Citations

Force analysis of musculoskeletal joint systems is a redundant problem since the number of unknowns exceeds the number of equilibrium and constraint equations. Such a problem has been analyzed previously by the method of permutation/combination and by optimization technique. This paper combines both methods and discusses the results in the light of a graphical presentation from which unique and nonunique solutions to the problem are elaborated. When the applied load is nominal, multiple solutions are possible to meet the functional requirements. However, under maximum strength, unique solution exists because the redundant muscles reach their physiological limits.

Abstract Much of the clinical research in osteoporosis is directed toward documenting a reduction in vertebral fracture rate, but there is considerable disagreement about defining and quantifying vertebral fractures. We have evaluated the technique of digitizing landmarks identified on lateral radiographs of thoracic and lumbar vertebrae and computing vertebral body area. Reduction in area indicates that fractures occurred. Radiographs from 10 patients with osteoporosis and vertebral fractures were obtained from each of two centers, Henry Ford Hospital (HFH) and Mayo Clinic (MC), and vertebral area for each individual in the complete set of 20 radiographs was calculated at each center. Measurements at the two centers differed by a multiplicative constant related to the method of recording landmarks on the radiographs that was estimated using 300 x-rays from HFH. After adjusting the MC areas for this multiplicative relationship, the average ratio of the HFH areas to the transformed MC areas of individual vertebrae (T4-L5) ranged from 0.98 to 1.06. The correlation between HFH and transformed MC areas for individual vertebrae averaged 0.85, with slopes between 0.87 and 1.00, intercept average -0.57. Within-patient rank correlation averaged 0.97. We conclude that radiographic digitization is a reliable and reproducible method of determining vertebral body dimensions that is suitable for evaluating radiographs obtained at different clinical sites and for comparison with normal data. This technique should prove useful for documenting the presence of a vertebral fracture that may not be readily apparent on visual inspection of radiographs and for monitoring serial changes in vertebral body dimensions in long-term epidemiologic and therapeutic studies.

Abstract In a 4 year clinical trial in 202 postmenopausal osteoporotic women receiving NaF at 75 mg/day or placebo (both groups received supplementary calcium at 1500 mg/day), we found (N Engl J Med 322:801, 1990) that NaF increased bone mineral density in the lumbar spine (LS-BMD) substantially but did not decrease vertebral fracture rate (VFR), and it increased the nonvertebral fracture rate. Additional analyses and extended observations are now available on 50 women from the NaF group followed for up to 6 years of treatment. In these women, LS-BMD increased linearly over the 6 years (median rate, 8.7%/year or 0.063 g/cm2/year). Because during the 4 year trial the NaF dosage was decreased (because of side effects) in 54 of the 101 women randomized to NaF, dose-response relationships could be evaluated. For the entire study population, serum F level correlated directly with increase in LS-BMD (r = 0.61, P < 0.001). When individual person-years of observation were grouped by deciles of LS-BMD, VFR (per 100 person-years) decreased to a nadir of 24 as mean LS-BMD for the group increased from 0.6 to 1.2 g/cm2 and then doubled to 52 in the group with mean LS-BMD of 1.6 g/cm2. Multivariate analyses and inspection of three-dimensional plots revealed a complex pattern in which VFR was influenced by interaction of several variables. When the effects of LS-BMD, changes in LS-BMD, and serum F were assessed simultaneously, VFR was seen to decrease with increasing LS-BMD except when the higher LS-BMD was associated with rapid rate of increase in LS-BMD or a large increase from baseline serum F. For some patients (noncompliers or nonresponders), serum F or LS-BMD failed to increase. Thus, it is possible that lower dosages of NaF produce moderate decreases in VFR.

Abstract Anti-Smith (Sm) D autoantibodies are specific for systemic lupus erythematosus. In this investigation, the influence of HLA-D genes on immune responses to SmD was investigated. Mice with HLA-DR3, HLA-DR4, HLA-DQ0601, HLA-DQ0604, or HLA-DQ8 transgenes were immunized with recombinant SmD1, and their Ab responses were analyzed. Analysis by ELISA showed that all strains responded well to SmD. However, when synthetic SmD peptides were used as substrate, DR3 mice had the highest Ab response followed by DQ8, DQ0604, DQ0601, and DR4. A similar trend was observed in Western blot analysis using WEHI 7.1 cell lysate as the substrate, with the exception that DR4 mice did not generate detectable amounts of Abs. Only sera from DR3 and DQ0604 mice immunoprecipitated A-ribonucleoprotein (RNP), SmB, and SmD. Intermolecular epitope spreading to A-RNP and SmB was evident in DR3 and DQ0604 mice, as sera depleted of anti-SmD Abs were reactive with these proteins. DR3 mice also generated an immune response to C-RNP. Anti-nuclear Abs were detected in the majority of the DR3 mice, whereas moderate reactivities were seen in DQ0604 and DQ8 mice. Interestingly, only DR3 mice mounted an anti-dsDNA Ab response. Approximately half of the anti-dsDNA Abs were cross-reactive with SmD. Ab responses correlated with the strength of the T cell responses. Thus, HLA-DR3 appears to be the dominant HLA-D gene that determines the magnitude and quality of the anti-SmD immune response. In addition, our findings provide insights into the origin of the anti-dsDNA Abs often detected in patients with systemic lupus erythematosus.

Analytic determination of muscle force across human joints encounters an indeterminate problem. A new optimization approach, based on minimizing the upper bound of muscle stress, is introduced to obtain a unique solution. Mathematical and physiological justification of this new approach distinguishes it from previously described methods. A complex joint, the elbow, was studied. The results of muscle forces in resisting the elbow flexion moment were obtained and compared with electromyographic observation, as well as with solution from other optimizing techniques. The resultant humero-ulnar joint forces at various elbow joint positions are calculated. In normal daily activities, resultant joint forces of 0.3–0.5 times body weight are commonly encountered.

In muscle force analysis, orientations and moment arms of the muscles about a joint provide essential coefficients in the equilibrium equations. For the determination of these parameters, several experimental techniques, including geometric measurement, tendon-joint displacement measurement and direct load measurement, are available. Advantages and disadvantages associated with each of the techniques are reviewed and compared based on our extensive experience.

Since the electrogoniometric method has been justified for the measurement of lower extremity joint motion, a similar device is developed for the measurement of elbow joint and forearm rotations. In this design, the axis of forearm rotation coincides with the anatomical axis which eliminates the cross talk existing in the regular triaxial goniometer. Although the axis of abduction-adduction is still offset from the elbow joint, special linkage arrangement was used to obtain equivalent motion. Experimental method was used to validate the accuracy of the device and model simulation was performed to emphasize the importance of accurate placement of the instrument on test subjects. Application of the present apparatus to normal subjects was studied to illustrate the range of elbow motion required in performing normal activities of daily living. This device is currently used in the functional evaluation of patients with elbow and forearm problems.

AbstractRecent studies have shown the importance of helper CD4 T cells in initiating and sustaining tumor-specific CD8 T-cell immunity. This has paved the way for identifying MHC class II epitopes that could be incorporated into class I–based vaccines. In this study, the goal was to identify an HLA-DR–degenerate epitope pool derived from insulin-like growth factor binding protein 2 (IGFBP-2). IGFBP-2, a regulator of insulin-like growth factor action, is overexpressed in the majority of breast and ovarian cancers. Using algorithms, we predicted 29 HLA-DR1–binding epitopes. Binding assays targeting 15 different HLA-DRs revealed that 10 epitopes were degenerate, binding to at least four different HLA-DR variants. An IFN-γ enzyme-linked immunosorbent spot assay was used to assess immunity to these 10 epitopes in 48 patients with either breast or ovarian cancer and 18 controls. Elevated T-cell immunity in patients was detected in 4 of the 10 epitopes (IGFBP2.17, IGFBP2.22, IGFBP2.249, and IGFBP2.293). The cumulative T-cell frequency of these four epitopes was elevated in patients relative to controls. All four peptides are naturally processed and presented to CD4 T-cells. The degenerate pool of peptides covers nearly 80% of patients and may be useful for augmenting CD4 T-cell immunity in patients undergoing immunization. [Cancer Res 2008;68(12):4893–901]

Abstract Barrett's esophagus, a columnar metaplasia of the lower esophagus epithelium related to gastroesophageal reflux disease, is the strongest known risk factor for the development of esophageal adenocarcinoma (EAC). Understanding the signal transduction events involved in esophageal epithelium carcinogenesis may provide insights into the origins of EAC and may suggest new therapies. To elucidate the molecular pathways of bile acid–induced tumorigenesis, the newly identified inflammation-associated signaling pathway involving IκB kinases β (IKKβ), tuberous sclerosis complex 1 (TSC1), and mammalian target of rapamycin (mTOR) downstream effector S6 kinase (S6K1) was confirmed to be activated in immortalized Barrett's CPC-A and CPC-C cells and esophageal cancer SEG-1 and BE3 cells. Phosphorylation of TSC1 and S6K1 was induced in response to bile acid stimulation. Treatment of these cells with the mTOR inhibitor rapamycin or the IKKβ inhibitor Bay 11-7082 suppressed bile acid–induced cell proliferation and anchorage-independent growth. We next used an orthotopic rat model to evaluate the role of bile acid in the progression of Barrett's esophagus to EAC. Of interest, we found high expression of phosphorylated IKKβ (pIKKβ) and phosphorylated S6K1 (pS6K1) in tumor tissues and the Barrett's epithelium compared with normal epithelium. Furthermore, immunostaining of clinical EAC tissue specimens revealed that pIKKβ expression was strongly correlated with pS6K1 level. Together, these results show that bile acid can deregulate TSC1/mTOR through IKKβ signaling, which may play a critical role in EAC progression. In addition, Bay 11-7082 and rapamycin may potentially be chemopreventive drugs against Barrett's esophagus–associated EAC. [Cancer Res 2008;68(8):2632–40]