Covalent modification of protein by drugs may disrupt self-tolerance, leading to lymphocyte activation. Until now, determination of the threshold required for this process has not been possible. Therefore, we performed quantitative mass spectrometric analyses to define the epitopes formed in tolerant and hypersensitive patients taking the β-lactam antibiotic piperacillin and the threshold required for T cell activation. A hydrolyzed piperacillin hapten was detected on four lysine residues of human serum albumin (HSA) isolated from tolerant patients. The level of modified Lys⁵⁴¹ ranged from 2.6 to 4.8%. Analysis of plasma from hypersensitive patients revealed the same pattern and levels of modification 1–10 d after the commencement of therapy. Piperacillin-responsive skin-homing CD4⁺ clones expressing an array of Vβ receptors were activated in a dose-, time-, and processing-dependent manner; analysis of incubation medium revealed that 2.6% of Lys⁵⁴¹ in HSA was modified when T cells were activated. Piperacillin–HSA conjugates that had levels and epitopes identical to those detected in patients were shown to selectively stimulate additional CD4⁺ clones, which expressed a more restricted Vβ repertoire. To conclude, the levels of piperacillin–HSA modification that activated T cells are equivalent to the ones formed in hypersensitive and tolerant patients, which indicates that threshold levels of drug Ag are formed in all patients. Thus, the propensity to develop hypersensitivity is dependent on other factors, such as the presence of T cells within an individual’s repertoire that can be activated with the β-lactam hapten and/or an imbalance in immune regulation.

Drug hypersensitivity involves the activation of T cells in an HLA allele–restricted manner. Because the majority of individuals who carry HLA risk alleles do not develop hypersensitivity, other parameters must control development of the drug-specific T cell response. Thus, we have used a T cell–priming assay and nitroso sulfamethoxazole (SMX-NO) as a model Ag to investigate the activation of specific TCR Vβ subtypes, the impact of programmed death -1 (PD-1), CTL-associated protein 4 (CTLA4), and T cell Ig and mucin domain protein-3 (TIM-3) coinhibitory signaling on activation of naive and memory T cells, and the ability of regulatory T cells (Tregs) to prevent responses. An expansion of the TCR repertoire was observed for nine Vβ subtypes, whereas spectratyping revealed that SMX-NO–specific T cell responses are controlled by public TCRs present in all individuals alongside private TCR repertoires specific to each individual. We proceeded to evaluate the extent to which the activation of these TCR Vβ–restricted Ag-specific T cell responses is governed by regulatory signals. Blockade of PD-L1/CTLA4 signaling dampened activation of SMX-NO–specific naive and memory T cells, whereas blockade of TIM-3 produced no effect. Programmed death-1, CTLA4, and TIM-3 displayed discrete expression profiles during drug-induced T cell activation, and expression of each receptor was enhanced on dividing T cells. Because these receptors are also expressed on Tregs, Treg-mediated suppression of SMX-NO–induced T cell activation was investigated. Tregs significantly dampened the priming of T cells. In conclusion, our findings demonstrate that distinct TCR Vβ subtypes, dysregulation of coinhibitory signaling pathways, and dysfunctional Tregs may influence predisposition to hypersensitivity.

BACKGROUND: Breast Cancer (BC) is the most common cancer and the leading cause of cancer death among women globally. The disease can be cured with limited resources if detected early. Breast self-examination (BSE) is considered a cost-effective feasible approach for early detection of that cancer in developing countries. AIM: To determine the correlation between BSE performance and demographic characteristics, risk factors and clinical stage of BC among Iraqi patients. METHODS: This retrospective study included a total of 409 female patients diagnosed with BC at the Referral Training Center for Early Detection of Breast Cancer and the National Cancer Research Center in Baghdad. The studied variables included the age of the patient, occupation, marital and educational status, parity, history of lactation, contraceptive pill intake, family history of cancer and the clinical stage of the disease. RESULTS: Our findings revealed that the most important predictors for practicing BSE was family history of BC or any other cancers (OR = 3.87, P = 0.018) followed by being a governmental employee (OR = 1.87, P = 0.024), history of contraceptive use (OR = 1.80, P = 0.011) and the high level of education (OR = 1.73, P = 0.004). On the other hand, there was no significant correlation between the practice of BSE and the BC stage at the time of presentation. CONCLUSION: There is a relatively poor practice of BSE among Iraqi patients diagnosed with BC. It is mandatory to foster the national cancer control strategies that focus on raising the level of awareness among the community through public education as a major approach to the early detection of cancer in Iraq.

OBJECTIVE: The current study was designed to determine the hepatoprotective effect of well-known drugs. Nitroglycerin, N-acetyl cysteine and Metoprolol in acute liver injury induced by CCL4. The antioxidant effects of b-blockers, especially carvedilol, have been described by several investigators. However, for metoprolol, the effect is a bit query as there is only one in-vitro study showing a little hepatoprotective effect. Thus, it is worthy to re-study the hepatoprotective effect of metoprolol. AIM: To explore the possible hepatoprotective effect of Nitroglycerin, N-acetyl cysteine and Metoprolol TartrateMATERIAL AND METHODS: The normal serum values of ALP, AST, ALT, TSB and TSP were determined in 35 healthy rabbits allocated to 5 groups before CCL4 induction and at three occasions 24, 72, 120 hrs after induction by CCL4 and treatment with the tested drugs: Nitroglycerin, N-acetyl cysteine and Metoprolol for five successive days.RESULTS: Showed significant decrease in serum levels of ALP, AST, ALT and TSB with a significant increase in TSP level of all the tested drugs measured at 120 hrs compared with the control and their levels measured at 24, 72 hrs.CONCLUSION: All the tested drugs proved in having a hepatoprotective effect when they are given orally to animals. The histopathological sections of the liver tissue supported the real effect of these drugs in the management of ALI.

Telaprevir, a protease inhibitor, was used alongside PEGylated interferon- and ribavirin to treat hepatitis C viral infections. The triple regimen proved successful; however, the appearance of severe skin reactions alongside competition from newer drugs restricted its use. Skin reactions presented with a delayed onset indicative of a T-cell mediated reaction. Thus, the aim of this study was to investigate whether telaprevir and/or its diastereomer, which is generated in humans, activates T-cells. Telaprevir in its S-configured therapeutic form and the R-diastereomer were cultured directly with peripheral blood mononuclear cells from healthy donors prior to the generation of T-cell clones by serial dilution. Drug-specific CD4(+) and CD8(+) T-cell clones responsive to telaprevir and the R-diastereomer were generated and characterized in terms of phenotype and function. The clones proliferated with telaprevir and diastereomer concentrations of 5-20 mu M and secreted IFN-, IL-13, and granzyme B. In contrast, the telaprevir M11 metabolite did not stimulate T-cells. The CD8(+) T-cell response was MHC I-restricted and dependent on the presence of soluble drug. Flow cytometric analysis showed that clones expressed chemokine receptors CCR4 (skin homing) and CXCR3 (migration to peripheral tissue) and 1 of 3 distinct TCR Vs; TCR V 2, 5.1, or 22. These data show the propensity of both R- and S-forms of telaprevir to generate skin-homing cytotoxic T-cells that may induce the adverse reactions observed in human patients.

BACKGROUND: Montelukast (Singulair) is a cysteinyl leukotriene receptor antagonist, used for the maintenance treatment of asthma and to relieve symptoms of seasonal allergic rhinitis and asthma, also used for exercise-induced bronchospasm. AIM: This study was performed to determine the prevalence of Montelukast use as an add-on therapy among Iraqi asthmatic patients on treatment. Comparing the effectiveness of regimens with and without montelukast. METHODS: This descriptive cross-sectional study was carried out on 73 Iraqi asthmatic patients on treatment of both sexes with age range (18-60) years old, attending Al-Kindy Teaching Hospital and Al-Zahraa Centre of Asthma and Allergy, Baghdad, for the period between February and March 2017. A questionnaire was specifically prepared to meet the objectives and was used to collect the data of the study. RESULTS: There was a significant statistical reduction of frequency in asthmatic attacks after Montelukast treatment (p-value < 0.05). Out of 73 patients, 39 were males, and 34 were females, 46 were jobless, 37 were married, 63 were urban residents, 63 were educated. Prevalence of exacerbation factors was as following: infection was found in 60.3% of the patients, exercise in 57.5%, dust in 72.6%, smoking in 60.6%, food in 24.7%, others (stress, perfumes) in 20.5%. The prevalence of Montelukast use in this study was 46% (34 patients). Out of 34 patients using Montelukast, 28 were using inhaled salbutamol, 5 were using oral salbutamol, 15 were using inhaled corticosteroids, 9 were using systematic corticosteroids, 2 were using xanthines, and 6 were using ketotifen. CONCLUSION: Montelukast was used as add-on therapy with the inhaled corticosteroids to reduce the required dose of inhaled corticosteroids also the use of Montelukast lead to reduced number of exacerbations which will be reflected on the use of inhaled salbutamol and systematic corticosteroids. Also, Montelukast was superior to xanthines and ketotifen as an add-on therapy.