Tumor necrosis factor alpha (TNF-alpha) coordinately regulates the expression of specific matrix metalloproteinases (MMPS) and angiogenic factors during fracture healing.

Recent studies from our laboratory demonstrate that TNF-alpha signaling contributes to the regulation of chondrocyte apoptosis and a lack of TNF-alpha signaling leads to a persistence of cartilaginous callus and delayed resorption of mineralized cartilage. This study examines how delays in the endochondral repair process affect the expression of specific mediators of proteolytic cartilage turnover and vascularization. Simple closed fractures were produced in wild type and TNF-alpha receptor (p55-/-/p75-/-)-deficient mice. Using ribonuclease protection assay (RPA) and microarray analysis, the expression of multiple mRNAs for various angiogenic factors and the metalloproteinase gene family were measured in fracture calluses. The direct actions of TNFalpha on the expression of specific angiogenic factors and metalloproteinases (MMPs) was examined in both cultured callus cells and articular chondrocytes to compare the effects of TNF-alpha in growth cartilage versus articular cartilage. MMPs 2, 9, 13, and 14 were quantitatively the most prevalent metalloproteases and all showed peaks in expression during the chondrogenic period. In the absence of TNF-alpha signaling, the expression of all of these mRNAs was reduced. The angiopoietin families of vascular regulators and their receptors were expressed at much higher levels than the VEGFs and their receptors and while the angiopoietins showed diminished or delayed expression in the absence of TNF-alpha signaling, VEGF and its receptors remained unaltered. The expression of vascular endothelial growth inhibitor (VEGI or TNFSF15) showed a near absence in its expression in the TNF-alpha receptor-deficient mice. In vitro assessment of cultured fracture callus cells in comparison to primary articular chondrocytes showed that TNF-alpha treatment specifically induced the expression of MMP9, MMP14, VEGI, and Angiopoietin 2. These results suggest that TNF-alpha signaling in chondrocytes controls vascularization of cartilage through the regulation of angiopoietin and VEGI factors which play counterbalancing roles in the induction of growth arrest, or apoptosis in endothelial cells. Furthermore, TNF-alpha appears to regulate, in part, the expression of two key proteolytic enzymes, MMP 9 and MMP14 that are known to be crucial to the progression of vascularization and turnover of mineralized cartilage. Thus, TNF-alpha signaling in healing fractures appears to coordinate the expression of specific regulators of endothelial cell survival and metalloproteolytic enzymes and is essential in the transition and progression of the endochondral phase of fracture repair.

The Paced Auditory Serial Addition Test: to what extent is it performed as instructed, and is it associated with disease course?

One commonly used outcome measure in multiple sclerosis (MS) clinical trials is the Multiple Sclerosis Functional Composite, which includes the Paced Auditory Serial Addition Test (PASAT) as a measure of cognitive function. Concerns have been raised about the standard PASAT scoring method, whereby the number of correct responses is summed. This method does not take into account whether the test is performed as intended, which may affect interpretation of the results. Accordingly, another scoring method has been proposed, which examines the number of times a correct response is immediately preceded by another correct response (termed a dyad). We compared the two scoring methods for the PASAT, and found that the mean percentage of correct responses not accounted for by dyads ranged from 27.5% to 49.5%, indicating that much of the time the test is not performed as instructed. We also examined disease course and the PASAT score, as studies have produced conflicting results as to whether disease course is associated with cognitive impairment. Although disease course was significantly associated with the PASAT score, it accounted for little of the variation in scores, even when adjusting for other predictors. Finally, as 14.2% of participants refused to do the PASAT or failed to complete it, we also examined whether the Perceived Deficits Questionnaire (PDQ), a self-reported measure of cognitive function, is a potential proxy measure for the PASAT. The correlation between the two tools was low (-0.14), suggesting that the PDQ is not a useful substitute for the PASAT.

Measurement of health-related quality of life in multiple sclerosis patients.

BACKGROUND: Patient outcomes in multiple sclerosis (MS) have generally been measured by their neurological impairment using specific scales such as the Kurtzke Expanded Disability Status Scale (EDSS). However, this scale does not measure the multiple dimensions of health-related quality of life (HRQOL) such as functional status and general well-being, which are also important outcomes along with disease-specific measurements. METHODS: HRQOL was measured in a group of 97 MS patients using the RAND 36-item Health Survey 1.0. The EDSS score was assigned by the clinic neurologist. Additional data were collected from the clinical record for each patient. RESULTS: MS patients scored poorly in a number of HRQOL domains such as physical and role functioning and energy or vitality. Disability as quantified by the EDSS correlated only with the physical functioning domain. Regression models were developed to measure the relationship between patient characteristics (independent variables) and HRQOL domains (dependent variables). DISCUSSION: A number of patient characteristics were associated with higher or lower scores on the HRQOL domains. Of particular interest is the finding that a family history of MS was associated with poorer physical and social functioning as well as more pain and less vitality. The occurrence of seizures had a negative impact on role functioning, social functioning and general health perceptions. HRQOL gives caregivers a broader measure of disease burden than the EDSS alone, and should be useful in planning and monitoring interventions.