Biomedical subjects

M A Smith

Publications and source records attributed to M A Smith.

At least 37 records · Page 2Linked to original sources

PubMed2005

Soft tissue sarcomas: are current referral guidelines sufficient?

INTRODUCTION: To investigate the adequacy of current early referral guidelines for patients with extremity soft tissue sarcomas. PATIENTS & METHODS: 365 patients with confirmed soft tissue sarcomas were evaluated. Data were collected prospectively and included the length of history and the presence of features in current guidelines suggestive of malignancy (pain, rapidity of growth, depth and tumour size). Statistical analysis included the t-test, ANOVA and the Chi test. RESULTS: Deep tumours were the commonest (306 patients with deep tumours). Pain was the least consistent feature (176 patients with pain). 345 patients with one or more of the guideline features had an average history of 19.86 months, 238 of these were seen after more than 3 months. CONCLUSION: Although the majority of soft tissue sarcomas in our patients had one or more of the clinical guideline features, there was still an unacceptable delay in referring these patients to a specialist unit. The referral guidelines should be modified with special emphasis on depth, which is the most sensitive, followed by size and a history of rapid growth. This combined with increased awareness of these guidelines and a well-advertised, open-access clinic linked to a specialist unit should allow for a more rapid evaluation of soft tissue tumours.

Adolescent↗

PubMed2005

Effect of age at presentation on outcome following arthroscopic debridement of subchondral cystic lesions of the medial femoral condyle: 85 horses (1993--2003).

REASONS FOR PERFORMING STUDY: Subchondral cystic lesions of the medial femoral condyle (SCMFC) are well documented in horses < or =3 years; arthroscopic debridement or enucleation of the cyst is currently the surgical treatment of choice. However, studies of occurence and outcome following surgery in older horses are lacking. OBJECTIVE: To identify factors important in outcome for horses with SCMFC treated by arthroscopic debridement. HYPOTHESIS: Age of horse at presentation has a significant influence on return to work following arthroscopic treatment for SCMFC. Clinical and diagnostic findings are also significant with respect to prognosis. METHODS: A retrospective review of medical records from 6 equine referral centres identified 85 horses that underwent arthroscopic debridement of SCMFC. Clinical examination, radiographic and arthroscopic findings were analysed together with follow-up data. Univariable analysis and multivariable logistic regression models were used to determine factors affecting return to soundness. Event-time analysis was performed to evaluate return to work. RESULTS: Older horses (>3 years) were less likely to return to soundness (P = 0.02) or to work (P = 0.04) than younger horses (< or = 3 years). Of 39 horses age 0-3 years, 25 (64%, 95% CI 49-79%) returned to soundness. Of 46 horses age >3 years, 16 (35%,95% CI 21-49%) returned to soundness. In addition, cartilage damage at sites other than the SCMFC negatively affected prognosis (P = 0.05). The hospital where treatment was performed had no influence on return to soundness. CONCLUSIONS: Older horses carry a worse prognosis for both return to soundness and return to work. POTENTIAL RELEVANCE: It is important for clients to be made aware of the difference in outcome between age groups.

Age Factors↗

PubMed2005

Effects of x-ray irradiation on material properties.

With a new commercial sterilisation technique about to enter the market, this article details a study that compared the effects of existing electron-beam irradiation with X-ray irradiation on different types of plastics commonly used in the manufacture of medical devices. The results are evaluated here.

Biocompatible Materials↗

PubMed2004

Emergency department evaluation of ischemic stroke and TIA: the BASIC Project.

OBJECTIVE: To identify demographic and clinical variables of emergency department (ED) practices in a community-based acute stroke study. METHODS: By both active and passive surveillance, the authors identified cerebrovascular disease cases in Nueces County, TX, as part of the Brain Attack Surveillance in Corpus Christi (BASIC) Project, a population-based stroke surveillance study, between January 1, 2000, and December 31, 2002. With use of multivariable logistic regression, variables independently associated with three separate outcomes were sought: hospital admission, brain imaging in the ED, and neurologist consultation in the ED. Prespecified variables included age, sex, ethnicity, insurance status, NIH Stroke Scale score, type of stroke (ischemic stroke or TIA), vascular risk factors, and symptom presentation variables. Percentage use of recombinant tissue plasminogen activator (rt-PA) was calculated. RESULTS: A total of 941 Mexican Americans (MAs) and 855 non-Hispanic whites (NHWs) were seen for ischemic stroke (66%) or TIA (34%). Only 8% of patients received an in-person neurology consultation in the ED, and 12% did not receive any head imaging. TIA was negatively associated with neurology consultations compared with completed stroke (odds ratio [OR] 0.35 [95% CI 0.21 to 0.57]). TIA (OR 0.14 [0.10 to 0.19]) and sensory symptoms (OR 0.59 [0.44 to 0.81]) were also negatively associated with hospital admission. MAs (OR 0.58 [0.35 to 0.98]) were less likely to have neurology consultations in the ED than NHWs. Only 1.7% of patients were treated with rt-PA. CONCLUSIONS: Neurologists are seldom involved with acute cerebrovascular care in the emergency department (ED), especially in patients with TIA. Greater neurologist involvement may improve acute stroke diagnosis and treatment efforts in the ED.

Aged↗

PubMed2004

Oxidative stress mechanisms and potential therapeutics in Alzheimer disease.

Oxidative damage of biological macromolecules is a hallmark of most neurodegenerative disorders such as Alzheimer, Parkinson and diffuse Lewy body diseases. Another important phenomenon involved in these disorders is the alteration of iron and copper homeostasis. Data from the literature support the involvement of metal homeostasis in mitochondrial dysfunction, protein alterations and nucleic acid damage which are relevant in brain function and consequently, in the development of neurodegenerative disorders. Although alterations in transition metal homeostasis, redox activity, and localization are well documented, it must be determined how alterations of specific copper- and iron-containing metalloenzymes are also involved in Alzheimer disease. The clarification of these phenomena can open a new window for understanding the mechanisms underlying neurodegeneration and, consequently, for the development of new therapeutic strategies such as gene therapy and new pharmaceutical formulations with antioxidant and chelating properties.

Alzheimer Disease↗

PubMed2004

Ischemic stroke subtypes among Mexican Americans and non-Hispanic whites: the BASIC Project.

Ischemic stroke subtype distribution was compared between Mexican Americans (MAs) and non-Hispanic whites (NHWs) in a community-based stroke surveillance study in Nueces County, TX. There was no difference in the distribution of stroke subtype by ethnicity (p = 0.19). There was a similar proportion of small-vessel and large-artery strokes between the two ethnic groups (p = 0.32). Differences in stroke rates among MAs and NHWs are not explained by the distribution of ischemic stroke subtypes.

Age Distribution↗

PubMed2004

The impact of PET scanning on management of paediatric oncology patients.

PURPOSE: Limited information is available on the use of positron emission tomography (PET) in paediatric oncology. The aim of this study was to review the impact of PET on the management of paediatric patients scanned over a 10-year period. METHODS: One hundred and sixty-five consecutive oncology patients aged 11 months to 17 years were included. Two hundred and thirty-seven scans were performed. Diagnoses included lymphoma (60 patients), central nervous system (CNS) tumour (59), sarcoma (19), plexiform neurofibroma with suspected malignant change (13) and other tumours (14). A questionnaire was sent to the referring clinician to determine whether the PET scan had altered management and whether overall the PET scan was thought to be helpful. RESULTS: One hundred and eighty-nine (80%) questionnaires for 126 patients were returned (63 relating to lymphoma, 62 to CNS tumours, 30 to sarcoma, 16 to plexiform neurofibroma and 18 to other tumours). PET changed disease management in 46 (24%) cases and was helpful in 141 (75%) cases. PET findings were verified by histology, clinical follow-up or other investigations in 141 cases (75%). The returned questionnaires indicated that PET had led to a management change in 20 (32%) lymphoma cases, nine (15%) CNS tumours, four (13%) sarcomas, nine (56%) plexiform neurofibromas and four (22%) cases of other tumours. PET was thought to be helpful in 47 (75%) lymphoma cases, 48 (77%) CNS tumours, 24 (80%) sarcomas, 11 (69%) neurofibromas and 11 (61%) cases of other tumours. PET findings were verified in 44 (70%) lymphoma cases, 53 (85%) CNS tumours, 21 (70%) sarcomas, 12 (75%) neurofibromas and 11 (61%) other tumour cases. CONCLUSION: PET imaging of children with cancer is accurate and practical. PET alters management and is deemed helpful (with or without management change) in a significant number of patients, and the results are comparable with the figures published for the adult oncology population.

Adolescent↗

PubMed2004

A population-based study of acute stroke and TIA diagnosis.

BACKGROUND: Acute stroke therapy is heavily dependent on the diagnostic acumen of the physician in the emergency department (ED). OBJECTIVE: To determine this diagnostic accuracy in a population-based multiethnic stroke study. METHODS: The Brain Attack Surveillance in Corpus Christi (BASIC) Project prospectively ascertained all acute stroke or TIA cases in an urban Texas county of 313,645 residents without an academic medical center. Cases were validated by board-certified neurologists using source documentation. Case validation was used as the gold standard to compare the diagnosis given by the ED physician. RESULTS: From January 2000 to August 2002, a total of 13,015 patients were screened. Of these, 1,800 were validated as stroke/TIA. Overall sensitivity of the emergency physician for the BASIC-validated diagnosis was 92%, and positive predictive value was 89%. Of the cases that the emergency physician thought were stroke, 11% were validated as no stroke. In multivariable modeling, motor symptoms was an independent predictor of protection from false-negative ED diagnosis of stroke/TIA (odds ratio [OR] = 0.61; 95% CI 0.41 to 0.89). Protection from false-positive stroke/TIA diagnosis was predicted by sensory symptoms (OR = 0.43; 95% CI 0.28 to 0.66), motor symptoms (OR = 0.44; 95% CI 0.32 to 0.62), and severe neurologic deficit (OR = 0.33; 95% CI 0.14 to 0.78). History of stroke/TIA predicted false-positive stroke diagnosis (OR = 1.72; 95% CI 1.23 to 2.40). The majority of disagreements occurred in patients with generalized neurologic or acute medical, nonneurologic syndromes. CONCLUSIONS: Physicians practicing in the ED are sensitive for stroke/TIA diagnosis. The modest positive predictive value argues for a systems approach with neurology support so that proper decisions regarding acute stroke therapy can be made.

Acute Disease↗

PubMed2004

Characterization of the G91del CRYBA1/3-crystallin protein: a cause of human inherited cataract.

Congenital cataract is a leading cause of visual disability in children. Inherited isolated (non-syndromic) cataract represents a significant proportion of cases and the identification of genes responsible for inherited cataract will lead to a better understanding of the mechanism of cataract formation at the molecular level both in congenital and age-related cataract. Crystallins are abundantly expressed in the developing human lens and represent excellent candidate genes for inherited cataract. A genome-wide search of a five-generation family with autosomal dominant lamellar cataract demonstrated linkage to the 17p12-q11 region. Screening of the CRYBA1/3 gene showed a 3 bp deletion, which resulted in a G91del mutation within the tyrosine corner, that co-segregated with disease and was not found in 96 normal controls. In order to understand the molecular basis of cataract formation, the mutant protein was expressed in vitro and its unfolding and refolding characteristics assessed using far-UV circular dichroism spectroscopy. Defective folding and a reduction in solubility were found. As the wild-type protein did not refold into the native conformation following unfolding, a corresponding CRYBB2 mutant was genetically engineered and its refolding characteristics analysed and compared with wild-type CRYBB2. Its biophysical properties support the hypothesis that removal of the glycine residue from the tyrosine corner impairs the folding and solubility of beta-crystallin proteins. This study represents the first comprehensive description of the biophysical consequences of a mutant beta-crystallin protein that is associated with human inherited cataract.

Amino Acid Sequence↗

PubMed2004

Neurofilament proteins in neurodegenerative diseases.

The function of neurofilaments, the major component in large myelinated neurons, is not well understood even though they were discovered as structures over 100 years ago. Recent studies have suggested that neuro-filaments are closely related to many neurodegenerative diseases, such as amyotrophic lateral sclerosis, Parkinson disease Alzheimer disease, and diabetes. Using in vitro assays, cultures and transgenic mice, these studies provided new insights into neurofilament function. The function of each subunit, the relationship of neurofilaments with other cytoskeletal elements and their clinical significance are topics of increasing attention.

Animals↗

PubMed2004

TNF-alpha expression patterns as potential molecular biomarker for human skin cells exposed to vesicant chemical warfare agents: sulfur mustard (HD) and Lewisite (L).

Studies were conducted to examine the effect of two vesicant chemical warfare agents (VCWA), one of them an arsenical, on cytokine gene expression in normal human epidermal keratinocyte (NHEK) cells. We tested 2,2'-dichlorethylsulfide (sulfur mustard, military designation HD) and 2,chlorovinyldichloroarsine (Lewisite, military designation L), which have significant differences in their chemical, physical, and toxicological properties. Human tumor necrosis factor-alpha (hTNF-alpha) cytokine was detected by using the enzyme-linked immunosorbent assay, a protein multiplex immunoassay, Luminex100, and reverse transcription-polymerase chain reaction (RT-PCR). The messenger RNA expression of hTNF-alpha was determined to provide a semi-quantitative analysis. HD-stimulated NHEK induced secretion of hTNF-alpha in a dose-dependent manner. Dose response effect of Lewisite decreased hTNF-alpha levels. Time-response data indicated that the maximum response for HD occurred at 24 h with an associated cytotoxic concentration of 10(-4) mol/L. NHEK cells stimulated with 10(-4) mol/L HD for 24 h at 37 degrees C increased detectable levels of hTNF-alpha from 5 to 28 ng/ml at an index of cell viability between 85 to 93% as detected by Luminex100. Our results indicated that the increased levels of hTNF-alpha by HD are dependent on the primary cultures, cell densities, and chemical properties of the stimulation. Lewisite under the same conditions as HD caused a reduction of hTNF-alpha from control levels of 1.5 ng/ml to 0.3 ng/ml after stimulation (10(-4) mol/L), with an index of cell viability of reverse similar 34%. We analyzed the transcriptional of hTNF-alpha gene and found that HD (10(-6) to 10(-4) mol/L) activates hTNF-alpha gene in cultured NHEK and that L at 10(-6) to 10(-4) mol/L markedly reduces hTNF-alpha gene. We conclude that the pro-inflammatory mediator, hTNF-alpha, could be a potential biomarker for differentiating between exposure of HD or L.

Adult↗

PubMed2004

Proliferative responses observed following vancomycin treatment in renal proximal tubule epithelial cells.

Vancomycin (VAN) is a glycopeptide antibiotic used to treat gram-positive infections. Nephrotoxicity is a common side effect observed with vancomycin therapy. However, the mechanism of vancomycin-induced nephrotoxicity has not been fully characterized. In this study we examined the effect of vancomycin on cellular proliferation in renal proximal tubule cells. A dose- and time-dependent increase in cell number and total cellular protein was observed following vancomycin exposure. Vancomycin exposure also caused an increase in BrdU incorporation followed by the accumulation of renal proximal tubule cells in G(2)/M phase of the cell cycle. These effects were inhibited by pretreatment with the mitogen-activated protein kinase inhibitor, PD098059, suggesting an association between the cell proliferative effect of VAN and the induction of the mitogen-activated protein kinase signaling pathway. Mitochondrial function in renal proximal tubule cells was assessed using oxygen consumption and ATP concentrations. We observed an increase in oxygen consumption and ATP concentrations following short-term exposure to vancomycin. Together, our data suggest that vancomycin treatment produces alterations in mitochondrial function that coincide with a cell proliferative response in renal proximal tubule epithelial cells.

Adenosine Triphosphate↗

PubMed2004

The p53 homologue p73 accumulates in the nucleus and localizes to neurites and neurofibrillary tangles in Alzheimer disease brain.

The molecular mechanisms that regulate neuronal survival vs. death during Alzheimer disease (AD) remain unclear. Nonetheless, a number of recent studies indicate that increased expression or altered subcellular distribution of numerous cell cycle proteins during AD may contribute to disease pathogenesis. Because homologues of p53, a key regulatory protein in the cell cycle, such as p73, have been identified and shown to participate in cellular differentiation and death pathways, we examined the expression and distribution of p73 in the hippocampus of eight control and 16 AD subjects. In control subjects, hippocampal pyramidal neurones exhibit p73 immunoreactivity that is distributed predominately in the cytoplasm. In AD hippocampus, increased levels of p73 are located in the nucleus of pyramidal neurones and p73 is located in dystrophic neurites and cytoskeletal pathology. Immunoblot analysis confirmed the presence of p73 in the hippocampus. These data indicate that p73 is expressed within hippocampal pyramidal neurones and exhibits altered subcellular distribution in AD.

Aged↗

PubMed2004

Phylogeography of Bufo fowleri at its northern range limit.

Many of the species that recolonized previously glaciated areas in the Great Lakes basin of North America over the past 10-12,000 years exhibit genetic evidence of multiple invasion routes and present-day secondary contact between deeply divergent lineages. With this in mind, we investigated the phylogeographical structure of genetic variability in Fowler's toads (Bufo fowleri) at the northern edge of its distribution where its range encircles the Lake Erie basin. Because B. fowleri is so closely tied to habitats along the Lake Erie shoreline, we would expect to find clear evidence of the number of invasions leading to the species' colonization of the northern shore. A 540 bp sequence from the mitochondrial control region was amplified and analysed for 158 individuals from 21 populations. Interpopulation sequence variation ranged from 0% to 6%. Phylogenetic analysis of p-distance using the neighbor-joining method revealed two deeply divergent (6% sequence divergence) mtDNA lineages (Phylogroup 1 and 2), possibly arising as a result of secondary contact of populations that entered the region from two separate glacial refugia. However, the phylogeographical pattern was not simple. The populations at Long Point, on the north shore of Lake Erie, clustered with the population from Indiana Dunes on Lake Michigan to form Phylogroup 2 whereas all other B. fowleri populations examined from both sides of Lake Erie constituted Phylogroup 1. Furthermore, mtDNA sequences from the related species Bufo americanus, obtained from populations outside the range of B. fowleri, clustered with mtDNA haplotypes of B. fowleri Phylogroup 1, indicating the possibility of partial introgression of mitochondria from one species to the other.

Analysis of Variance↗

PubMed2004

Hypoxia tolerance in mammalian heterotherms.

Heterothermic mammals tolerate severe hypoxia, as well as a variety of central nervous system insults, better than homeothermic mammals. Tolerance to hypoxia may stem from adaptations associated with the ability to survive hibernation and periodic arousal thermogenesis. Here, we review evidence and mechanisms of hypoxia tolerance during hibernation, euthermy and arousal in heterothermic mammals and consider potential mechanisms for regenerative-like processes, such as synaptogenesis, observed within hours of hypoxic stress associated with arousal thermogenesis.

Adaptation, Physiological↗

PubMed2004

Mitotic and gender parallels in Alzheimer disease: therapeutic opportunities.

In this review, we discuss the role of cell cycle dysfunction in the pathogenesis of Alzheimer disease and propose that such mitotic catastrophe, as one of the earliest events in neuronal degeneration, may, in fact, be sufficient to initiate the neurodegenerative cascade. The question as to what molecule initiates cell cycle dysfunction is now beginning to become understood and, in this regard, the gender-predication, age-related penetrance and regional susceptibility of specific neuronal populations led us to consider luteinizing hormone as a key mediator of the abnormal mitotic process. As such, agents targeted toward luteinizing hormone or downstream sequelae may be of great therapeutic value in the treatment of Alzheimer disease.

Alzheimer Disease↗

PubMed2004

Agonist and antagonist effects of benzodiazepines on motor performance: influence of intrinsic efficacy and task difficulty.

Previous studies have shown that low-efficacy benzodiazepines may function as full agonists, partial agonists or antagonists, depending upon the sensitivity of the assay to detect a drug's agonist effects. To date, these differential effects have only been observed across tasks, as these drugs rarely produce full agonist and antagonist effects in a single preparation. The purpose of the present study was to examine the agonist and antagonist effects of various benzodiazepines in a motor task in which the sensitivity of the task differed across conditions. To this end, rats were trained to walk on a rotorod apparatus rotating at low (4 rpm), medium (20 rpm) and high (36 rpm) speeds, and the motor-impairing effects of representative low (bretazenil), intermediate (clonazepam) and high (diazepam) efficacy benzodiazepines were examined. Diazepam and clonazepam reduced the latency for rats to fall from the rotorod at all three speeds, with both drugs being more potent at the high speed than at lower speeds. Bretazenil was also effective at decreasing motor performance at the high speed, but was not effective at lower speeds. In drug combination tests, bretazenil antagonized the effects of diazepam and clonazepam under conditions in which it was not effective when administered alone, effectively demonstrating both full agonist and antagonist effects in the same preparation. These data indicate that the sensitivity of a motor task to detect a drug's agonist effects can be manipulated by altering its relative level of difficulty, and that lower-efficacy benzodiazepines are more sensitive than higher-efficacy benzodiazepines to these manipulations.

Animals↗

PubMed2003

Oxidative stress and predominant Abeta42(43) deposition in myopathies with rimmed vacuoles.

This study was undertaken to determine the C terminus of amyloid beta protein (Abeta), accumulated in vacuolated muscle fibers, and compare these findings to the level of oxidative stress. Eight patients with myopathies characterized by rimmed vacuoles (RVs) were analyzed. Monoclonal antibodies specific to Abeta40 or Abeta42(43) revealed that the Abeta42(43) immunoreactivity was solely distributed in the vacuolated muscle fibers, and that only a part was also immunopositive for anti-Abeta40. Quantitative analyses in four specimens, in which eight or more vacuolated muscle fibers were observed, revealed that the mean incidence of Abeta42(43)-positive muscle fibers was 79.5+/-6.2% in total vacuolated muscle fibers, whereas that of the Abeta40-positive fibers was 42.9+/-12.6%. The predominance of Abeta42(43) deposition was statistically significant ( P<0.05). Abeta deposition was then compared with the distribution of oxidative nucleic acid damage in muscle fibers using a monoclonal antibody against 8-hydroxy-2'-deoxyguanosine and 8-hydroxyguanosine (8OHdG&G). The cytoplasmic staining for anti-8OHdG&G was found not only in vacuolated muscle fibers, but also in other muscle fibers including morphologically normal ones. Positive staining was completely abolished by RNase pretreatment and, thus, was suggested to reflect an increase of cellular RNA oxidation. The distribution of 8OHdG&G was much broader than the Abeta deposition. These data suggest that Abeta42(43) is predominantly involved in the pathogenesis of muscle fiber degeneration with RVs, and that oxidative damage may precede Abeta deposition in muscle fibers and play a key role in the pathomechanism of myopathies with RVs.

Adult↗