Identification of HLA-DRPheβ47 as the susceptibility marker of hypersensitivity to beryllium in individuals lacking the berylliosis-associated supratypic marker HLA-DPGluβ69

BACKGROUND: Susceptibility to beryllium (Be)-hypersensitivity (BH) has been associated with HLA-DP alleles carrying a glutamate at position 69 of the HLA-DP β-chain (HLA-DPGlu69) and with several HLA-DP, -DQ and -DR alleles and polymorphisms. However, no genetic associations have been found between BH affected subjects not carrying the HLA-DPGlu69 susceptibility marker. METHODS: In this report, we re-evaluated an already described patient populations after 7 years of follow-up including new 29 identified BH subjects. An overall population 36 berylliosis patients and 38 Be-sensitization without lung granulomas and 86 Be-exposed controls was analysed to assess the role of the individual HLA-class II polymorphisms associated with BH-susceptibility in HLA-DPGlu69 negative subjects by univariate and multivariate analysis. RESULTS: As previously observed in this population the HLA-DPGlu69 markers was present in higher frequency in berylliosis patients (31 out of 36, 86%) than in Be-sensitized (21 out of 38, 55%, p = 0.008 vs berylliosis) and 41 out of 86 (48%, p < 0.0001 vs berylliosis, p = 0.55 vs Be-sensitized) Be-exposed controls. However, 22 subjects presenting BH did not carry the HLA-DPGlu69 marker. We thus evaluated the contribution of all the HLA-DR, -DP and -DQ polymorphisms in determining BH susceptibility in this subgroup of HLA-Glu69 subjects. In HLA-DPGlu69-negatives a significant association with BH was found for the HLA-DQLeu26, for the HLA-DRB1 locus residues Ser13, Tyr26, His32, Asn37, Phe47 and Arg74 and for the HLA-DRB3 locus clusterized residues Arg11, Tyr26, Asp28, Leu38, Ser60 and Arg74. HLA-DRPhe47 (OR 2.956, p < 0.05) resulting independently associated with BH. Further, Be-stimulated T-cell proliferation in the HLA-DPGlu69-negative subjects (all carrying HLA-DRPhe47) was inhibited by the anti-HLA-DR antibody (range 70–92% inhibition) significantly more than by the anti-HLA-DP antibody (range: 6–29%; p < 0.02 compared to anti-HLA-DR) while it was not affected by the anti-HLA-DQ antibody. CONCLUSION: We conclude that HLA-DPGlu69 is the primary marker of Be-hypersensitivity and HLA-DRPhe47 is associated with BH in Glu69-negative subjects, likely playing a role in Be-presentation and sensitization

Mapping Philanthropic Foundations’ Characteristics: towards an international integrative framework of foundation types

As philanthropic foundations take on increasingly prominent sociopolitical roles, the need for stronger conceptualizations of foundations as an organizational form is articulated widely across academic, policy, and practice contexts. Building on institutional research’s tradition of categorizing, classifying and typologizing organizational forms, our article critically explores the different ways in which foundations have been cast and differentiated in international academic and practice literatures. Examining and integrating these, we propose an integrative framework of foundation types. Incorporating 13 categories—three contextual, five organizational, and five strategic ones—the framework allows for clarifying distinctions and identifying commonalities between different foundation forms, offering a basis for developing more reflective and differentiated research and practice knowledge

Resveratrol Acts Not through Anti-Aggregative Pathways but Mainly via Its Scavenging Properties against Aβ and Aβ-Metal Complexes Toxicity

It has been recently suggested that resveratrol can be effective in slowing down Alzheimer's disease (AD) development. As reported in many biochemical studies, resveratrol seems to exert its neuro-protective role through inhibition of β-amyloid aggregation (Aβ), by scavenging oxidants and exerting anti-inflammatory activities. In this paper, we demonstrate that resveratrol is cytoprotective in human neuroblastoma cells exposed to Aβ and or to Aβ-metal complex. Our findings suggest that resveratrol acts not through anti-aggregative pathways but mainly via its scavenging properties

Efecto de Piridazino (4-5-b)indoles en Trombano Sintetasa : Nuevos inhibidores selectivos. Antiagregantes plaquetarios

Se han realizado los ensayos como inhibidores selectivos de Tromboexa no Sintetasa de siete comouestos de éstructura relativa a piridazino (45-b)indol. La inhibición en la segunda onda de agregación inducida en plaquetas humanas por ADP, en la inducida por ácido araquidónico y por prostaglandina H2 (PGH2), así como en la producción de Tromboxano B2 (TXB2), han permitido determinar que dos de estos compuestos, 3,4-dihidro-4-oxo-5H-piridazino (4,5-b)indol (I) y 3,4-dihidro-4-oxo-5H-8-benciloxi-piridazino (4, 5-b)indol (VII), son nuevos inhibidores selectivos de este sistema enzimático.Assays were performed which identified seven compounds with the general structure indol-piridazine (4,5-b) as selective inhibitors of Thromboxane Synthetase. Compounds whose activities includes inhibition of human platelet aggregation induced by Arachidonic acid (AA) and Prostaglandin H2 (PGH2), and inhibition of the second wave of platelet aggregation induced by ADP, were subjected to radioimmunoassay studies to measue TXB2 and PGE2 levels in the samples using AA as the aggregating agent. This work has determined that two of the compounds, 3,4-dihydro-4-oxo-5H-pyridazino-(4,5-b)indole(I) and 3,4-dihydro-4-oxo-5H 8-benzyloxypyridazino (4,5-b)indole (VII), are new selective inhibitors of this enzymatic systemColegio de Farmacéuticos de la Provincia de Buenos Aire

Efecto de Piridazino (4-5-b)indoles en Trombano Sintetasa : Nuevos inhibidores selectivos. Antiagregantes plaquetarios

Se han realizado los ensayos como inhibidores selectivos de Tromboexa no Sintetasa de siete comouestos de éstructura relativa a piridazino (45-b)indol. La inhibición en la segunda onda de agregación inducida en plaquetas humanas por ADP, en la inducida por ácido araquidónico y por prostaglandina H2 (PGH2), así como en la producción de Tromboxano B2 (TXB2), han permitido determinar que dos de estos compuestos, 3,4-dihidro-4-oxo-5H-piridazino (4,5-b)indol (I) y 3,4-dihidro-4-oxo-5H-8-benciloxi-piridazino (4, 5-b)indol (VII), son nuevos inhibidores selectivos de este sistema enzimático.Assays were performed which identified seven compounds with the general structure indol-piridazine (4,5-b) as selective inhibitors of Thromboxane Synthetase. Compounds whose activities includes inhibition of human platelet aggregation induced by Arachidonic acid (AA) and Prostaglandin H2 (PGH2), and inhibition of the second wave of platelet aggregation induced by ADP, were subjected to radioimmunoassay studies to measue TXB2 and PGE2 levels in the samples using AA as the aggregating agent. This work has determined that two of the compounds, 3,4-dihydro-4-oxo-5H-pyridazino-(4,5-b)indole(I) and 3,4-dihydro-4-oxo-5H 8-benzyloxypyridazino (4,5-b)indole (VII), are new selective inhibitors of this enzymatic systemColegio de Farmacéuticos de la Provincia de Buenos Aire