␤-Lactam antibiotics provide the cornerstone of treatment and reduce the rate of decline in lung function in patients with cystic fibrosis, but their use is limited by a high frequency of delayedtype allergic reactions. The objective of this study was to use cloned T-cells expressing a single T-cell receptor from five piperacillin-hypersensitive patients to characterize both the cellular pathophysiology of the reaction and antigen specificity to define the mechanism of activation of T-cells by piperacillin. More than 400 piperacillin-responsive CD4ϩ, CD4ϩCD8ϩ, or CD8ϩ T-cell clones were generated from lymphocyte transformation test and ELIspot-positive patients. The T-cell response (proliferation, T helper 2 cytokine secretion, and cytotoxicity) to piperacillin was concentration-dependent and highly specific. Enzyme-linked immunosorbent assay, gel electrophoresis, and mass spectrometry revealed that piperacillin bound exclusively to albumin in T-cell culture. Irreversible piperacillin binding at Lys 190, 195, 199, 432, and 541 on albumin and the stimulation of T-cells depended on incubation time. A synthetic piperacillin albumin conjugate stimulated T-cell receptors via a major histocompatibility complex-and processing-dependent pathway. Flucloxacillin competes for the same Lys residues on albumin as piperacillin, but the resulting conjugate does not stimulate T-cells, indicating that binding of the ␤-lactam hapten in peptide conjugates confers structural specificity on the activation of the T-cell receptors expressed on drug-specific clones. Collectively, these data describe the cellular processes that underlie the structural specificity of piperacillin antigen binding in hypersensitive patients with cystic fibrosis.

These data indicate that inhibition of Aurora Kinase A inhibits cell growth in medulloblastoma through inhibition of pro-proliferative signaling pathways Wnt, Myc, and RB. Additionally, combining Aurora Kinase A inhibition with other chemotherapeutic agents significantly lowers their IC(50), which make it a promising small molecule target for medulloblastoma therapy.

Recognition of drugs by immune cells is usually explained by the hapten model, which states that endogenous metabolites bind irreversibly to protein to stimulate immune cells. Synthetic metabolites interact directly with protein generating antigenic determinants for T-cells; however, experimental evidence relating intracellular metabolism in immune cells and the generation of physiologically relevant antigens to functional immune responses is lacking. The aim of this study was to develop an integrated approach using both animal and human experimental systems to characterize sulfamethoxazole (SMX) metabolism-derived antigenic protein adduct formation in immune cells and define the relationship between adduct formation, cell death, co-stimulatory signalling and stimulation of a T-cell response. Formation of SMX-derived adducts in antigen presenting cells was dose- and time-dependent, detectable at non-toxic concentrations and dependent on drug metabolizing enzyme activity. Adduct formation above a threshold induced necrotic cell death, dendritic cell co-stimulatory molecule expression and cytokine secretion. Antigen presenting cells cultured with SMX for 16h, the time needed for drug metabolism, stimulated T-cells from sensitized mice and lymphocytes and T-cell clones from allergic patients. Enzyme inhibition decreased SMX-derived protein adduct formation and the T-cell response. Dendritic cells cultured with SMX and adoptively transferred to recipient mice initiated an immune response; however, T-cells were stimulated with adducts derived from SMX metabolism in antigen presenting cells, not the parent drug. This study shows that antigen presenting cells metabolize SMX; subsequent protein binding generates a functional T-cell antigen. Adduct formation above a threshold stimulates cell death, which provides a maturation signal for dendritic cells.

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Exposure to sulfamethoxazole (SMX) is associated with T-cell-mediated hypersensitivity reactions in human patients. T-cells can be stimulated by the putative metabolite nitroso SMX, which binds irreversibly to protein. The hydroxylamine and nitroso derivatives of three arylamine benzenesulfonamides, namely, sulfamethozaxole, sulfadiazine, and sulfapyridine, were synthesized, and their T-cell stimulatory capacity in the mouse was explored. Nitroso derivatives were synthesized by a three-step procedure involving the formation of nitro and hydroxylamine sulfonamide intermediates. For immune activation, female Balb-c strain mice were administered nitroso sulfonamides four times weekly for 2 weeks. After 14 days, isolated splenocytes were incubated with the parent compounds, hydroxylamine metabolites, and nitroso derivatives to measure antigen-specific proliferation. To explore the requirement of irreversible protein binding for spleen cell activation, splenocytes were incubated with nitroso derivatives in the presence or absence of glutathione. Splenocytes from nitroso sulfonamide-sensitized mice proliferated and secreted interleukin (IL)-2, IL-4, IL-5, and granulocyte monocyte colony-stimulating factor following stimulation with nitroso derivatives but not the parent compounds. Splenocytes from sensitized mice were also stimulated to proliferate with hydroxylamine and nitroso derivatives of the structurally related sulfonamides. The addition of glutathione inhibited the nitroso-specific T-cell response. Hydroxylamine metabolites were unstable in aqueous solution: Spontaneous transformation yielded appreciable amounts of nitroso and azoxy compounds as well as the parent compounds within 0.1 h. T-cell cross-reactivity with nitroso sulfonamides provides a mechanistic explanation as to why structurally related arylamine benzenesulfonamides are contraindicated in hypersensitive patients.

Background Atrial fibrillation (AF) is a common arrhythmia and one of the complications in the setting of ST‐elevation myocardial infarction (STEMI). Our objective of the present study was to investigate the incidence, predictors, and outcomes of NOAF in patients with acute STEMI managed with pharmacoinvasive strategy (PIS) versus those managed with primary percutaneous coronary intervention (PPCI). Methods The study included 530 patients with STEMI divided into two groups according to the method of treatment. Group I: 269 patients subjected to pharmacoinvasive strategy (PIS), group II: 261 patients managed with primary percutaneous coronary intervention (PPCI). Incidence, predictors, and outcomes of NOAF were assessed in each group separately. Results The incidence of NOAF was 25 patients (9.3%) in group I and 24 patients (9.2%) in group II. Multivariate regression analysis identified the independent predictors of NOAF that were (advanced age ˃65 years, history of hypertension, left atrial volume index (LAVI) ˃34 ml/m 2 , E/e’ ratio ˃ 12, right coronary artery (RCA) as a culprit vessel and presence of heart failure). There was no statistically significant difference between both groups regarding the occurrence of MACE. Conclusion New‐onset AF represents one of the common complications in the setting of STEMI. Advanced age, hypertension, LAVI ˃34 ml/m 2 , E/e’ ratio ˃12, RCA culprit vessel, and heart failure were the independent predictors of NOAF.

No-reflow phenomenon and the risk of recurrent ischemia is significantly lower in patients undergoing PCI very early after successful fibrinolytic therapy, but the risk of bleeding is increased in this time. So it is recommended that patients received successful fibrinolytic therapy to be subjected to very early PCI within 3 to 12 h from fibrinolysis.

Background: Ischemic mitral regurgitation (IMR) is a common complication of acute inferior ST elevation myocardial infarction (MI). Current evidences suggest that revascularization of the culprit vessels with primary percutaneous coronary artery intervention (PCI) or coronary artery bypass grafting can be beneficial for relieving IMR. The aim was to study the effect of successful primary percutaneous coronary intervention (PCI) of the culprit vessel on the degree of ischemic mitral regurgitation in patients with acute inferior STEMI.Patients and methods: 200 patients diagnosed as acute inferior STEMI with ischemic MR & subjected for primary percutaneous coronary intervention (PCI). Assessment of LV function and dimensions by echocardiography and assessment degree of mitral regurgitation by jet area before and after PCI.Result: Mean MR jet area decreased from (5.3±2.2 cm 2 ) to (3.2±2.5cm 2 ), (p value<0.05) after PCI, and this improvement in MR was evident in all degrees of MR. There was a significant improvement in the degree of MR among non-diabetic patients in comparison with diabetic patients. Shorter onset-to-reperfusion time and no total occlusion before PCI were the independent predictors of early improvement of IMR. Conclusion:PPCI in Patients with ischemic mitral regurgitation associated with inferior STEMI led to a decrease in the severity of mitral regurgitation at 40days post PCI. No further improvement in the severity of mitral regurgitation occurred after 40days post PCI. Patients with moderate and severe mitral incompetence after 40days had a higher incidence of hospitalization with decompensated heart failure and more left ventricular remodeling changes at 6 months follow up.