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Thermodynamic arguments imply that global mean rainfall increases in a warmer atmosphere; however, dynamical effects may result in more significant diversity of regional precipitation change. Here we investigate rainfall changes in the mid-Pliocene Warm Period (~ 3 Ma), a time when temperatures were 2-3ºC warmer than the pre-industrial era, using output from the Pliocene Model Intercomparison Projects phases 1 and 2 and sensitivity climate model experiments. In the Mid-Pliocene simulations, the higher rates of warming in the northern hemisphere create an interhemispheric temperature gradient that enhances the southward cross-equatorial energy flux by up to 48%. This intensified energy flux reorganizes the atmospheric circulation leading to a northward shift of the Inter-Tropical Convergence Zone and a weakened and poleward displaced Southern Hemisphere Subtropical Convergences Zones. These changes result in drier-than-normal Southern Hemisphere tropics and subtropics. The evaluation of the mid-Pliocene adds a constraint to possible future warmer scenarios associated with differing rates of warming between hemispheres.

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OBJECTIVES:: Previous reports have revealed that several cytokines (including platelet-derived growth factor-BB, transforming growth factors-ß1 and insulin-like growth factor-1) can enhance the rate of bone formation and synthesis of extracellular matrix in orthopaedics or periodontology. This study aimed to determine the concentration of cytokines within platelet-rich fibrin microstructures and investigate whether there are differences in the different portions of platelet-rich fibrin, which has implications for proper clinical use of platelet-rich fibrin gel. METHODS:: Whole blood was obtained from six New Zealand rabbits (male, 7 to 39 weeks old, weight 2.7-4 kg); it was then centrifuged for preparation of platelet-rich fibrin gels and harvest of plasma. The resultant platelet-rich fibrin gels were used for cytokine determination, histological analyses and scanning electron microscopy. All plasmas obtained were subject to the same cytokine determination assays for the purpose of comparison. RESULTS:: Cytokines platelet-derived growth factor-BB and transforming growth factor-ß1 formed concentration gradients from high at the red blood cell end of the platelet-rich fibrin gel (p=1.88×10-5) to low at the plasma end (p=0.19). Insulin-like growth factor-1 concentrations were similar at the red blood cell and plasma ends. The porosities of the platelet-rich fibrin samples taken in sequence from the red blood cell end to the plasma end were 6.5% ± 4.9%, 24.8% ± 7.5%, 30.3% ± 8.5%, 41.4% ± 12.3%, and 40.3% ± 11.7%, respectively, showing a gradual decrease in the compactness of the platelet-rich fibrin network. CONCLUSION:: Cytokine concentrations are positively associated with platelet-rich fibrin microstructure and portion in a rabbit model. As platelet-rich fibrin is the main entity currently used in regenerative medicine, assessing cytokine concentration and the most valuable portion of PRF gels is essential and recommended to all physicians.

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OBJECTIVES: Previous reports have revealed that several cytokines (including platelet-derived growth factor-BB, transforming growth factors-β1 and insulin-like growth factor-1) can enhance the rate of bone formation and synthesis of extracellular matrix in orthopaedics or periodontology. This study aimed to determine the concentration of cytokines within platelet-rich fibrin microstructures and investigate whether there are differences in the different portions of platelet-rich fibrin, which has implications for proper clinical use of platelet-rich fibrin gel. METHODS: Whole blood was obtained from six New Zealand rabbits (male, 7 to 39 weeks old, weight 2.7-4 kg); it was then centrifuged for preparation of platelet-rich fibrin gels and harvest of plasma. The resultant platelet-rich fibrin gels were used for cytokine determination, histological analyses and scanning electron microscopy. All plasmas obtained were subject to the same cytokine determination assays for the purpose of comparison. RESULTS: Cytokines platelet-derived growth factor-BB and transforming growth factor-β1 formed concentration gradients from high at the red blood cell end of the platelet-rich fibrin gel (p=1.88×10-5) to low at the plasma end (p=0.19). Insulin-like growth factor-1 concentrations were similar at the red blood cell and plasma ends. The porosities of the platelet-rich fibrin samples taken in sequence from the red blood cell end to the plasma end were 6.5% ± 4.9%, 24.8% ± 7.5%, 30.3% ± 8.5%, 41.4% ± 12.3%, and 40.3% ± 11.7%, respectively, showing a gradual decrease in the compactness of the platelet-rich fibrin network. CONCLUSION: Cytokine concentrations are positively associated with platelet-rich fibrin microstructure and portion in a rabbit model. As platelet-rich fibrin is the main entity currently used in regenerative medicine, assessing cytokine concentration and the most valuable portion of PRF gels is essential and recommended to all physicians.

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BACKGROUND: Current guidelines for acute coronary syndrome recommend clopidogrel for an optimal period of 12 months in order to reduce the risk of reinfarction and mortality. Premature clopidogrel discontinuation has been associated with higher rates of rehospitalization, coronary stent thrombosis, and mortality. No data exist regarding the effect of the Medicare Part D coverage gap on medical costs and outcomes in Medicare beneficiaries who discontinue their clopidogrel upon entering the coverage gap. METHODS: Beneficiaries with a Medicare Advantage plan in 2009 who had a diagnosis of acute coronary syndrome were taking clopidogrel 75 mg daily, and reached the gap in the same year representing the study sample. From this cohort, those who filled at least two prescriptions for clopidogrel (continued) versus those that did not (discontinued) while in the gap were compared with regard to outcomes related to acute coronary syndrome and expenditure 30 days after the last prescription was filled and during any time while in the gap. Descriptive and multivariate analyses were used to compare these differences. RESULTS: A total of 1365 beneficiaries with acute coronary syndrome met the inclusion criteria, of which 705 beneficiaries entered into the coverage gap, wherein 103 (14.6%) and 602 (85.4%) of beneficiaries discontinued and continued clopidogrel, respectively. Compared with those who continued clopidogrel during the gap, beneficiaries who discontinued clopidogrel showed a higher trend in the number of hospitalizations related to acute coronary syndrome and emergency room visits, albeit not statistically significant. Those who discontinued clopidogrel showed a higher mean adjusted cost per member per month in hospitalizations ($3604) related to acute coronary syndrome and outpatient visits ($1144) related to acute coronary syndrome and total medical costs ($5614), albeit not statistically significant. CONCLUSION: Medicare beneficiaries who face large out-of-pocket costs for clopidogrel while in the coverage gap and discontinue therapy may experience adverse events related to acute coronary syndrome.

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ETHNOPHARMACOLOGICAL RELEVANCE: Propolis has long been used as a popular folk medicine by various ethnic groups due to its wide spectrum of alleged biological and pharmaceutical properties including anti-microbial, anti-cancer and anti-inflammatory functions. All these can be linked to the modulation of immune function. Therefore, it will be relevant for us to find out whether there is any novel compound that can account for such action and the mechanism involved. AIM OF THE STUDY: We investigated the immune modulating effect of Brazilian green propolis (PBrazil) and its constituent Artepillin C (Art-C) by using mixed leukocytes reaction. MATERIALS AND METHODS: The cytotoxic effect of Art-C on non-tumorigenic human liver cell line miHA and non-tumorigenic human kidney cell line HK-2 as well as human peripheral blood mononuclear cells (PBMCs) were measured by XTT cell proliferation assay. The effect of PBrazil and Art-C on T cell proliferation and activation were determined by using carboxyfluorescein succinimidyl ester (CFSE) and by CD25 expression, respectively. Cytokines including tumor necrosis factor-α (TNF-α), interferon-gamma (IFN-γ), interleukins such as IL-2, IL-17 were measured by intracellular cytokine staining and IL-10 was measured by ELISA. The effect of PBrazil and Art-C on regulatory T cells (Treg) induction was determined by the Foxp3 expression. The apoptotic effect of these compounds on CFSE labeled alloreactive T cells was measured by using Annexin V. RESULTS: Using mixed leukocytes reaction we demonstrated for the first time that both Art-C and PBrazil significantly inhibited the alloreactive CD4 T cell proliferation, activation, and suppressed the expressions of IL-2, IFN-γ and IL-17 in these alloreactive CD4 T cells. The inhibitions of Art-C and PBrazil on CD4 T cells were not due to direct cytotoxic effect on PBMC or inducing regulatory T cells differentiation. Both Art-C and PBrazil were found to selectively induce apoptosis in proliferating T cells. The anti-proliferative effect of Art-C and PBrazil were reversible and were also applied to the activated T cells. CONCLUSIONS: In conclusion, our results indicated that Art-C and PBrazil can suppress alloreactive CD4 T cell responses in vitro, suggesting that Art-C could be used as a potential immunosuppressant, either solely or as adjunct agent in treating graft versus host disease.

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