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Biomedical subjects

T S Smith

Publications and source records attributed to T S Smith.

At least 19 recordsLinked to original sources
PubMed2006

Cortical bone viscoelasticity and fixation strength of press-fit femoral stems: an in-vitro model.

Cementless total hip femoral components rely on press-fit for initial stability and bone healing and remodeling for secondary fixation. However, the determinants of satisfactory press-fit are not well understood. In previous studies, human cortical bone loaded circumferentially to simulate press-fit exhibited viscoelastic, or time dependent, behavior. The effect of bone viscoelastic behavior on the initial stability of press-fit stems is not known. Therefore, in the current study, push-out loads of cylindrical stems press-fit into reamed cadaver diaphyseal femoral specimens were measured immediately after assembly and 24 h with stem-bone diametral interference and stem surface treatment as independent variables. It was hypothesized that stem-bone interference would result in a viscoelastic response of bone that would decrease push-out load thereby impairing initial press-fit stability. Results showed that push-out load significantly decreased over a 24 h period due to bone viscoelasticity. It was also found that high and low push-out loads occurred at relatively small amounts of stem-bone interference, but a relationship between stem-bone interference and push-out load could not be determined due to variability among specimens. On the basis of this model, it was concluded that press-fit fixation can occur at relatively low levels of diametral interference and that stem-bone interference elicits viscoelastic response that reduces stem stability over time. From a clinical perspective, these results suggest that there could be large variations in initial press-fit fixation among patients.

Adult↗
PubMed2005

MRS of oligodendroglial tumors: correlation with histopathology and genetic subtypes.

BACKGROUND: Oligodendroglial neoplasms with combined loss of chromosomes 1p and 19q may have a good prognosis and respond to procarbazine-lomustine (CCNU)-vincristine (PCV) chemotherapy. OBJECTIVE: To determine whether single voxel magnetic resonance spectroscopy (SV-MRS) obtained through routine clinical practice distinguishes between histopathologic and genetic subtypes of oligodendroglial tumors. METHODS: Forty-eight patients with oligodendroglial tumors (19 oligodendrogliomas and 29 oligoastrocytomas) underwent molecular genetic analysis to determine allelic imbalance in chromosomes 1p36 and 19q13. SV-MRS was obtained pretherapy to determine tumor metabolite ratios. RESULTS: Grade III oligodendroglial tumors had higher choline (Mann-Whitney; p = 0.002), methyl lipid (Mann-Whitney; p = 0.002), and combined methylene lipid and lactate ratios (Mann-Whitney; p < 0.001) than grade II tumors. Lactate did not distinguish between tumor types (Fisher exact test; p = 0.342) or grade (Fisher exact test; p = 0.452). There were no significant associations when tumors were analyzed according to histopathology or genetic subtypes. CONCLUSION: As a noninvasive diagnostic tool used in routine clinical practice, SV-MRS has the potential benefit of determining oligodendroglial tumor grade but not subtypes classified by histopathology or molecular genetics. MRS may be useful for determining the timing of therapy but is unlikely to predict chemosensitivity.

Adult↗
PubMed2005

An orientation distribution function for trabecular bone.

We describe a new method for quantifying the orientation of trabecular bone from three-dimensional images. Trabecular lattices from five human vertebrae were decomposed into individual trabecular elements, and the orientation, mass, and thickness of each element were recorded. Continuous functions that described the total mass (M(phi,theta)) and mean thickness (tau(phi,theta)) of all trabeculae as a function of orientation were derived. The results were compared with experimental measurements of the elastic modulus in three principal anatomic directions. A power law scaling relationship between the anisotropies in mass and elastic modulus was observed; the scaling exponent was 1.41 (R2=0.88). As expected, the preponderance of trabecular mass was oriented along the cranial-caudal direction; on average, there was 3.4 times more mass oriented vertically than horizontally. Moreover, the vertical trabeculae were 30% thicker, on average, than the horizontal trabeculae. The vertical trabecular thickness was inversely related to connectivity (R2=0.70; P=0.07), suggesting a possible organization into either few, thick trabeculae or many thin trabeculae. The method, which accounts for the mechanical connectedness of the lattice, provides a rapid way to both visualize and quantify the three-dimensional organization of trabecular bone.

Aged↗
PubMed2001

S1 screw bending moment with posterior spinal instrumentation across the lumbosacral junction after unilateral iliac crest harvest.

STUDY DESIGN: A biomechanical study comparing fixation across the lumbosacral junction. OBJECTIVES: To determine which long posterior construct across the lumbosacral junction produces the least bending moment on the S1 screw when only one ilium is available for fixation. SUMMARY OF BACKGROUND DATA: Recent in vitro studies have demonstrated the benefit of anterior support and fixation into the ilium when instrumenting a long posterior construct across the lumbosacral junction. METHODS: Four L2-sacrum constructs were tested on six synthetic models of the lumbar spine and pelvis simulating that the right ilium had been harvested. Construct 1: L2-S1 bilateral screws. Construct 2: L2-S1 + left iliac bolt. Construct 3: L2-S1 + left iliac bolt + right S2 screw. Construct 4: L2-S1 + bilateral S2 screws. The four constructs were then retested with an anterior L5-S1 strut. A flexion-extension moment was applied across each construct, and the moment at the left and right S1 pedicle screw was measured with internal strain gauges. RESULTS: Iliac bolt fixation was found to significantly decrease the flexion-extension moment on the ipsilateral S1 screw by 70% and the contralateral screw by 26%. An anterior L5-S1 strut significantly decreased the S1 screw flexion-extension moment by 33%. Anterior support at L5-S1 provided no statistical decrease in the flexion-extension moment when bilateral posterior fixation beyond S1 was present with either a unilateral iliac bolt and contralateral S2 screw, or bilateral S2 screws. CONCLUSIONS: There is a significant decrease in the flexion-extension moment on the S1 screw when extending long posterior constructs to either the ilium or S2 sacral screw. There is no biomechanical advantage of the iliac bolt over the S2 screw in decreasing the moment on the S1 screw in flexion and extension. Adding anterior support to long posterior constructs significantly decreases the moment on the S1 screw. Adding distal posterior fixation to either the ilium or S2 decreases the moment on S1 screws more than adding anterior support. Further, adding anterior support when bilateral distal fixation past S1 is already present does not significantly decrease the moment on the S1 screws in flexion and extension.

Bone Screws↗
PubMed2001

Three-dimensional microimaging (MRmicroI and microCT), finite element modeling, and rapid prototyping provide unique insights into bone architecture in osteoporosis.

With the proportion of elderly people increasing in many countries, osteoporosis has become a growing public health problem, with rising medical, social, and economic consequences. It is well recognized that a combination of low bone mass and the deterioration of the trabecular architecture underlies osteoporotic fractures. A comprehensive understanding of the relationships between bone mass, the three-dimensional (3D) architecture of bone and bone function is fundamental to the study of new and existing therapies for osteoporosis. Detailed analysis of 3D trabecular architecture, using high-resolution digital imaging techniques such as magnetic resonance microimaging (MRmicroI), micro-computed tomography (microCT), and direct image analysis, has become feasible only recently. Rapid prototyping technology is used to replicate the complex trabecular architecture on a macroscopic scale for visual or biomechanical analysis. Further, a complete set of 3D image data provides a basis for finite element modeling (FEM) to predict mechanical properties. The goal of this paper is to describe how we can integrate three-dimensional microimaging and image analysis techniques for quantitation of trabecular bone architecture, FEM for virtual biomechanics, and rapid prototyping for enhanced visualization. The integration of these techniques provide us with an unique ability to investigate the role of bone architecture in osteoporotic fractures and to support the development of new therapies.

Aged↗
PubMed2001

Identification, genomic organization, and mRNA expression of LACTB, encoding a serine beta-lactamase-like protein with an amino-terminal transmembrane domain.

Database searching with bacterial serine beta-lactamases identified mouse expressed sequence tags (ESTs) with significant similarity scores.The cloned mouse cDNA encodes a novel 551-amino-acid protein, LACTB, with a predicted amino-terminal transmembrane domain but no signal peptide. It contains an active site motif related to C-class beta-lactamases. Homologues were detected in sequence data from human, rat, cow, rabbit, pig, toad, zebrafish, and Caenorhabditis elegans, but not in Saccharomyces cerevisiae or Drosophila melanogaster. The genes were mapped to human chromosome 15q22.1 and mouse chromosome 9. Sequencing of a 14.7-kb fragment of mouse genomic DNA defined six exons. A virtual human cDNA and a 549-residue protein, predicted from unfinished genomic sequence, showed the same intron/exon structure. Northern blot analysis showed expression of the 2.3-kb mRNA predominantly in mouse liver and human skeletal muscle. This is the first reported vertebrate example of this microbial peptidase family.

Amino Acid Sequence↗
PubMed2001

Neurotoxic Abeta peptides increase oxidative stress in vivo through NMDA-receptor and nitric-oxide-synthase mechanisms, and inhibit complex IV activity and induce a mitochondrial permeability transition in vitro.

Beta amyloid (Abeta) peptides accumulate in Alzheimer's disease and are neurotoxic possibly through the production of oxygen free radicals. Using brain microdialysis we characterized the ability of Abeta to increase oxygen radical production in vivo. The 1-40 Abeta fragment increased 2,3-dehydroxybenzoic acid efflux more than the 1-28 fragment, in a manner dependent on nitric oxide synthase and NMDA receptor channels. We then examined the effects of Abeta peptides on mitochondrial function in vitro. Induction of the mitochondrial permeability transition in isolated rat liver mitochondria by Abeta(25-35) and Abeta(35-25) exhibited dose dependency and required calcium and phosphate. Cyclosporin A prevented the transition as did ruthenium red, chlorpromazine, or N-ethylmaleimide. ADP and magnesium delayed the onset of mitochondrial permeability transition. Electron microscopy confirmed the presence of Abeta aggregates and swollen mitochondria and preservation of mitochondrial structure by inhibitors of mitochondrial permeability transition. Cytochrome c oxidase (COX) activity was selectively inhibited by Abeta(25-35) but not by Abeta(35-25). Neurotoxic Abeta peptide can increase oxidative stress in vivo through mechanisms involving NMDA receptors and nitric oxide sythase. Increased intracellular Abeta levels can further exacerbate the genetically driven complex IV defect in sporadic Alzheimer's disease and may precipitate mitochondrial permeability transition opening. In combination, our results provide potential mechanisms to support the feed-forward hypothesis of Abeta neurotoxicity.

Amyloid beta-Peptides↗
PubMed2001

Does the aggressive use of polyvalent antivenin for rattlesnake bites result in serious acute side effects?

OBJECTIVE: To determine the incidence and severity of acute side effects from the use of polyvalent antivenin in victims of rattlesnake bites. DESIGN: We retrospectively reviewed the records of all patients who presented with rattlesnake bites to a university teaching hospital during an 11-year period. From patient medical records, we extracted demographic data, clinical measurements, and outcomes during emergency department evaluation and subsequent hospitalization. Data regarding serum sickness were not collected. OUTCOME MEASURES: Primary outcome variables were the occurrence of immediate hypersensitivity reaction to antivenin, the type of reaction, permanent disability at hospital discharge, and mortality. RESULTS: We identified a total of 73 patients with rattlesnake bites during the study period. Bite envenomation was graded as nonenvenomated, 7 patients (10%); mild, 23 patients (32%); moderate, 32 patients (44%); and severe, 11 patients (15%). We identified 65 patients who received antivenin. Antivenin doses ranged from 1 to 30 vials per patient (mean, 12.0 +/- 6.0), for a total of 777 vials. In 43 patients (66%), 10 or more vials of antivenin were given. The mean number of vials of antivenin given to each snakebite grade were as follows: mild, 8.4 (+/-4.0); moderate, 11.8 (+/-5.7); and severe, 18.7 (+/-6.3). No deaths, amputations, or permanent disability from snakebite occurred in the patients receiving antivenin. Acute side effects of antivenin-occurring within the first 6 hours after administration-were seen in 12 patients (18%; 95% confidence interval, 10%-30%). Acute side effects consisted solely of urticaria in all but 1 patient (2%; 95% confidence interval, 0%-8%). This patient had a history of previous antivenin reaction and required a short course of intravenous epinephrine for blood pressure support. No other complications occurred. CONCLUSION: The administration of polyvalent Crotalidae antivenin is safe. Acute hypersensitivity, when it occurs, consists solely in most cases of urticaria. Serious side effects are uncommon.

Adolescent↗
PubMed2000

Sequencing, tissue distribution and chromosomal assignment of a novel ubiquitin-specific protease USP23.

We have identified human and mouse cDNAs encoding a novel ubiquitin-specific protease designated USP23. Both cDNAs encode a 62-kDa protein containing the highly conserved His and Cys domains characteristic of the C19 cysteine protease family of ubiquitin-specific processing proteases (UCH-2). Human tissue Northern blots revealed USP23 to be ubiquitously expressed, whereas USP12, its closest human paralogue, displayed a more restricted expression pattern. The human USP23 gene mapped to chromosome 1q22.

Amino Acid Sequence↗
PubMed1999

Molecular interaction of Agouti protein and Agouti-related protein with human melanocortin receptors.

Agouti protein and the Agouti-related protein (AGRP) are antagonists of the melanocortin-3 receptor and melanocortin-4 receptor. Both proteins contain 10 cysteines in the C-terminal domain arranged in five disulfide bonds. One possible arrangement of the disulfide bonds predicts an octapeptide loop, and the chemical properties of four residues within this loop (residues 111-114 in human AGRP) bear striking resemblance to those of several melanocortin peptides, including alpha-MSH, MT-II, and SHU-9119. We showed that cyclic synthetic octapeptides based on the sequence of this loop from Agouti protein or human AGRP are functional antagonists of the human melanocortin-4 receptor. All peptides had a lower affinity for the melanocortin-3 receptor than for the melanocortin-4 receptor. Substitution of serines for cysteines resulted in linear peptides which had reduced binding affinities for both receptors. Mutational analysis of human AGRP indicated that its C-terminal domain is functionally equivalent to the intact human AGRP. The RFF111-113 triplet appears to be the most critical portion of AGRP in determining the binding affinity for both melanocortin-3 and melanocortin-4 receptors. These data strongly suggest that the loop defined by Cys-110 and Cys-117 is critical in determining the antagonist activity of human AGRP. Our data provide indirect evidence for the suggestion that the Cys-110 to Cys-117 octapeptide loop of human AGRP mimics the conformation of alpha-MSH, MT-II, and SHU-9119.

Agouti Signaling Protein↗
PubMed1999

Effects of single and multiple treatments with L-dihydroxyphenylalanine (L-DOPA) on dopamine receptor-G protein interactions and supersensitive immediate early gene responses in striata of rats after reserpine treatment or with unilateral nigrostriatal lesions.

We studied effects of L-dihydroxyphenylalanine (L-DOPA) treatment in rats following reserpine treatment or unilateral 6-hydroxydopamine (6-OHDA) injections into medial forebrain bundle. Quantitative in situ hybridization for mRNA's coding for the zinc finger immediate early gene (IEG) zif/268 or Jun family IEG jun b revealed that single L-DOPA injections accentuated IEG expression 3- to 7-fold in the dopamine (DA)-depleted striatum. This increased IEG response did not derive from any alterations in DA receptor-G protein coupling, assayed by DA stimulation of 35S-guanosine-5' (gamma-thio) triphosphate (35S-GTP-gamma-S) binding to striatal sections. Reserpine treatment increased both basal and maximal striatal DA-stimulated 35S-GTP-gamma-S binding. The augmented IEG responses to single L-DOPA treatments involved dependency on both D1 and D2 receptors and acutely to N-methyl-D-aspartate (NMDA) channels. Repetitive L-DOPA treatments yielded persistently elevated (zif/268) or additionally up-regulated (jun b) IEG response in the denervated striatum and down-regulated IEG responses in the control striatum. Degraded L-DOPA responses and appearance of involuntary movements after chronic L-DOPA use in advanced Parkinson's disease may derive from these IEG changes.

Animals↗
PubMed1999

Characteristics of pedicle screw loading. Effect of surgical technique on intravertebral and intrapedicular bending moments.

STUDY DESIGN: A static nondestructive bending analysis of pedicle screws inserted into vertebral analogues was conducted. Pedicle screw load was studied as a function of variables in insertion technique. OBJECTIVES: To determine how the sagittal bending moment in pedicle screws is affected by changes in pedicle screw length, insertional depth, and sagittal placement. BACKGROUND DATA: An unexpectedly high rate of clinical failure has been observed in pedicle screws used in short-segment instrumentation for unstable burst fractures. The majority of screws fail in sagittal bending within the pedicle. Little is known of the insertion technical factors that affect in situ loads incurred by pedicle screws. METHODS: Synthetic vertebral analogues were fabricated. Pedicle screws internally instrumented with strain gauges were used as load transducers to determine screw bending moments within the pedicle and body of the analogue. Analogues were loaded in compression to simulate loading of an unstable burst fracture. RESULTS: Screw bending moments within the pedicle increased 33% and 52% when screws were left 3 mm and 5 mm short of full insertion. Intrapedicular moments increased 20% to 29% in screws inserted superiorly or inferiorly within the pedicle. Thirty-five-millimeter screws developed intrapedicular moments 16% higher than 40-mm and 45-mm screws. CONCLUSIONS: In situ pedicle screw loads increased significantly as a direct result of variations in surgical technique. Screws left short of full insertion, placed off center in the sagittal plane of the pedicle, or less than 40 mm long developed increased intrapedicular bending moments.

Bone Screws↗
PubMed1999

Identification of a novel aspartic protease (Asp 2) as beta-secretase.

The Alzheimer's disease beta-amyloid peptide (Abeta) is produced by excision from the type 1 integral membrane glycoprotein amyloid precursor protein (APP) by the sequential actions of beta- and then gamma-secretases. Here we report that Asp 2, a novel transmembrane aspartic protease, has the key activities expected of beta-secretase. Transient expression of Asp 2 in cells expressing APP causes an increase in the secretion of the N-terminal fragment of APP and an increase in the cell-associated C-terminal beta-secretase APP fragment. Mutation of either of the putative catalytic aspartyl residues in Asp 2 abrogates the production of the fragments characteristic of cleavage at the beta-secretase site. The enzyme is present in normal and Alzheimer's disease (AD) brain and is also found in cell lines known to produce Abeta. Asp 2 localizes to the Golgi/endoplasmic reticulum in transfected cells and shows clear colocalization with APP in cells stably expressing the 751-amino-acid isoform of APP.

Alzheimer Disease↗
PubMed1998

Napsins: new human aspartic proteinases. Distinction between two closely related genes.

cDNA sequences were elucidated for two closely related human genes which encode the precursors of two hitherto unknown aspartic proteinases. The (pro)napsin A gene is expressed predominantly in lung and kidney and its translation product is predicted to be a fully functional, glycosylated aspartic proteinase (precursor) containing an RGD motif and an additional 18 residues at its C-terminus. The (pro)napsin B gene is transcribed exclusively in cells related to the immune system but lacks an in-frame stop codon and contains a number of polymorphisms, one of which replaces a catalytically crucial Gly residue with an Arg. Consideration is given to whether (pro)napsin B may be a transcribed pseudogene or whether its putative protein product undergoes rapid intracellular degradation.

Amino Acid Sequence↗
PubMed1998

Phase 2 studies of adenosine cardioplegia.

BACKGROUND: Laboratory evidence supports the use of adenosine-supplemented cardioplegia. An initial phase 1 dose-ranging clinical evaluation demonstrated that an adenosine concentration of 15 mumol/L could be safely administered with warm blood cardioplegia and suggested that phase 2 studies were warranted. METHODS AND RESULTS: Two separate double-blind, randomized, placebo-controlled trials were performed in patients undergoing primary, isolated, nonemergent coronary artery bypass graft surgery. Patients were randomized to receive adenosine 15 mumol/L versus placebo in the first study (n = 200) and adenosine 50 or 100 mumol/L versus placebo in the second study (n = 128). Adenosine was infused with both initial and final doses of warm antegrade blood cardioplegia. The data from the 2 trials were combined using the methods of Mantel and Haenszel, and the results of the meta-analysis are presented as the relative risk with their associated 95% confidence intervals (CI). The different study groups were comparable with respect to all preoperative clinical characteristics, angiographic findings, and intraoperative variables. In both trials 1 and 2, no differences were found between groups in the incidence of the individual primary or secondary outcomes. Similarly, when both studies were combined, there was no significant evidence of any consistent treatment benefit (primary: death: relative risk [RR] = 1.02, 95% CI = 0.06, 16.6; myocardial infarction by CK-MB: RR = 0.84, CI = 0.54, 1.31; low output syndrome: RR = 1.38, CI = 0.29, 6.42; any of the above: RR = 0.98, CI = 0.78, 1.25; secondary: Q-wave myocardial infarction: RR = 1.30, CI = 0.41, 4.13; myocardial infarction by troponin T: RR = 0.7, CI = 0.40, 1.21; inotrope requirement: RR = 0.9, CI = 0.46, 1.79; intra-aortic balloon pump requirement: RR = 0.6, CI = 0.07, 4.81; P > 0.20). CONCLUSIONS: Despite promising experimental data, adenosine supplementation of warm blood cardioplegia did not demonstrate any statistically significant benefit in patients undergoing elective coronary artery bypass graft surgery. Although sample sizes were relatively small, based on our interim analyses, it is unlikely that increased patient enrollment would reveal any substantive clinical differences between groups.

Adenosine↗
PubMed1998

Pramipexole reduces reactive oxygen species production in vivo and in vitro and inhibits the mitochondrial permeability transition produced by the parkinsonian neurotoxin methylpyridinium ion.

Sporadic Parkinson's disease is associated with a defect in the activity of complex I of the mitochondrial electron transport chain. This electron transport chain defect is transmitted through mitochondrial DNA, and when expressed in host cells leads to increased oxygen free radical production, increased antioxidant enzyme activities, and increased susceptibility to programmed cell death. Pramipexole, a chemically novel dopamine agonist used for the treatment of Parkinson's disease symptoms, possesses antioxidant activity and is neuroprotective toward substantia nigral dopamine neurons in hypoxic-ischemic and methamphetamine models. We found that pramipexole reduced the levels of oxygen radicals produced by methylpyridinium ion (MPP+) both when incubated with SH-SY5Y cells and when perfused into rat striatum. Pramipexole also exhibited a concentration-dependent inhibition of opening of the mitochondrial transition pore induced by calcium and phosphate or MPP+. These results suggest that pramipexole may be neuroprotective in Parkinson's disease by attenuating intracellular processes such as oxygen radical generation and the mitochondrial transition pore opening, which are associated with programmed cell death.

1-Methyl-4-phenylpyridinium↗