Donor IFN-gamma receptors are critical for acute CD4(+) T cell-mediated cardiac allograft rejection.

Recent studies using mouse models demonstrate that CD4(+) T cells are sufficient to mediate acute cardiac allograft rejection in the absence of CD8(+) T cells and B cells. However, the mechanistic basis of CD4-mediated rejection is unclear. One potential mechanism of CD4-mediated rejection is via elaboration of proinflammatory cytokines such as IFN-gamma. To determine whether IFN-gamma is a critical cytokine in CD4-mediated acute cardiac allograft rejection, we studied whether the expression of IFN-gamma receptors on the donor heart was required for CD4-mediated rejection. To investigate this possibility, purified CD4(+) T cells were transferred into immune-deficient mice bearing heterotopic cardiac allografts from IFN-gamma receptor-deficient (GRKO) donors. While CD4(+) T cells triggered acute rejection of wild-type heart allografts, they failed to trigger rejection of GRKO heart allografts. The impairment in CD4-mediated rejection of GRKO hearts appeared to primarily involve the efferent phase of the immune response. This conclusion was based on the findings that GRKO stimulator cells provoked normal CD4 proliferation in vitro and that intentional in vivo challenge of CD4 cells with wild-type donor APC or the adoptive transfer of in vitro primed CD4 T cells failed to provoke acute rejection of GRKO allografts. In contrast, unseparated lymph node cells acutely rejected both GRKO and wild-type hearts with similar time courses, illustrating the existence of both IFN-gamma-dependent and IFN-gamma-independent mechanisms of acute allograft rejection.

Radiographic grading for knee osteoarthritis. A revised scheme that relates to alignment and deformity.

OBJECTIVE: To develop a radiographic grading scheme for osteoarthritis of the knee that would relate to arthritic progression and deformity. METHODS: The scheme of Scott, et al was revised to include new fields of Tibial Erosion and Subluxation; the fields of Tibial Osteophytes and Sclerosis were removed. The worst affected compartment only was scored on frontal Standardized Knee Images, which were used to define knee alignment variables. RESULTS: The interreader reliability (kappa = 0.92) and correlation for total scores (r = 0.94) were both excellent (p < 0.001). Individual field scores and total knee scores both correlated well with most limb alignment variables, especially the hip-knee-ankle angle (r = 0.77, p < 0.001). CONCLUSION: These findings encourage further evaluations for outcome measurement, diagnostic sensitivity, and sensitivity to define arthritic change over time.

Kinematics of the knee joint in deep flexion: a radiographic assessment.

The purpose of this study is to describe the kinematics of normal knees in vivo, assessed in deep flexion, using bi-planar radiographs. Antero-posterior and lateral views were obtained from five healthy males during three sequential positions of kneeling. In the first position, the subject knelt with the knees fully flexed (deep flexion between 150 and 165 degrees) and torso upright. In the second position, the subject bowed forward to an intermediate position (about 120 degrees of knee flexion). In the third position, the subject bowed further until his head touched the floor, supporting the upper torso with hands and with the knees flexed at about 90 degrees. The results show that past 135 degrees of knee flexion, the patella cleared the femoral groove and was in contact only with the condyles. For these particular postures, and during deep flexion, motion of the femur on the tibia did not reveal the classical femoral 'roll back'. Rather the lateral femoral condyle rolled further over the postero medial aspect of the lateral tibial plateau while contact of the medial femoral condyle occurred more anteriorly, but still in the posterior part of the medial plateau. This asymmetric rolling motion indicated an element of internal tibial rotation. Furthermore, the tibia was found to articulate with the femur at the most proximal points of the condyles in deep flexion. These data on the kinematics and contact characteristics of the tibio-femoral joint must be considered in any approach to design for a Deep Flexion Knee Implant.

Evaluation of new vaccines in the mouse and guinea pig model of tuberculosis.

The results of this study provide the first evidence that two completely separate vaccine approaches, one based on a subunit vaccine consisting of a mild adjuvant admixed with purified culture filtrate proteins and enhanced by the cytokine interleukin-2 and the second based on immunization with DNA encoding the Ag85A protein secreted by Mycobacterium tuberculosis, could both prevent the onset of caseating disease, which is the hallmark of the guinea pig aerogenic infection model. In both cases, however, the survival of vaccinated guinea pigs was shorter than that conferred by Mycobacterium bovis BCG, with observed mortality of these animals probably due to consolidation of lung tissues by lymphocytic granulomas. An additional characteristic of these approaches was that neither induced skin test reactivity to commercial tuberculin. These data thus provide optimism that development of nonliving vaccines which can generate long-lived immunity approaching that conferred by the BCG vaccine is a feasible goal.

Knee kinematics in-vivo of kneeling in deep flexion examined by bi-planar radiographs.

Squatting and kneeling are important daily activities for Middle and Far East cultures that require positioning the knee in deep flexion. In these activities, the limb becomes fully flexed with a knee flexion angle reaching between 150 and 160 degrees and the heel reaching the posterior surface of the upper thigh. Existing knee prostheses do not allow a full return to normal activities for this large population since they are limited to achieving knee flexion of about 120 degrees. Also, there is very limited information on knee kinematics and/or forces in the range beyond 120 degrees. The purpose of this study is to describe the kinematics of normal knees in-vivo, assessed in deep flexion, using bi-planar radiographs. A-P and lateral views were obtained from 5 healthy subjects during three sequential positions of kneeling. In the 1st position, the subject knelt with the knees fully flexed (deep flexion between 150 degrees and 160 degrees) and torso upright. In the 2nd position, the subject bowed forward to an intermediate position (about 120 degrees of knee flexion). In the 3rd position, the subject bowed further until his/her head touched the floor, supporting the upper torso with hands and attaining a knee flexion of about 90 degrees. The results show that past 135 degrees of knee flexion, the patella was found to clear the femoral groove and was in contact only with the condyles. The results also show that the classical femoral "roll back" does not appear to occur in deep flexion. It seems that the lateral femoral condyle rolls over the postero medial aspect of the lateral tibial plateau while contact of the medial femoral condyle occurs more anteriorly, but still in the posterior aspect of the medial tibial plateau. This asymmetric rolling motion implies an element of internal tibial rotation. Furthermore, the tibia was found to articulate with the femur at the most proximal points of the condyles in deep flexion. These data on the kinematics and contact characteristics of the tibio-femoral joint must be considered in any approach to design for a Deep Flexion Knee Implant.

Low-dose aerosol infection model for testing drugs for efficacy against Mycobacterium tuberculosis.

As a paradigm for chronic infectious diseases, tuberculosis exhibits a variety of clinical presentations, ranging from primary pulmonary tuberculosis to reactivation tuberculosis and cavitary disease. To date, the animal models used in evaluating chemotherapy of tuberculosis have been high-dose intravenous models that mimic the disseminated forms of the disease. In the present study, we have used a low-dose aerosol exposure model which we feel better reflects newly diagnosed tuberculosis in patients converting to tuberculin positivity. As appropriate examples of chemotherapy, four rifamycins (rifampin, rifabutin, rifapentine, and KRM-1648) were tested, first in an in vitro murine macrophage model and then in the low-dose aerosol infection model, for their activity against Mycobacterium tuberculosis. In both models, KRM-1648 had the highest level of activity of the four compounds. In the infected-lung model, rifabutin, rifapentine, and KRM-1648 all had sterilizing activity when given orally at 5 mg/kg of body weight per day. When given at 2.5 mg/kg/day, KRM-1648 had the highest level of activity of the four drugs, reducing the bacterial load by 2.7 logs over 35 days of therapy.