IDEC-131 (Anti-CD154), Sirolimus and Donor-Specific Transfusion Facilitate Operational Tolerance in Non-Human Primates

CD154-specific antibody therapy prevents allograft rejection in many experimental transplant models. However, initial clinical transplant trials with anti-CD154 have been disappointing suggesting the need for as of yet undetermined adjuvant therapy. In rodents, donor antigen (e.g., a donor blood transfusion), or mTOR inhibition (e.g., sirolimus), enhances anti-CD154's efficacy. We performed renal transplants in major histocompatibility complex-(MHC) mismatched rhesus monkeys and treated recipients with combinations of the CD154-specific antibody IDEC-131, and/or sirolimus, and/or a pre-transplant donor-specific transfusion (DST). Therapy was withdrawn after 3 months. Triple therapy prevented rejection during therapy in all animals and led to operational tolerance in three of five animals including donor-specific skin graft acceptance in the two animals tested. IDEC-131, sirolimus and DST are highly effective in preventing renal allograft rejection in primates. This apparently clinically applicable regimen is promising for human renal transplant trials.     

Canadian Consensus Recommendations for the Optimal Use of Enfuvirtide in HIV/AIDS Patients.

BACKGROUND AND OBJECTIVES: An eight-member group consisting of Canadian infectious disease and immunology specialists and a family physician with significant experience in HIV management was convened to update existing recommendations, specifically intended for use by Canadian HIV-treating physicians, on the appropriate use of enfuvirtide in HIV/AIDS patients with resistance to other antiretroviral drugs. METHODS: Evidence from the literature and expert opinions of the group members formed the basis of the guidelines. Comments on the draft guidelines were obtained from other physicians across Canada with HIV expertise. The final guidelines represent the group's consensus agreement. RESULTS AND CONCLUSIONS: The recommendations were developed to guide physicians in optimal practices in patient selection for enfuvirtide treatment and subsequent patient management. The issues considered include positive predictors of response to enfuvirtide, stage of disease, optimization of the background regimen, early indicators of enfuvirtide response, and patient education and support.     

Development of neurochemical separation of ON and OFF channels at retinal ganglion cells

Anatomical and physiological segregation of neurons into ON (brightening detector) and OFF (darkening detector) channels in the retina and subsequent visual system ensure the high sensitivity required for contrast detection and spatial discrimination. This segregation is finest at the visual axis. Neurochemically, ON and OFF ganglion cells at the visual axis seem to be distinguished by different inhibitory transmitters but not excitatory transmitters. Microiontophoretic studies of inhibitory transmitters on the retinal ganglion cells in kittens and adult cats suggest that this neurochemical distinction is poor in immature ganglion cells at the visual axis. Initially both ON and OFF cells seem to be supplied by GABAergic, glycinergic, and catecholaminergic amacrine cells, but in adults, ON cells remain supplied only by GABAergic amacrines, while OFF cells are supplied by glycinergic amacrines. Postnatal elimination of multiple inputs and strengthening of the appropriate inputs, as seen in the central nervous system, also seem to occur at the retinal neurotransmitter synapses during development.     

Different effects of unilateral versus bilateral subthalamic nucleus stimulation on walking and reaching in Parkinson's disease.

The purpose of this study was to determine the effects of unilateral versus bilateral subthalamic nucleus (STN) stimulation on quantitative measures of walking and reaching in Parkinson's disease (PD). We used kinematic measures and the Unified Parkinson's Disease Rating Scale (UPDRS) motor subscale (subscale III) to evaluate the movement of 6 people with PD who had bilateral STN stimulators implanted for at least 6 months and withheld their anti-parkinson medication for at least 8 hours. Subjects were studied with both stimulators off, one on, and both on. Kinematic data were collected as subjects walked, reached to a target, and were rated using the UPDRS motor subscale. STN stimulation improved walking speed and stride length, with the greatest benefit from bilateral stimulation. Reaching speed was improved by unilateral STN stimulation alone, with no additive effect of bilateral stimulation. UPDRS motor subscale ratings paralleled the kinematic findings. STN stimulation did not restore PD subjects' movements to the level of age-matched controls. Overall, these results provide further evidence that the basal ganglia pathways involved in control of walking and reaching may be distinct. We speculate that basal ganglia may influence walking through bilateral pedunculopontine projections and reaching through ipsilateral thalamocortical projections. Our findings also suggest that maximal improvement of walking requires bilateral rather than unilateral STN stimulation.     

Prevalence of knee abnormalities in patients with osteoarthritis and anterior cruciate ligament injury identified with peripheral magnetic resonance imaging: a pilot study.

OBJECTIVES: 1) To assess, with a peripheral magnetic resonance imaging system (pMRI), the prevalence of bony and soft tissue abnormalities in the knee joints of normal subjects, osteoarthritis (OA) patients, and individuals who have suffered an anterior cruciate ligament (ACL) rupture; and 2) to compare the prevalence among groups. METHODS: Magnetic resonance (MR) images of 28 healthy, 32 OA, and 26 ACL damaged knees were acquired with a 1.0-T pMRI system. Two radiologists graded the presence and severity of 9 MR image features: cartilage degeneration, osteophytes, subchondral cyst, bone marrow edema, meniscal abnormality, ligament integrity, loose bodies, popliteal cysts, and joint effusion. RESULTS: Ten of 28 healthy (35.7%), 24 of 26 ACL (92.3%), and all OA knees (100%) showed prevalent cartilage defects; 5 healthy (17.9%), 20 ACL (76.9%), and all OA knees (100%) had osteophytes; and 9 normal (32.1%), 21 ACL (80.8%), and 29 OA knees (90.6%) had meniscal abnormalities. One-half of the knees in the OA group (16 of 32, 50%) had subchondral cysts, and almost one-half had bone marrow edema (15 of 32, 46.9%). These features were not common in the ACL group (7.7%, and 11.5%, respectively) and were not observed in healthy knees. The OA group had the most severe cartilage defects, osteophytes, bone marrow edema, subchondral cysts, and meniscal abnormalities; the ACL group showed more severe cartilage defects, osteophytes, and meniscal abnormalities than did normal subjects. CONCLUSION: The results suggest that knees that have sustained ACL damage have OA-like reatures; most subjects (19 of 26, 73.1%) could be identified as in the early stage of OA. The prominent abnormalities present in ACL-damaged knees are cartilage defects, osteophytes, and meniscal abnormalities.     

Osteogenic potential of postnatal skeletal muscle-derived stem cells is influenced by donor sex.

This study compared the osteogenic differentiation of F-MDSCs and M-MDSCs. Interestingly, M-MDSCs expressed osteogenic markers and underwent mineralization more readily than F-MDSCs; a characteristic likely caused by more osteoprogenitor cells within the M-MDSCs than the F-MDSCs and/or an accelerated osteogenic differentiation of M-MDSCs. INTRODUCTION: Although therapies involving stem cells will require both female and male cells, few studies have investigated whether sex-related differences exist in their osteogenic potential. Here, we compared the osteogenic differentiation of female and male mouse skeletal muscle-derived stem cells (F- and M-MDSCs, respectively), a potential cell source for orthopedic tissue engineering. MATERIALS AND METHODS: F- and M-MDSCs were stimulated with bone morphogenetic protein (BMP)4, followed by quantification of alkaline phosphatase (ALP) activity and expression of osteogenic genes. F- and M-MDSCs were also cultured as pellets in osteogenic medium to evaluate mineralization. Single cell-derived colonies of F- and M-MDSCs were stimulated with BMP4, stained for ALP, and scored as either Low ALP+ or High ALP+ to detect the presence of osteoprogenitor cells. F- and M-MDSCs were transduced with a BMP4 retrovirus (MDSC-BMP4 cells) and used for the pellet culture and single cell-derived colony formation assays. As well, F- and M-MDSC-BMP4 cells were implanted in the intramuscular pocket of sex-matched and sex-mismatched hosts, and bone formation was monitored radiographically. RESULTS AND CONCLUSIONS: When stimulated with BMP4, both F- and M-MDSCs underwent osteogenic differentiation, although M-MDSCs had a significantly greater ALP activity and a larger increase in the expression of osteogenic genes than F-MDSCs. In the pellet culture assay, M-MDSCs showed greater mineralization than F-MDSCs. BMP4 stimulation of single cell-derived colonies from M-MDSCs showed higher levels of ALP than those from F-MDSCs. Similar results were obtained with the MDSC-BMP4 cells. In vivo, F-MDSC-BMP4 cells displayed variability in bone area and density, whereas M-MDSC-BMP4 cells showed a more consistent and denser ectopic bone formation. More bone formation was also seen in male hosts compared with female hosts, regardless of the sex of the implanted cells. These results suggest that M-MDSCs may contain more osteoprogenitor cells than F-MDSCs, which may have implications in the development of cellular therapies for bone healing.     

Changes to osteoporosis prevalence according to method of risk assessment.

The impact of clinical risk factor-based absolute risk methods on the prevalence of high risk for osteoporotic fracture is unknown. We applied absolute risk methods to 6646 subjects and found that the prevalence of elderly women deemed to be at high risk increased substantially, whereas the overall prevalence was highly dependent on the threshold used to designate high risk. INTRODUCTION: Many groups have advocated using absolute risk methods that incorporate clinical risk factors to target patients for osteoporosis therapy. We examined how the application of such absolute risk classification systems influences the prevalence of those considered to be at high risk for osteoporotic fracture and compared these systems to one based solely on BMD. MATERIALS AND METHODS: Using 6646 subjects from the Canadian Multicentre Osteoporosis Study (CaMos), a prospective, randomly selected, population-based cohort, we assessed three different systems for determining prevalence of high risk for osteoporotic fracture: a BMD-based system; a simplified risk factor system incorporating age, sex, BMD, and two clinical risk factors; and a comprehensive system, incorporating age, sex, BMD, and seven clinical risk factors. The 10-year absolute risks of incident fragility fracture were compared across systems using three different high-risk thresholds. RESULTS: The prevalence of a T score < or = -2.5 was 18.8% (95% CI: 17.7-19.9%) in women and 3.9% (95% CI: 3.0-4.7%) in men. Using a 15% 10-year risk of fracture threshold, the prevalence of women at high risk increased to 46.9% (95% CI: 45.4-48.4) and 42.5% (95% CI: 41.1-43.9) when the comprehensive and simplified risk factor classification systems were used, respectively. Using a 25% 10-year absolute risk threshold, the prevalence of high risk was similar to that of the BMD-based system, whereas the 20% threshold gave intermediate rates. All thresholds analyzed resulted in an increased prevalence of older women at high risk for fracture, whereas only the 15% 10-year risk of fracture threshold resulted in an increase in the prevalence of men at high risk. CONCLUSIONS: The application of risk factor-based systems results in an increased prevalence of older women at high risk. The prevalence of individuals at high risk may increase with changes to the methods used to determine those who are eligible for therapy. These data have important implications for the pattern of care and costs of treating osteoporotic fractures.