Citations

Concavity-compression is an important mechanism for keeping a joint centered despite a large range of motion. The purpose of this study was to explain how the results of a test measuring the joint intrinsic stability can be interpreted and related to joint architecture. As an example, the method was demonstrated for the glenohumeral joint although the versatility allows any articulating joint, whether natural or prosthetic, to be analyzed. The initial slope from the central point was relatively steep, indicating a large resistance to translation. The peak translation force occurred within the first 5 mm of displacement for the glenohumeral joint, indicating a high congruence between the humerus and glenoid surfaces. Stability ratio, calculated as the maximum translation force divided by the applied joint compressive force, makes it possible to compare the stabilizing effect under different compressive loads for different anatomical directions. In hanging arm position, the joint stability ratio ranged from 30.5% to 60.1%. Finally, the effective depth of the concavity and the maximum range of joint translation can be measured by completely dislocating the joint. For the glenohumeral specimen, the smallest glenoid concavity depth, 3.8 mm, occurred in the anterior direction. The joint translation limit was smallest in the anterior-posterior direction (28.0 mm). The methodology presented in this study will allow consistent testing parameters between different trials, easily allowing parametric studies to gain a more complete understanding of articular joints.

The purpose of this study is to develop an electromechanical system for dynamic simulation of the stance phase of a human gait using cadaveric foot specimens. The system can be used for quantification of foot and ankle pathomechanics and design of foot and ankle reconstructive surgeries. Servo-pneumatic systems were used for application of the tibial weight loading and muscle loadings. A four-bar mechanism was constructed to provide the progressive motion of a tibia during the simulation while the external loadings were simultaneously applied. Muscle loadings were estimated based on the physiological cross-sectional area and normal electromyography (EMG) data with the assumption of the linear EMG–force relationship. Ad hoc tuning of the unknown muscle gains was conducted until a reasonable match with the normal vertical ground reaction force profile, center of pressure advancement, and characteristic foot motion events (heel strike, foot flat, heel rise and toe-off) could be made. Three cadaver feet and an artificial foot were tested with five repeated trials. The simulator reproduced the stance phase of a human gait in the sagittal plane with reasonable accuracy and consistency without compromising either kinematics or kinetics of the foot and ankle complex.

The supraspinatus tendon is frequently involved in rotator cuff tears. It has been suggested that joint position affects the structural mechanics of the tendon–bone complex. The purpose of this study was to determine regional variations in structural properties of the supraspinatus tendon in two glenohumeral positions. Supraspinatus tendons from 17 fresh frozen cadavers were divided into three strips of equal width and tested with a material-testing machine. The arm orientation was either in hanging position or 60 degrees glenohumeral abduction corresponding to 90 degrees arm abduction assuming 30 degrees scapular rotation. Tensile force, tendon elongation and failure mode were recorded. Overall, there was no significant difference in structural properties between hanging arm position and 60 degrees of glenohumeral abduction (p>0.05). However, the mean ultimate load (385 N, SD 56 N) and mean ultimate stress (14 MPa, SD 3 MPa) of the anterior tendon section with the arm in glenohumeral abduction were lower in 60 degrees abduction than in the hanging arm position (611 N, SD 276 N; 24 MPa, SD 10 MPa). In hanging arm position, the anterior tendon portion had a significantly greater ultimate load and stiffness than the middle and posterior portions (p<0.05). The regional variation in structural properties substantiates the clinical finding that rotator cuff ruptures easily extend posteriorly. Our study suggests that glenohumeral abduction reduces the failure strength of the supraspinatus tendon, specifically of its anterior portion. In our study, the maximum load of the anterior portion was substantially higher than predicted maximum loads transmitted physiologically through the entire tendon.

CD28 is the quintessential costimulatory molecule expressed on CD4+ and CD8+ T cells. During chronic infections and the normal aging process, CD28 expression is lost, compromising the functional activity of T cells. CD28 loss is promoted by replicative stress, particularly in the presence of tumor necrosis factor–α, owing to an inoperative CD28 initiator element. It is currently unknown whether CD28 loss is irreversible. The present study examined cytokines for their ability to reinduce CD28 expression. CD4+CD28null T cells constitutively expressed interleukin-12 (IL-12) α and β receptors, which were functional and allowed for the up-regulation of the signal transducer and activator of transcription–4 (STAT-4)–dependent gene CD161. Costimulation of the T-cell and IL-12 receptors induced the transcription of CD28 in approximately 50% of CD4+CD28null T-cell clones and lines. IL-12 by itself did not restore CD28 expression. Up-regulation of CD28 after IL-12 exposure correlated with the reassembly of the CD28–initiator protein complex. The re-expressed CD28 was functional and restored the ability of CD4+CD28null T cells to express CD25 and CD40 ligand. Our data suggest that IL-12 may, in part, functionally rescue senescent CD4+ T cells.

Abstract Tissue structural cells are known in some situations to play a role in the presentation of antigen and in immunoregulation. We assessed the expression of B7 homologs, known to be involved in antigen presentation and lymphocyte costimulation, in human airway epithelial cells. Flow cytometry performed on the airway epithelial cell line BEAS-2B, as well as primary bronchial epithelial cells (PBEC), showed that B7-H2 was constitutively expressed on both BEAS-2B and PBEC, whereas B7-1 and B7-2 were undetectable on either epithelial cell type. B7-H2 expression was confirmed by Western blot using a specific antibody. Stimulation with various cytokines, including tumor necrosis factor-α, interferon-γ, and interleukin-4, slightly downregulated B7-H2 expression detected by flow cytometry, but did not significantly alter the apparent level of protein as assessed by Western blotting. Northern blotting detected mRNA for B7-H2 and B7-1, but not B7-2. B7-H2 was cloned from BEAS-2B cells and the sequence verified. Expression of B7-H2 mRNA was detected by real-time reverse transcriptase–polymerase chain reaction in PBEC from three independent donors. Immunohistochemical analysis of airway derived from autopsies revealed expression of B7-H2 in human airway epithelial cells. These results demonstrate that airway epithelial cells express the costimulatory molecule B7-H2, and suggest the possibility that B7-H2 may participate in antigen presentation by epithelial cells.

Imatinib mesylate (Gleevec), a small molecule inhibitor of abl, kit, and platelet-derived growth factor receptor (PDGFR) tyrosine kinases, has been reported to be effective in the treatment of hypereosinophilic syndrome (HES) and a rare eosinophilia-associated chronic myeloid disorder (eos-CMD) characterized by the t(5;12)(q33;p13) cytogenetic abnormality. In the current study, we sought to confirm the preliminary observations in HES as well as evaluate the therapeutic value of imatinib in eos-CMD that is not associated with t(5;12)(q33;p13). Five patients with HES (all men, median age = 46 years) and 2 with eos-CMD (both men, aged 45 and 58 years) were treated with imatinib at a starting dose of 100 to 400 mg/day. Cytogenetic studies showed no evidence of either the bcr-abl translocation or t(5;12)(q33;p13) in any patient. Screening of exons encoding the intracellular catalytic domains and extracellular ligand binding domains of PDGFRβ (exons 2-23) and c-kit (exons 1-21) in 6 patients demonstrated mostly previously known polymorphisms. At a median follow-up of 17 weeks (range, 10-33 weeks), 2 patients with HES and 1 with eos-CMD have achieved complete clinical remission and 1 additional patient with HES has achieved a partial remission. In contrast to previous observations, all 4 responding patients had elevated serum interleukin-5 levels. Although the drug was well tolerated in most patients, a previously unrecognized treatment toxicity of acute left ventricular dysfunction occurred in a responding patient with HES within the first week of treatment. Myocardial biopsy revealed eosinophilic infiltration and degranulation, and the cardiogenic shock was reversed with the prompt institution of corticosteroid therapy.

Purpose: To evaluate the antitumor activity, safety, immune response, and replication of CI-1042 (ONYX-015), an E1B 55-kd gene-deleted replication-selective adenovirus, administered intravenously to patients with metastatic colorectal cancer Patients and Methods: Eighteen patients with metastatic colorectal cancer for whom prior chemotherapy failed were enrolled onto an open-label, multicenter, phase II study. CI-1042 was administered intravenously at a dose of 2 × 1012 viral particles every 2 weeks. Patients were evaluated for tumor response and toxicity; in addition, blood samples were taken for adenovirus DNA and neutralizing antibody analysis. Results: Common toxicities included flu-like symptoms, nausea, and emesis. All 18 patients eventually were removed from study because of progressive disease. Seven patients were assessed as having stable disease after 2 months of treatment, whereas two patients were considered to have stable disease after 4 months. Detectable circulating CI-1042 DNA was identified in 36% of patients 72 hours after last infusion, which is suggestive of ongoing viral replication. Conclusion: In this phase II study, intravenous CI-1042 was administered safely to patients with advanced colorectal cancer. Toxicity was manageable, consisting primarily of flu-like symptoms. Stable disease was experienced by seven patients for 11 to 18 weeks.

Purpose: To investigate the effect of granulocyte colony-stimulating factor (G-CSF) on hematopoietic toxicities, supportive care requirements, time to complete intensive therapy, and event-free survival (EFS) and overall survival (OS) in children with high-risk acute lymphoblastic leukemia (HR-ALL). Patients and Methods: A total of 287 children with HR-ALL were randomly assigned to intensive chemotherapy regimens (New York I [NY I] or NY II) as part of the Children’s Cancer Group (CCG)-1901 protocol. The induction phases consisted of five drugs (vincristine, prednisone, l-asparaginase, daunorubicin, and cyclophosphamide). Initial consolidation comprised six-agent chemotherapy combined with 18 Gy of total-brain irradiation. Patients were randomly assigned to receive G-CSF (5 μg/kg/day) during either induction or initial consolidation. A crossover study analysis was done on the 259 patients who completed both phases of therapy. Results: The mean time to neutrophil recovery (≥ 0.5 × 109/L) was reduced with G-CSF (16.7 v 19.1 days, P = .0003); however, patients who received G-CSF did not have significantly reduced episodes of febrile neutropenia (149 v 164, P = .41), positive blood cultures (57 v 61, P = .66), or serious infections (75 v 79, P = .62). Hospitalization (14.0 v 13.9 days, P = .87) and induction therapy completion times (NY I, 30.3 v 31.3 days, P = .11; NY II, 33.4 v 32.3 days, P = .40) were not significantly altered. There were no differences in 6-year EFS (P = .24) or OS (P = .54) between patients receiving or not receiving G-CSF on CCG-1901, NY I and NY II. Conclusion: Children with high-risk ALL do not appear to benefit from prophylactic G-CSF.