Adjuvant Cannabinoid Receptor Type 2 Agonist Modulates the Polarization of Microglia Towards a Non-Inflammatory Phenotype in Experimental Pneumococcal Meningitis.

Background: Microglia initiates and sustains the inflammatory reaction that drives the pathogenesis of pneumococcal meningitis. The expression of the G-protein cannabinoid receptor type 2 (CB2) in the brain is low, but is upregulated in glial cells during infection. Its activation down-regulates pro-inflammatory processes, driving microglia towards an anti-inflammatory phenotype. CB2 agonists are therefore therapeutic candidates in inflammatory conditions like pneumococcal meningitis. We evaluated the effects of JWH-133, a specific CB2 agonist on microglial cells, inflammation, and damage driven by S. pneumoniaein vitro and in experimental pneumococcal meningitis. Materials/methods: Primary mixed glial cultures were stimulated with live or heat-inactivated S. pneumoniae, or lipopolysaccharide and treated with JWH-133 or vehicle. Nitric oxide and cytokines levels were measured in the supernatant. In vivo, pneumococcal meningitis was induced by intracisternal injection of live S. pneumoniae in 11 days old Wistar rats. Animals were treated with antibiotics (Ceftriaxone, 100 mg/kg, s.c. bid) and JWH-133 (1 mg/kg, i.p. daily) or vehicle (10% Ethanol in saline, 100 µl/25g body weight) at 18 h after infection. Brains were harvested at 24 and 42 h post infection (hpi) for histological assessment of hippocampal apoptosis and cortical damage and determination of cyto/chemokines in tissue homogenates. Microglia were characterized using Iba-1 immunostaining. Inflammation in brain homogenates was determined using membrane-based antibody arrays. Results: In vitro, nitric oxide and cytokines levels were significantly lowered by JWH-133 treatment. In vivo, clinical parameters were not affected by the treatment. JWH-133 significantly lowered microglia activation assessed by quantification of cell process length and endpoints per microglia. Animals treated with JWH-133 demonstrated significantly lower parenchymal levels of chemokines (CINC-1, CINC-2α/ß, and MIP-3α), TIMP-1, and IL-6 at 24 hpi, and CINC-1, MIP-1α, and IL-1α at 42 hpi. Quantitative analysis of brain damage did not reveal an effect of JWH-133. Conclusions: JWH-133 attenuates microglial activation and downregulates the concentrations of pro-inflammatory mediators in pneumococcal infection in vitro and in vivo. However, we didn't observe a reduction in cortical or hippocampal injury. This data provides evidence that inhibition of microglia by adjuvant CB2 agonists therapy effectively downmodulates neuroinflammation but does not reduce brain damage in experimental pneumococcal meningitis.

Performance of PROMIS Global-10 Compared With Legacy Instruments for Rotator Cuff Disease.

BACKGROUND: The Patient-Reported Outcomes Measurement Information System (PROMIS) Global-10 was recently developed to assess physical and mental health and provide an estimated EuroQol-5 Dimension (EQ-5D) score. This instrument needs to be validated for specific patient cohorts such as those with rotator cuff pathology. HYPOTHESIS: There is moderate to high correlation between the PROMIS Global-10 and legacy patient-reported outcome measures; PROMIS Global-10 will not show ceiling effects; and estimated EQ-5D scores will show good correlation and low variance with actual EQ-5D scores. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 2. METHODS: A total of 323 patients with rotator cuff disease were prospectively enrolled before treatment. Each patient completed the PROMIS Global-10, EQ-5D, American Shoulder and Elbow Surgeons (ASES) shoulder assessment form, and Single Assessment Numeric Evaluation (SANE), and those with known rotator cuff tears completed the Western Ontario Rotator Cuff Index (WORC). Spearman correlations were calculated. Bland-Altman agreement tests were conducted between estimated EQ-5D scores from the PROMIS and actual EQ-5D scores. Ceiling and floor effects were assessed, defined as ≥15% respondents with highest or lowest possible score. RESULTS: Correlation between the PROMIS Global-10 and EQ-5D was excellent (0.70, P < .0001). Correlation of the PROMIS physical scores was excellent-good with the ASES (0.62, P < .0001), good with the WORC (0.47, P < .0001), and good with the SANE (0.41, P < .0005). Correlation between the PROMIS mental scores was poor with the ASES (0.34, P < .0001), the WORC (0.32, P = .0016), and the SANE (0.24, P < .0001). No floor or ceiling effects were found. Agreement analysis showed substantial variance in individual scores, despite the overall similarity in mean scores between the estimated and actual EQ-5D scores, indicating poor agreement. Bland-Altman 95% limits of agreement for estimated EQ-5D scores ranged from 34% below to 31% above actual EQ-5D scores. CONCLUSION: Physical function scores of the PROMIS Global-10 show high correlation with legacy patient-reported outcome instruments, suggesting that it is a reliable tool for outcome assessment in a population with rotator cuff pathology. The large variability in 95% limit of agreement suggested that the estimated EQ-5D scores from the PROMIS Global-10 cannot replace traditional EQ-5D scores.

Performance of PROMIS Global-10 compared with legacy instruments in patients with shoulder arthritis.

BACKGROUND: The Patient-Reported Outcomes Measurement Information System (PROMIS) Global-10 measures physical and mental health and provides an estimated EuroQol-5 Dimension (EQ-5D) score. The purpose of this study was to determine the correlation between the PROMIS Global-10 and several gold-standard legacy measures to validate its overall performance and usefulness in patients with shoulder arthritis. METHODS: The study prospectively enrolled 161 patients with shoulder arthritis before treatment. Each patient completed the PROMIS, EQ-5D, American Shoulder and Elbow Surgeons (ASES) Assessment Form, Single Assessment Numeric Evaluation (SANE), and Western Ontario Osteoarthritis of the Shoulder (WOOS) Index. Spearman correlations were calculated, and Bland-Altman agreement tests were conducted between estimated EQ-5D scores from the PROMIS and actual EQ-5D scores. Ceiling and floor effects were determined. RESULTS: Correlation between the PROMIS and EQ-5D was excellent (0.72, P < .001). However, agreement for estimated EQ-5D ranged from 0.37 below to 0.36 above actual EQ-5D scores. Correlation of the PROMIS physical score was good with the ASES score (0.57, P < .001) and poor with the SANE score (0.23, P = .0045) and WOOS score (0.11, P = .3743). Correlation of the PROMIS mental score was poor when compared with all patient-reported outcome instruments investigated (ASES score, 0.26 [P = .0012]; SANE score, 0.13 [P = .1004]; and WOOS score, 0.09 [P = .4311]). No floor or ceiling effects were observed. CONCLUSION: PROMIS Global-10 physical scores show excellent correlation with the EQ-5D. However, the PROMIS Global-10 cannot replace actual EQ-5D scores for cost-effectiveness assessment in this population because of the large variance in agreement between actual and PROMIS Global-10-estimated EQ-5D scores. PROMIS Global-10 physical scores showed good correlation with the ASES score but poor correlation with other gold-standard patient-reported outcome instruments, suggesting that it is an inappropriate instrument for outcome measurement in populations with shoulder arthritis.