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T S Smith

Publications and source records attributed to T S Smith.

At least 37 records · Page 2Linked to original sources

Pathomechanics of closed rupture of the flexor tendon pulleys in rock climbers.

We performed a study on twenty-one cadaveric fingers (seven non-paired forearms) to determine the pathomechanics of closed traumatic rupture of the flexor tendon pulleys in rock climbers. The ages of the individuals at the time of death ranged from sixty-one to eighty-four years (mean, seventy-four years). The forearm was placed in a custom-made loading apparatus, and individual fingers were tested separately under simulated in vivo loading conditions. The flexor digitorum superficialis and profundus tendons of each digit were attached to computer-controlled linear stepper motors that were equipped with force transducers, and the force in the tendons was simultaneously increased until avulsion of the tendons or osseous failure occurred. The force in the tendons, the excursion of the tendons, and the force at the fingertip were measured. Damage to the pulleys and bowstringing of the tendons were visualized with a fiberoptic camera. Two fingers fractured before complete rupture of the pulleys. Seventeen of the remaining nineteen fingers sustained an isolated rupture of either the A2 or the A4 pulley as the initial failure event; the A4 pulley ruptured first in fourteen digits (p < 0.001). The A3 and A4 pulleys ruptured simultaneously in one finger, and the A2, A3, and A4 pulleys ruptured simultaneously in another. Subtle bowstringing of the flexor digitorum profundus tendon occurred only after two consecutive pulleys had ruptured (either the A2 and A3 pulleys or the A3 and A4 pulleys). Rupture of all three pulleys was required to produce obvious bowstringing. Isolated rupture of the A2 or A4 pulley did not result in detectable bowstringing of the flexor digitorum profundus tendon. The A1 pulley always remained intact.

Aged↗

Elevated reactive oxygen species and antioxidant enzyme activities in animal and cellular models of Parkinson's disease.

The dopaminergic neurotoxin N-methyl,4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) causes a syndrome in primates and humans which mimics Parkinson's disease (PD) in clinical, pathological, and biochemical findings, including diminished activity of complex I in the mitochondrial electron transport chain. Reduced complex I activity is found in sporadic PD and can be transferred through mitochondrial DNA, suggesting a mitochondrial genetic etiology. We now show that MPTP treatment of mice and N-methylpyridinium (MPP+) exposure of human SH-SY5Y neuroblastoma cells increases oxygen free radical production and antioxidant enzyme activities. Cybrid cells created by transfer of PD mitochondria exhibit similar characteristics; however, PD cybrids' antioxidant enzyme activities are not further increased by MPP+ exposure, as are the activities in control cybrids. PD mitochondrial cybrids are subject to metabolic and oxidative stresses similar to MPTP parkinsonism and provide a model to determine mechanisms of oxidative damage and cell death in PD.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

Mitochondrial toxins in models of neurodegenerative diseases. I: In vivo brain hydroxyl radical production during systemic MPTP treatment or following microdialysis infusion of methylpyridinium or azide ions.

Mitochondrial electron transport chain (ETC) function is selectively reduced in multiple tissues, including brain, from patients with Parkinson's disease (PD) and Alzheimer's disease (AD). The ETC defects are specific to each illness, involve complex I in PD and complex IV in AD, are transferable with mitochondrial DNA (mtDNA) and lead to increased production of reactive oxygen species (ROS) in mtDNA-deficient clonal neuronal cells hybridized with mtDNA ('cybrids') from PD or AD patients. C57BL/6 mice treated with MPTP developed elevated tissue hydroxyl radical ('OH) levels in striatum and ventral midbrain but not cerebellum. In brain microdialysis in awake rats, striatal 'OH output increased 3-5-fold after infusion of methylpyridinium ion (MPP+), a complex I inhibitor, or sodium azide, a complex IV inhibitor. Elevated 'OH after MPP+ was blocked stereospecifically by infusion of the nitric oxide synthase (NOS) inhibitor nitro-L-arginine or by the NMDA channel blocker MK801. Neither NOS inhibition nor NMDA blockade altered azide-induced 'OH production. ETC inhibition in vivo increases production of toxic 'OH, but the underlying mechanisms vary as a function of which ETC complex is inhibited. These results support the concept of developing oxygen free radical scavengers for both AD and PD and further suggest that inhibition of NOS and blockade of NMDA receptor function may alter progression of idiopathic PD.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

Mitochondrial toxins in models of neurodegenerative diseases. II: Elevated zif268 transcription and independent temporal regulation of striatal D1 and D2 receptor mRNAs and D1 and D2 receptor-binding sites in C57BL/6 mice during MPTP treatment.

Sporadic Parkinson's disease (PD) may arise from a defect in complex I of the mitochondrial electron transport chain (ETC), transmitted through mitochondrial DNA mutations. The N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of experimental PD is believed to arise from loss of complex I activity in dopamine (DA) neurons after accumulation of MPP+, a potent complex I inhibitor and the two electron monoamine oxidase B oxidation product of MPTP. Acute MPP+ infusion into striatum, possibly mimicking the in vivo situation after MPTP treatment, increases release of DA and production of hydroxyl radical (-OH). We treated C57BL/6 mice with MPTP and followed the expression of the immediate-early gene zif268 in striatum as a marker of DA synaptic activity, determined the pharmacology of its activation during MPTP toxicity, and assayed the time course of MPTP effects on striatal DA transporter (DAT), and D1 and D2 DA receptor-binding sites and their mRNAs. MPTP (24 mg/kg b.i.d. for 4 doses) increased striatal zif268 expression, with peak effects observed 24 h after starting MPTP. Increased striatal zif268 was dependent mainly on DA D1 and to a lesser extent on non-NMDA glutamate receptors and was not altered by inhibition of nitric oxide synthase (NOS). Our MPTP schedule resulted in a loss of about one-third of nigral DA neurons. We observed with [3H]mazindol autoradiography that loss of striatal DAT sites after starting MPTP was heterogenous and greatest in centromedial striatum, reached a maximum at 48 h and showed a slight recovery at 2 weeks. Striatal D1 and D2 receptor-binding sites (measured with [3H]SCH23390 and [3H]spiperone binding, respectively) and mRNA levels for D1 and D2 receptors (determined with quantitative in situ hybridization) were altered after MPTP treatment in temporally independent manners. MPTP toxicity to the nigrostriatal system likely induces substantial striatal DA release in vivo and stimulates transcription of at least one major IEG, zif268, in striatal neurons. Increased striatal zif268 expression after MPTP appears to derive mainly from DA released onto D1 receptors, not by a NO-dependent process which has been described in striatal neurons in vitro. The rapid loss of striatal DA terminals after MPTP treatment alters D1 and D2 receptor sites independently of changes in their mRNA levels. Increased D1 and D2 gene transcription in this model may depend on re-innervation by DA terminals of striatal neurons and likely is not related to the increased zif268 transcription observed after MPTP.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

The effect of bone quality on pedicle screw loading in axial instability. A synthetic model.

STUDY DESIGN: In this biomechanical analysis of pedicle screw bending moments, custom-fabricated vertebral analogues were loaded in axial compression to produce sagittal bending forces. Moments were measured directly from internally instrumented pedicle screws. OBJECTIVES: To establish the role of cancellous vertebral modulus on pedicle screw bending moments within the vertebral body and the vertebral pedicle. SUMMARY OF BACKGROUND DATA: Pedicle screws are often used to manage axial instability of the spine. Clinical studies report a high incidence of screw bending failure, resulting in kyphosis and pain in some patients. Factors predisposing to bending failure are not well understood, although recent studies have shown that vertebral morphometry is important. METHODS: Axially canullated 7.0-mm pedicle screws, internally instrumented with paired strain gauges, were inserted into analogue vertebrae of uniform dimension. Cancellous modulus was varied from 25-100 MPa. Screws were rigidly mounted to a vertical testing frame, and axial loads were applied to the superior vertebral endplate, producing sagittal bending moments. Moments were recorded from gauges applied in the intrapedicular and intravertebral portions of the screw. Mean moments were compared using a Student's t test, with significance defined as P < 0.05. RESULTS: Cancellous modulus did not affect bending moments experienced in either the intrapedicular or intravertebral portions of the pedicle screws. Gauge accuracy was excellent, and with no gauge drift. CONCLUSIONS: Although small changes in pedicle morphometry can alter screw bending moments significantly, changes in cancellous modulus had no measurable impact on bending moments at these same loads. Bone density is likely to play a limited role in screw bending failure.

Biomechanical Phenomena↗

Cloning and characterization of a microsomal aminopeptidase from the intestine of the nematode Haemonchus contortus.

In order to characterise the integral membrane glycoprotein H11 from the intestinal microvilli of the nematode Haemonchus contortus, cDNA libraries prepared using mRNA from adult worms from the UK and Australia were immunoscreened with anti-H11 sera. Antibodies affinity purified on the protein expressed by insert DNA (295 bp) of a positive clone from a UK library bound specifically to H11. A longer clone (948 bp) was obtained from the Australian library by hybridisation. Using a primer based on sequence common to these, a polymerase chain reaction product of 3.3 kb was generated from cDNA from UK H. contortus. The sequences from the UK and Australian nematodes were essentially identical over the 929 bp region in which both were represented. All three cloned DNAs hybridised to mRNA of about 3.5 kb. Analysis of the deduced amino acid sequence, which showed 32% identity with those of mammalian microsomal aminopeptidases, indicated that H11 has a short N-terminal cytoplasmic tail, a single transmembrane region and a long extracellular region with putative N-linked glycosylation sites and the HEXXHXW motif characteristic of microsomal aminopeptidases. Microsomal aminopeptidase activity co-purifies with H11. It is inhibited by bestatin, phenanthroline and amastatin. The recombinant protein has been expressed in active form in insect cells.

Amino Acid Sequence↗

The effect of pedicle morphometry on pedicle screw loading. A synthetic model.

STUDY DESIGN: Static nondestructive bending analysis of pedicle screws inserted into vertebral analogues was conducted. Pedicle screw bending load was studied as a function of pedicle morphometry. OBJECTIVES: To determine how sagittal bending moment in pedicle screws is affected by changes in pedicle height, length, and width. BACKGROUND DATA: An unexpectedly high rate of clinical failure has been observed in pedicle screws used in short-segment instrumentation for axially unstable fractures. The majority of screws fail in sagittal bending within the pedicle. To date, little is known of the exogenous factors that affect in situ loads incurred by pedicle screws. METHODS: Synthetic vertebral analogues were fabricated, varying pedicle height, length, or width independently. Pedicle screws internally instrumented with strain gages 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 incrementally with increasing pedicle length, rising 30% as length increased from 8.0 mm to 12.0 mm. Screw moment increased 20% when pedicle height dropped below 15.0 mm, consistent with a threshold effect. Changes in pedicle width did not affect screw loads within the pedicle. CONCLUSIONS: In situ pedicle screw loads increased significantly as pedicle length increased and as pedicle height decreased. Pedicle screws instrumented internally with strain gages are an effective research instrument allowing measurement of in situ loading along the axis of the screw.

Biomechanical Phenomena↗

Surface remodeling of trabecular bone using a tissue level model.

We propose a two-dimensional mathematical model of trabecular bone remodeling that simulates the surface-based addition and removal of material in the actual physiological process. The model is based on a finite element representation of individual trabecular struts in which the material properties of the subtrabecular elements are constant. The remodeling stimulus is strain energy density, sensed and communicated through the osteocytic network as proposed by Mullender et al. We propose a modified osteocyte communication scheme that incorporates bone-lining cells and examines the implications of set point locations in one or the other of these two cell types. This model produces trabecular struts that align with its general loading direction. Placing the set point in the bone-lining cells rather than in the osteocytes makes the model more sensitive to changes in the other biological parameters. Introduction of a dead zone causes the model to reach a less oscillatory equilibrium in fewer iterations and produces better in-filling of trabecular strut intersections. The model gravitates to equilibrium states in which the average strain energy density is inversely proportional to the bone volume fraction to the 3.2 power.

Bone Remodeling↗

Patellar strain and patellofemoral contact after bone-patellar tendon-bone harvest for anterior cruciate ligament reconstruction.

OBJECTIVE: To characterize the morbific consequences of harvesting a patellar tendon graft for use in reconstructing the anterior cruciate ligament (ACL) of the knee, specifically, (1) to measure changes in patellar strain and patellofemoral contact due to graft harvest, (2) to evaluate the ability of bone-grafting the patellar defect to mitigate these effects, and (3) to characterize failure of the extensor mechanism after harvest of a patellar tendon graft. DESIGN: Twenty-two cadaver knee joints were tested before and after harvest of a patellar tendon graft and after filling the patellar defect with polymethylmethacrylate to simulate a healed bone graft, Knees were positioned in 30 degrees, 60 degrees, and 90 degrees flexion and loaded while measuring axial strain in the anterior patella and patellofemoral contact. Knees were then loaded to failure. RESULTS: Harvest of the graft produced increases in axial strain at all flexion angles. Filling the defect restored axial strain to normal values. Patellofemoral contact in the presence of a defect, either filled or empty, was not different from contact for intact patellae. Most knees failed by transpatellar fracture; mean extension moment at failure was 112.8Nm. The best predictors of failure were age and gender. CONCLUSION: Patients undergoing ACL reconstruction with a patellar tendon graft are at increased risk of anterior knee pain and disruption of the extensor mechanism. Bone-grafting the patellar defect created by graft harvest can reduce these risks. Our findings underscore the importance of carefully controlled rehabilitation and suggest that if an accelerated program of rehabilitation is anticipated, the patellar defect should be bone-grafted. Older patients, particularly women, are at increased risk of catastrophic failure of the knee extensor mechanism after ACL reconstruction using patellar tendon graft.

Adult↗

Vaccination against Haemonchus contortus with denatured forms of the protective antigen H11.

As part of a systematic examination of the protective epitopes on H11, groups of sheep were vaccinated with preparations of purified H11 used untreated (group A), or progressively denatured (linearized) by incubation with sodium dodecyl sulphate (SDS) (group B) or by boiling with SDS in the presence of dithiothreitol (group C). All the sheep developed antibodies which bound to the untreated H11. When challenged with 10,000 infective larvae of Haemonchus contortus the mean levels of protection relative to the mean values for adjuvant controls were 99.8%, 85% and 79% for faecal egg counts and 95%, 79% and 54% for worm burden at post-mortem for groups A, B and C respectively. The H11-specific antibodies inhibited the microsomal aminopeptidase activity of H11 in vitro up to 80%. The levels of inhibition by sera from individual animals correlated with levels of protection with r2, of 0.69-0.87.

Aminopeptidases↗

Modified transverse locking nail fixation of proximal femoral fractures.

It was hypothesized that transverse locking screws of intramedullary nails, seated above the lesser trochanter, provide equal strength to that of reconstruction nails, and that screws placed through the medial cortex of the femoral neck do not have adverse biomechanical effects during physiologic loading. Synthetic femurs (n = 10) and paired anatomic specimen femurs (n = 14) were tested intact and with an intramedullary device in place. Intact specimens were loaded nondestructively, then a segmental subtrochanteric defect was created and either a high seated transverse locking nail or a reconstruction nail was inserted and statistically locked. Axial and torsional stiffness were determined followed by axial failure testing. Mechanical parameters evaluated were stiffness, displacement, and energy. The implanted specimens did not show any statistically significant difference between transverse or reconstruction screw constructs with any of the measured parameters (stiffness, displacement, and energy). Failure tests in implanted specimens also did not show any statistically significant difference in yield load, yield displacement, or energy to failure between implant constructs. All anatomic specimens failed, with fractures of the proximal fragment involving medial and lateral cortices. Synthetic specimens did not fracture but showed failure with implant deformation at the level of the skeletal defect. The use of high seated transverse locking nails for complex proximal femoral fractures is a viable option and has comparable in vitro mechanical performance with reconstruction nails. Although not shown to be a problem in the present study, clinical evaluation of screws through the medial femoral neck cortex is required.

Bone Nails↗

Haemonchus contortus glycoproteins contain N-linked oligosaccharides with novel highly fucosylated core structures.

Structural studies on the N-linked oligosaccharides of Haemonchus contortus, an economically important nematode that parasitizes domestic ruminants, have revealed core fucosylation of a type not previously observed in any eukaryotic glycoprotein. Mass spectrometric analyses were performed on detergent extracts of homogenized adult H. contortus and on purified H11, a glycoprotein isolated from intestinal brush borders which has been previously shown to be an effective vaccine antigen. The major N-linked glycans identified in the present study have up to three fucose residues attached to their chitobiose cores. The fucoses are found at the 3- and/or 6-positions of the proximal GlcNAc and at the 3-position of the distal GlcNAc. The latter substitution is unique in N-glycans. Most anti-H11 monoclonal antibodies are known to recognize carbohydrate epitopes, and it is possible that the newly discovered multifucosylated core structures are highly immunogenic in this glycoprotein.

Acetylglucosamine↗

Short-segment pedicle instrumentation. Biomechanical analysis of supplemental hook fixation.

STUDY DESIGN: This biomechanical study of fractures in cadaver vertebrae used specially designed pedicle screws to determine screw strains during loading of two different fixation constructs. OBJECTIVES: The authors determined the relative benefit of adding offset sublaminar hooks to standard pedicle screw constructs to reduce screw bending moments and prevent fixation failure and sagittal collapse. SUMMARY OF BACKGROUND DATA: Clinical studies have demonstrated a high incidence of early screw failure in short-segment pedicle instrumentation constructs used to treat unstable burst fractures. Strategies to prevent early construct failure include longer constructs, anterior strut graft reconstruction, and use of offset sublaminar hooks at the ends of standard short-segment pedicle instrumentation constructs. METHODS: Human cadaver spines with an L1 burst fracture were instrumented with a standard short-segment pedicle instrumentation construct using specially instrumented pedicle screws. Mechanical testing was carried out in flexion, extension, side bending, and torsion, and stiffness and screw bending moments were recorded. Offset hooks were applied initially, then removed and testing repeated. Stiffness data were compared to intact and postfracture results, and between augmented and standard constructs. RESULTS: Addition of offset laminar hooks, supralaminar at T11 and infralaminar at L2, to standard short-segment pedicle instrumentation constructs increased stiffness in flexion by 268%, in extension by 223%, in side bending by 161%, and in torsion by 155% (all were significant except torsion). Sublaminar hooks also reduced pedicle screw bending moments to roughly 50% of standard in both flexion and extension (P < 0.05). CONCLUSIONS: Supplemental offset hooks significantly increase construct stiffness without sacrificing principles of short-segment pedicle instrumentation, and absorb some part of the construct strain, thereby reducing pedicle screw bending moments and the likelihood of postyield deformation and clinical failure.

Aged↗

Dopamine neurons from transgenic mice with a knockout of the p53 gene resist MPTP neurotoxicity.

We have examined MPTP toxicity to dopamine neurons of mice homozygous for a transgenic knockout of the p53 growth control gene (p53-/-). MPTP at a total dose of 96 mg/kg administered in four doses over two days produced a non-homogeneous loss of striatal dopamine transport sites and quantitatively reduced 3H-mazindol binding to similar degrees in p53-/- and wild type controls 2 and 3 weeks after starting MPTP. Nigral DA neurons stained immunohistochemically for tyrosine hydroxylase were counted using both manual and automated methods and found to be reduced 29-34% in wild type controls but were not reduced in p53-/-. Mean DA neuronal surface areas were reduced 63-68% by MPTP in controls and 35-50% in p53-/-. We conclude that p53 protein appears necessary for complete expression of MPTP neurotoxicity to dopamine neurons. Our findings suggest that the p53 gene and other growth control genes may regulate dopamine neuronal death in PD.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

A device for the measurement of pedicle screw moments by means of internal strain gauges.

Pedicle screws are commonly used in spinal reconstruction, and failure of pedicle screws due to bending is a significant clinical problem. To measure the moments typically placed on pedicle screws in situ we instrumented 7 mm Cotrel-Dubousset (CD) pedicle screws with internally mounted strain gauges. The screws were designed to measure flexion-extension moments at a single cross-section as dictated by strain gauge placement. It is possible to measure moments of up to 12 Nm at any location along the length of the screw by constructing transducers with varying strain gauge placements. These transducers are capable of measuring moments at points located within the vertebra including the pedicle, which is where failure usually occurs clinically. Transducer output was both linear and reproducible. These transducers are being used to investigate the load transfer characteristics between the pedicle screw and the vertebra. This technique could be applied to investigations of load sharing in reconstruction plates, lag-screws, and cross-locked intramedullary nails.

Biomechanical Phenomena↗

Freeze clamping musculo-tendinous junctions for in vitro simulation of joint mechanics.

Incorporation of physiologic muscle tensions to simulate normal in vivo joint loading in cadaveric biomechanical studies has been a challenging problem, especially about the knee, foot, and shoulder. Simulation of muscle contraction requires attachment of tension producing devices to musculotendinous units. To this end, we modified the 'cryo-jaw' device, first described by Riemersma and Schamhardt (1982, J. Biomechanics 15, 619-620) to couple linear actuators to fresh cadaver tendons. These clamps were used in the simulation of 11 different muscles in laboratory investigations of shoulder, elbow, knee, and foot function. The clamps were able to transmit repetitively 3500 N of quadriceps force in eight knees and 2000 N of Achilles force in 11 feet. Overall success rate was 95%.

Ankle Joint↗

Influence of extrinsic plantar flexors on forefoot loading during heel rise.

This investigation studied the effects of simulated plantar flexor muscle activity on forefoot loading using a static cadaver model. Nine cadaver feet were mounted in an apparatus in the heel rise position. Using computer-controlled and pneumatic actuators, forces were simultaneously applied to the tendons of the triceps surae, flexor hallucis longus, flexor digitorum longus, peroneus brevis and longus, and tibialis posterior until 750 N of ground reaction force was achieved, at which time forefoot plantar pressure patterns were captured immediately with a pedobarograph. Second metatarsal bending moments were calculated from strain gauge data collected concurrently. Consecutive loading cycles were performed with sequential elimination of simulated muscle force from each tendon except the Achilles. Loss of simulated flexor hallucis longus activity significantly decreased great toe contact forces and significantly increased forces under the forefoot. Simulated loss of both the flexor hallucis longus and flexor digitorum longus caused significant decreases in contact area, pressure, and force beneath the toes and significant increases in contact area and force under the forefoot. Bending moments in the second metatarsal were shown to vary directly with peak pressure under the second metatarsal head (r = 0.801). These findings demonstrate the load distributing function of the extrinsic plantar flexors during heel rise.

Adult↗

Strain and loading of the second metatarsal during heel-lift.

Metatarsal stress fractures occur in military recruits after long marches and in athletes after episodes of overtraining involving running or jumping. It has been demonstrated that contraction of the plantar flexors of the toes helps to counteract the moments placed on the metatarsals by body weight. It is possible that physiological fatigue due to strenuous or repetitive exercise reduces the rate and force of contraction of the plantar flexors, thereby increasing metatarsal strain per cycle, and that this mechanism is the primary cause of stress fractures of these bones. To test the hypothesis that fatigue of the plantar flexors causes increased metatarsal loading, thereby predisposing these bones to stress fracture, we measured metatarsal strains in nine fresh cadaveric feet with use of an apparatus that simulated physiological loading due to body weight as well as contraction of the plantar flexors. Each foot was loaded to 750 newtons of ground-reaction force by simulated contraction of the triceps surae, and strains were recorded in the mid-part of the shaft of the second metatarsal. Tests were repeated with use of simulated activity of different combinations of the flexor digitorum longus, flexor hallucis longus, peroneus brevis, peroneus longus, and tibialis posterior muscles. In situ bending moments and axial loads subsequently were derived for each configuration. Dorsal strain was significantly reduced by simulated contraction of the flexor hallucis longus. Plantar-dorsal bending was significantly reduced by simulated contraction of the flexor digitorum longus.

Achilles Tendon↗