Citations

Abstract Multiple myeloma (MM) and primary systemic amyloidosis (AL) remain incurable disorders, and new treatments targeted to the malignant plasma cells are needed. Alemtuzumab is a humanized monoclonal antibody to CD52 and has activity in chronic lymphocytic leukemia. We examined the CD52 expression on CD45+ and CD45- plasma cell populations to evaluate the potential for using alemtuzumab for these disorders. Bone marrows from 61 patients (29 AL, 23 MM, and 9 MGUS [monoclonal gammopathies of undetermined significance]) were studied using 3-color (CD38/45/52) flow cytometry. Among those with MGUS, MM, and AL, 67%, 52%, and 35%, respectively, were positive for CD52 expression. The CD52 expression was predominantly confined to the clonal CD38+/CD45+ plasma cell fraction with median expression of 68%, 88%, and 82% in MGUS, MM, and AL, respectively, compared with 18%, 6%, and 9% among the CD45- plasma cell population. Clinical trials are warranted in these diseases to learn the therapeutic benefit of anti-CD52 immunotherapy.

AbstractT cells are produced through 2 mechanisms, thymopoiesis and proliferative expansion of postthymic T cells. Thymic output generates diversity of the pool, and proliferation achieves optimal clonal size of each individual T cell. To determine the contribution of these 2 mechanisms to the formation of the initial T-cell repertoire, we examined neonates of 30 to 40 weeks' gestation. Peripheral T cells were in a state of high proliferative turnover. In premature infants, 10% of T cells were dividing; the proliferation rates then declined but were still elevated in mature newborns. Throughout the third trimester, concentrations of T-cell–receptor excision circles (TRECs) were 10 per 100 T cells. Stability of TREC frequencies throughout the period of repertoire generation suggested strict regulation of clonal size to approximately 10 to 20 cells. Neonatal naive CD4+ and CD8+ T cells were explicitly responsive to IL-7; growth-promoting properties of IL-15 were selective for newborn CD8+ T cells. Neonatal T cells expressed telomerase and, in spite of the high turnover, built up a telomeric reserve. Thus, proliferative expansion, facilitated by increased cytokine responsiveness, and thymopoiesis complement each other as mechanisms of T-cell production in neonates. Maintaining optimal clonal size instead of filling the space in a lymphopenic host appears to regulate homeostatic T-cell proliferation during fetal development.

Exposure and ritual prevention (EX/RP) is an effective treatment for obsessive compulsive disorder (OCD), although it is neither universally nor completely helpful. Compliance with EX/RP treatment procedures has been linked theoretically to posttreatment outcome, yet empirical exploration of this relationship has been insufficient. In this study, therapists were asked to rate the treatment compliance of 28 consecutive patients who received EX/RP on a fee-for-service basis. Results indicated that understanding the treatment rationale and compliance with insession and homework exposure instructions, but not with ritual prevention and self-monitoring of rituals, was significantly related to posttreatment OCD symptom severity. Clinical implications of these findings and future directions in treatment compliance research with OCD patients are discussed.

This study identified the salient issues of caregiving for family members of persons with dementia using computer-assisted content analysis followed by factor analysis. Differences in responses between caregivers in two treatment groups were also noted. Caregivers (N = 226) were interviewed on three occasions over 12 months. They consistently identified the following themes of caregiving in order of significance: (a) making meaning of the experience; (b) defining the caregiver role; (c) identifying specific caregiving strategies; (d) dealing with change, unpredictability, and vulnerability; (e) evaluating past and future decisions and quality of care; and (f) finding help and support. This representation of the caregiving experience is useful to home care nurses by providing a framework to address issues most important to caregivers and upon which therapeutic interventions can be developed.

Abstract Glucocorticoids (GCs) are commonly used to treat inflammatory disease; unfortunately, the long-term use of these steroids leads to a large number of debilitating side effects. The antiinflammatory effects of GCs are a result of GC receptor (GR)-mediated inhibition of expression of proinflammatory genes as well as GR-mediated activation of antiinflammatory genes. Similarly, side effects are most likely due to both activated and repressed GR target genes in affected tissues. An as yet unachieved pharmaceutical goal is the development of a compound capable of separating detrimental side effects from antiinflammatory activity. We describe the discovery and characterization of AL-438, a GR ligand that exhibits an altered gene regulation profile, able to repress and activate only a subset of the genes normally regulated by GCs. When tested in vivo, AL-438 retains full antiinflammatory efficacy and potency comparable to steroids but its negative effects on bone metabolism and glucose control are reduced at equivalently antiinflammatory doses. The mechanism underlying this selective in vitro and in vivo activity may be the result of differential cofactor recruitment in response to ligand. AL-438 reduces the interaction between GR and peroxisomal proliferator-activated receptor γ coactivator-1, a cofactor critical for steroid-mediated glucose up-regulation, while maintaining normal interactions with GR-interacting protein 1. This compound serves as a prototype for a unique, nonsteroidal alternative to conventional GCs in treating inflammatory disease.

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.