: Published and unpublished English language literature, 1981-1996. METHODS: Data on the staging performance of EUS were retrieved and evaluated. Summary receiver operator characteristic methodology was used for synthesis, and a summary estimate of performance, Q*, obtained. Multiple regression analysis was used to assess study validity and investigate reasons for differences in performance. RESULTS: Twenty seven primary articles were assessed in detail. Thirteen supplied results for staging oesophageal cancer, 13 for gastric cancer, and four for cancers at the gastro-oesophageal junction. For gastric T staging, Q*=0.93 (95% confidence interval (CI) 0.91-0.95) and for oesophageal T staging, Q*=0.89 (95% CI 0.88-0.92). For gastro-oesophageal T staging, including cancers at the gastro-oesophageal junction, Q*=0.91 (95% CI 0.89-0.93). Inclusion of cases with non-traversable stenosis was found to slightly reduce staging performance. For N staging, Q*=0.79 (95% CI 0.75-0.83). In articles that compared EUS directly with incremental computed tomography, EUS performed better. None of the variables assessed in the regression analysis was significant using a Bonferroni correction. Three variables (anatomical location, traversability, and blinding) showed strong relationships for future research and validation. CONCLUSIONS: EUS is highly effective for discrimination of stages T1 and T2 from stages T3 and T4 for primary gastro-oesophageal carcinomas. The failure rate of EUS from non-traversability of a stenotic cancer may be a limitation in some patient groups.

Confidence Intervals↗
PubMed2001

Implications of ocular kinematics for the internal updating of visual space.

Recent studies have suggested that during saccades cortical and subcortical representations of visual targets are represented and remapped in retinal coordinates. If this is correct, then the remapping processes must incorporate the noncommutativity of rotations. For example, our three-dimensional (3-D) simulations of the commutative vector-subtraction model of retinocentric remapping predicted centripetal errors in saccade trajectories between "remembered" eccentric targets, whereas our noncommutative model predicted accurate saccades. We tested between these two models in five head-fixed human subjects. Typically, a central fixation light appeared and two peripheral targets were flashed. With all targets extinguished, subjects were required to saccade to the remembered location of one of the peripheral targets and saccade between their remembered locations. Subjects showed minor misestimations of the spatial locations of targets, but failed to show the cumulative pattern of errors predicted by the commutative model. This experiment indicates that if targets are remapped in a retinal frame, then the remapping process also takes the noncommutativity of 3-D eye rotations into account. Unlike other noncommutative aspects of eye rotations that may have mechanical explanations, the noncommutative aspects of this process must be entirely internal.

Adult↗
PubMed2001

Stem cell factor: biology and relevance to clinical practice.

The type III tyrosine kinase receptor c-KIT and its ligand stem cell factor (SCF; also known as KIT ligand, mast cell growth factor and steel factor) are closely involved in the regulation of a wide range of tissues at different stages of life. This review provides an outline of the discovery, structure and expression of SCF and c-KIT but concentrates on their respective roles in the regulation of human haemopoiesis and how this knowledge might be exploited in the clinical setting.

Animals↗
PubMed2001

Barriers to acute stroke therapy and stroke prevention in Mexican Americans.

BACKGROUND AND PURPOSE: The purpose of this study was to identify specific targets to improve acute stroke treatment and stroke prevention in the Mexican American (MA) community. METHODS: A professional, academic survey research team provided structured questions and elicited responses from 719 subjects identified by random-digit dialing in the biethnic community of Corpus Christi, TEXAS: This community of approximately 300 000 is approximately half MA and half non-Hispanic white (NHW). The cooperation rate for the survey was 58%. RESULTS: MAs (n=357) were younger, less well educated, and had lower family income than NHWs (n=362, P=0.001). MAs had a higher prevalence of diabetes mellitus (P=0.001) but similar rates of hypertension, elevated cholesterol, and current tobacco use. MAs less commonly recognized that acute stroke therapy existed (P=0.029), were less likely to acknowledge a time window for acute stroke treatment (P=0.001), and were more reticent to say they would call 911 for stroke symptoms (P=0.01) than NHWS: MAs were significantly less able to recall stroke symptoms and risk factors than NHWS: Only approximately 20% of both groups identified stroke as the NO: 1 cause of disability. MAs expressed less confidence in their ability to prevent stroke (P<0.001), more distrust in the medical establishment (P=0.007), and more concern that money impedes their seeking medical care (P<0.001). CONCLUSIONS: There are significant barriers to both acute stroke treatment and stroke prevention in MAS: This study identifies specific targets amenable for testing in an intervention project following confirmation by a methodology other than telephone survey.

Acute Disease↗