Local bone formation due to combined mechanical loading and intermittent hPTH-(1-34) treatment and its correlation to mechanical signal distributions.

We evaluated the local response of cortical bone in the rat tibia due to combined treatment with synthetic parathyroid hormone, hPTH-(1-34), and mechanical stimulation by four-point bending. Forty-eight female retired breeder Sprague-Dawley rats were divided into six groups. Mechanically stimulated animals included the following groups: (1) Bend+PTH, (2) Sham+PTH, (3) Bend+Vehicle, (4) Sham+Vehicle. Non-mechanically stimulated animals included a (5) Control group that received neither loading nor injections, and a (6) PTH group that received only hPTH-(1-34) injections. The right limbs of mechanically loaded animals were exposed to a peak force of 50 N for 36 cycles at 2 Hz, three days per week for four weeks, and PTH-treated animals received injections equivalent to 50 microg/kg BW. Fluorochrome labeling was used to measure local formation at 12 sectors about the endocortical periphery. The distributions of endocortical bone formation were compared to the local formation differences between treatment groups and to a variety of potential mechanical stimuli signals. Results indicated that hPTH-(1-34) exerted a potent anabolic effect with near-uniform formation about the endocortical surface, and that localized formation peaks due to bending were further augmented in the presence of hPTH-(1-34) treatment. Correlation of formation patterns to mechanical signal distributions highlighted several candidate signals including the mid-principal stress, the dilatational strain, and the radial gradient of the local radial strain.

Design and analysis of robust total joint replacements: finite element model experiments with environmental variables.

Computer simulation of orthopaedic devices can be prohibitively time consuming, particularly when assessing multiple design and environmental factors. Chang et al. (1999) address these computational challenges using an efficient statistical predictor to optimize a flexible hip implant, defined by a midstem reduction, subjected to multiple environmental conditions. Here, we extend this methodology by: (1) explicitly considering constraint equations in the optimization formulation, (2) showing that the optimal design for one environmental distribution is robust to alternate distributions, and (3) illustrating a sensitivity analysis technique to determine influential design and environmental factors. A thin midstem diameter with a short stabilizing distal tip minimized the bone remodeling signal while maintaining satisfactory stability. Hip joint force orientation was more influential than the effect of the controllable design variables on bone remodeling and the cancellous bone elastic modulus had the most influence on relative motion, both results indicating the importance of including uncontrollable environmental factors. The optimal search indicated that only 16 to 22 computer simulations were necessary to predict the optimal design, a significant savings over traditional search techniques.

Arthrodesis as an early alternative to nonoperative management of charcot arthropathy of the diabetic foot.

BACKGROUND: This study was performed to evaluate the use of arthrodesis of the tarsal-metatarsal area for the treatment of Eichenholtz stage-I Charcot arthropathy in patients with diabetes. Currently, the standard treatment of stage-I Charcot arthropathy is the application of a non-weight-bearing total-contact cast. Although this treatment can be effective for allowing a patient to walk without undergoing an operation, a nonunion or malunion may still result. The subsequent deformities may lead to complications, including ulceration of the foot and the need for operative intervention. Recently, a group of patients who had had early operative intervention for a variety of reasons provided us with the opportunity to objectively evaluate the effects of such treatment. This analysis provided valuable information about whether this treatment is a reasonable alternative to current nonoperative approaches. METHODS: Between January 1991 and December 1996, fourteen patients had an operation because of Eichenholtz stage-I diabetic neuropathy. The classification of the disease as Eichenholtz stage I (the developmental stage) was based on radiographic evidence of varying degrees of articular-surface and subchondral-bone resorption and fragmentation as well as joint subluxation or dislocation without evidence of coalescence or callus formation. The operative procedure consisted of extensive debridement, open reduction, and internal fixation of the tarsal-metatarsal region with autologous bone graft. Postoperative treatment consisted of immobilization of the limb in a non-weight-bearing cast for a minimum of six weeks. All of the patients returned for a final follow-up visit at a mean of forty-one months (range, 25.3 to 77.3 months) postoperatively, at which time clinical and radiographic evaluations as well as gait analysis (with measurement of plantar pressures) were performed. The gait-analysis data was compared with similar data from a group of fourteen patients with diabetic neuropathy who had had a below-the-knee amputation and with that from a group of fourteen patients with diabetic neuropathy who had no history of plantar ulceration. RESULTS: All of the arthrodesis procedures were successful. Clinically, none of the patients had immediate or long-term complications postoperatively. No patient reported ulceration after the operation. The mean time to assisted weight-bearing was 10 +/- 3.3 weeks (range, six to fifteen weeks), the mean time to unassisted weight-bearing was 15 +/- 8.8 weeks (range, eight to thirty-four weeks), and the mean time to return to the use of regular shoes was 27 +/- 14.4 weeks (range, twelve to sixty weeks). All of the patients regained the level of walking ability that they had had prior to the arthropathy. The calculated confidence intervals revealed no differences between the arthrodesis group and either of the two comparison groups with regard to the time-distance gait parameters of velocity, cadence, and stride length or with regard to the minimum, maximum, and total range of motion of each of the joints. In contrast to able-bodied subjects, all three groups showed a reduction in sagittal-plane ankle motion that was primarily related to loss of plantar flexion. The first metatarsal, great toe, and heel showed the highest peak plantar pressures, with little difference among the groups. CONCLUSIONS: To our knowledge, the present study is the first to demonstrate the potential for early operative treatment to restore anatomical alignment and improve function of diabetic patients with stage-I Charcot arthropathy.

Bootstrap prediction and confidence bands: a superior statistical method for analysis of gait data.

Gait analysis studies typically utilize continuous curves of data measured over the gait cycle, or a portion of the gait cycle. Statistical methods which are appropriate for use in studies involving a single point of data are not adequate for analysis of continuous curves of data. This paper determines the operating characteristics for two methods of constructing statistical prediction and confidence bands. The methods are compared, and their performance is evaluated using cross-validation methodology with a data set of the sort commonly evaluated in gait analysis. The methods evaluated are the often-used point-by-point Gaussian theory intervals, and the simultaneous bootstrap intervals of Sutherland et al. The Development of Mature Walking, MacKeith Press, London, 1988 and Olshen et al. Ann. Statist. 17 (1989) 1419-40. The bootstrap bands are shown to provide appropriate coverage for continuous curve gait data (86% coverage for a targeted coverage of 90%). The Gaussian bands are shown to provide inadequate coverage (54% for a targeted coverage of 90%). The deficiency in the Gaussian method can lead to inaccurate conclusions in gait studies. Bootstrap prediction and confidence bands are advocated for use as a standard method for evaluating gait data curves because the method is non-parametric and maintains nominal coverage levels for entire curves of gait data.

Robust optimization of total joint replacements incorporating environmental variables.

Direct search techniques for the optimal design of biomechanical devices are computationally intensive requiring many iterations before converging to a global solution. This, along with the incorporation of environmental variables such as multiple loading conditions and bone properties, makes direct search techniques infeasible. In this study, we introduced new methods that are based on the statistical design and analysis of computer experiments to account efficiently for environmental variables. Using data collected at a relatively small set of training sites, the method employs a computationally inexpensive predictor of the structural response that is statistically motivated. By using this predictor in place of the simulator (e.g., finite element model), a sufficient number of iterations can be performed to facilitate the optimization of the complex system. The applicability of these methods was demonstrated through the design of a femoral component for total hip arthroplasty incorporating variations in joint force orientation and cancellous bone properties. Beams on elastic foundation (BOEF) finite element models were developed to simulate the structural response. These simple models were chosen for their short computation time. This allowed us to represent the actual structural response surface by an exhaustive enumeration of the design and environmental variable space, and provided a means by which to validate the statistical predictor. We were able to predict the structural response and the optimal design accurately using only 16 runs of the computer code. The general trends predicted by the BOEF models were in agreement with previous three-dimensional finite element computer simulations, and experimental and clinical results, which demonstrated that the important features of intramedullary fixation systems were captured. These results indicate that the statistically based optimization methods are appropriate for optimization studies using computationally demanding models.

Exponential model for the tensile true stress-strain behavior of as-irradiated and oxidatively degraded ultra high molecular weight polyethylene.

Following sterilization by gamma radiation, ultra high molecular weight polyethylene components for total joint replacement undergo oxidative degradation upon exposure to air and the in vivo environment. Oxidative degradation is accompanied by an increase in density. The primary objective of this study was to develop a mathematical model to predict the monotonic tensile mechanical behavior of these sterilized components as a function of changes in density arising from oxidative degradation. Tensile specimens of ultra high molecular weight polyethylene were sterilized with gamma radiation and then oxidatively degraded in an air furnace. The average density of each specimen was measured using a density gradient column. Differential scanning calorimetry and Fourier transform infrared spectroscopy were conducted on selected specimens to characterize the physical and chemical changes due to accelerated aging as opposed to ambient shelf aging. Mechanical testing was conducted in monotonic uniaxial tension. An exponential model was fitted to the true stress-strain data (up to a true strain of 0.12). The observed fitted stress had a correlation coefficient of 0.996. The model permits a quantitative prediction of the association between the true stress-strain curve and density for the ultra high molecular weight polyethylene components. The proposed exponential model effectively describes changes in the large-strain monotonic tensile behavior of as-irradiated and oxidatively degraded ultra high molecular weight polyethylene components.

Changes in the moment arms of the rotator cuff and deltoid muscles with abduction and rotation.

The behavior of the moment arms of the rotator cuff and deltoid muscles was studied during simple and combine movements of abduction and rotation about the glenohumeral joint. This was done by experimental measurement of excursions of the muscles in an in vitro cadaver model and by use of a multiple-regression analysis to delineate the changes in the moment arms as a function of abduction and rotation. The results demonstrated the potential of some rotator cuff muscles to contribute to both abduction and rotation, the sensitivity of the abductor moment-arm lengths to internal and external rotation and of the rotator moment-arm lengths to the degree of abduction, and the capacity of the abductor moment-arm lengths of the deltoid to increase with increasing abduction. Characterization of this behavior resulted in an increased understanding of the complex role of the rotator cuff and deltoid muscles about the gleno-humeral joint and provided quantitative descriptions of functional relationships. This study demonstrates the capacity of the infraspinatus and subscapularis muscles to contribute not only to external and internal rotation, respectively, but also to elevation of the arm in the plane of the scapula, a role for which these muscles have been given little or no consideration. Furthermore, it demonstrates that the contribution of the infraspinatus to abduction is enhanced with internal rotation while that of the subscapularis is enhanced with external rotation. Thus, dysfunction of the supraspinatus muscle need not preclude good elevation of the arm, and rehabilitation to reprogram and strengthen the remaining muscles becomes an important consideration.

The effect of temperature, stress and microstructure on the creep of compact bovine bone.

Creep tests of 117 compact bovine bone specimens were conducted at three temperatures (25, 37, and 43 degrees C), with applied stresses between 71 and 115 MPa. Following testing, the amount of secondary haversian bone in the gage region of the specimens was estimated. The resulting steady-state creep rates (epsilon) were fit to an Arrhenius (e-Qc/RT) model (where Qc is the activation energy for the mechanism(s) controlling creep, R is the gas constant, and T is the absolute temperature) of the type used to describe the classic steady-state creep behavior of metals, ceramics, and metamorphic rocks. The empirical model developed was epsilon = 5.6 x 10(-9) e4.6F sigma 5.2 e-5330/T, where epsilon is the estimated mean steady-state creep rate, F is the volume fraction of secondary haversian bone, sigma is the applied stress, and T is the absolute temperature. There was a positive, significant association between the estimated mean steady-state creep rate and F, sigma, and T. Qc was determined to be 44.3 kJ mol-1, a reasonable value when compared to activation energies for creep in ceramics. It is hypothesized that permanent deformation during creep of compact bovine bone is primarily due to damage mechanisms associated with dislocations in the hydroxyapatite mineral lattice structure.

The lack of association between femoral shaft fractures and hypotensive shock.

A retrospective review of all patients with femur fractures was performed to determine whether isolated femoral shaft fractures were associated with hypotensive shock. One hundred patients were identified who had either an isolated femoral shaft fracture (group F, 62 patients) or a femoral shaft fracture in addition to other non-shock producing fractures or minor injuries (group A, 38 patients). No patients in this study were in class III or IV (hypotensive) shock; however, 11% progressed from no shock to class I and 13% from class I to class II. Logistic regression showed no association between class II shock and age, sex, or weight. The presence of additional fractures (p = 0.004) and total fluids received from fracture to stabilization (p = 0.014) had a highly significant association with class II shock in a joint analysis. Mechanism of injury, although significant as an independent variable, was highly associated with the presence of additional fractures and so is not required in the joint model. Femur fractures alone or in combination with other minor injuries should not be considered the cause of hypotensive shock in the traumatized patient. In the traumatized patient who presents with a closed femoral shaft fracture and hypotension, an alternative source of hemorrhage should be sought.

Measurement reproducibility of two commercial knee test devices.

Objective evaluation of patients' knee motion using mechanical devices, whether for diagnostic purposes or for assessing rehabilitative procedures, requires that these devices be reproducible, in order to avoid errors independent of the patients' condition. This study prospectively evaluates the reproducibility of two commercial knee test systems, the KT 1000 Knee Ligament Arthrometer and the Genucom Knee Analysis System, by performing repeated measurements on twenty normal men. Average knee motion, between-subject variance, and within-subject variance were determined by performing repeat tests on the same day and one week later. No significant difference was found between measurements taken on the two different test days, but the within-subject variation was high. We found that larger applied forces or moments resulted in a larger variation in mean displacements. However, the percent variation about the mean (coefficient of variation) decreased with increasing applied loads. The coefficient of variation for the KT 1000 varied from 8 to 33% and for the Genucom, from 13 to 87%. On an individual basis, large variations were found in repeated measures for both devices. To minimize errors, we recommend that repeated tests be performed, higher forces and moments utilized, and specific flexion angles be used for each device and test. Even under these conditions, caution must be exercised when evaluating individual subjects.

Torque production in the shoulder of the normal young adult male. The interaction of function, dominance, joint angle, and angular velocity.

Shoulder torque measurements were obtained from 36 normal young adult males during flexion, abduction, internal rotation, and external rotation. Normative, angle-specific torque measurements were determined under isometric conditions and isokinetically at 48 deg/sec. The effects of dominance, angular velocity, and joint position were determined and a method provided for determining the expected maximal torque at a specific speed and position based upon torque measurements from the contralateral shoulder. This method can be used in cases of unilateral shoulder abnormalities to predict normative torque values for the affected side based on torque measurements from the unaffected shoulder.

Maternal antibodies to Ro (SS-A) are associated with both early onset of disease and male sex among children with systemic lupus erythematosus.

In this study of 71 children with systemic lupus erythematosus (SLE) and 188 of their first-degree relatives, we demonstrated that the development of SLE in male children younger than age 18, and in all children younger than age 10 at the time of diagnosis, is strongly correlated with the presence of antibodies to Ro (SS-A) in the mother's serum. When the relative antibody concentration was quantified, increased quantities of antibody to Ro (SS-A) were also found in mothers of male probands and mothers of probands whose SLE was diagnosed before age 10. No similar association was found for the presence or amount of antibody to Ro (SS-A) in other first-degree relatives or for antibody to La (SS-B) or nuclear RNP in any relative. The explanation for the association of maternal anti-Ro (SS-A) antibodies and early diagnosis of SLE or male sex is not apparent. These findings extend the association of maternal antibodies to Ro (SS-A) from transient "neonatal" SLE to SLE in childhood, and suggest that maternal antibodies to Ro (SS-A) may be of fundamental importance in the pathogenesis of some cases of childhood SLE.

Transfusion requirements after HLA-identical marrow transplantation in 82 patients with aplastic anemia.

Red blood cell (RBC) and platelet (PLT) transfusion requirements during the first 13 weeks after HLA-identical marrow transplantation were studied in 82 patients with aplastic anemia. On the average, patients were given 9 units of RBCs (1-82) and 44 units of PLTS (6-468). The greatest need for support was during the first 4 weeks postgrafting. A multivariate statistical analysis of 22 variables showed that RBC and PLT requirements increased with age. In addition, RBC requirements increased if the patient had isohemagglutinins against the marrow donor's RBC, i.e., if the marrow transplant was across a major ABO barrier.

An analysis of comparative carcinogenesis experiments based on multiple times to tumor.

Methods are given for the comparison of two treatment groups in experiments giving rise to multiple tumors. Methods based on the gaps in time between successive tumors are emphasized, but, for comparison, one method based directly on times to tumor is also presented. When applied to the results of an experimental animal carcinogenesis study, these analyses show that a diet supplemented with retinyl acetate reduces the hazard of mammary tumors, compared with controls, in every gap, and they allow one to combine evidence from the several gaps to obtain a powerful test for treatment effect.