Expression of costimulatory molecules (CD80, CD86, CD28, CD152), accessory molecules (TCR alphabeta, TCR gammadelta) and T cell lineage molecules (CD4+, CD8+) in PBMC of leprosy patients using Mycobacterium leprae antigen (MLCWA) with murabutide and T cell peptide of Trat protein

In leprosy, cell-mediated immunity (CMI) is more significant than humoral response to eliminate intracellular pathogen. T cell defect is a common feature in lepromatous leprosy (LL) patients as compared to tuberculoid type (TT) patients. For efficient initiation of CD4+, T cell response requires T cell receptor (TCR) activation and costimulation provided by molecules on antigen-presenting cells (APC) and their counter receptors on T cells. In our previous study, the defective T cell function in LL patients was restored to a proliferating state with the release of TH1 type cytokines using mycobacterial antigen(s) with two immunomodulators (Murabutide (MDP-BE) and T cell epitope of Trat protein of Escherichia coli) by presenting the antigen in particulate form in vitro to PBMC derived from leprosy patients. This observation prompted us to study the expression of the costimulatory molecules (CD80, CD86, CD28, CD152), other accessory molecules (TCR alphabeta/gammadelta) and T cell lineage molecules (CD4+ and CD8+) during constitutive and activated state of peripheral blood mononuclear cells (PBMC) derived from normal and leprosy individuals using different formulations of Mycobacterium leprae total cell wall antigen (MLCWA), Trat and MDP-BE using flow cytometric analysis. An increased surface expression of CD80, CD86 and CD28 but decreased CD152 expression was observed when PBMC of normal, BT/TT (tuberculoid) and BL/LL (lepromatous) patients were stimulated in vitro with MLCWA+MDP-BE+Trat peptide using liposomal mode of antigen delivery, while opposite results were obtained with the antigen alone. Antibody inhibition study using antihuman CD80 or CD86 completely abolished the T cell lymphoproliferation, thereby reconfirming the importance of these costimulatory molecules during T cell activation/differentiation. Though the liposome-entrapped antigen formulation has no effect on expression of alphabeta/gammadelta T cell receptor, the constitutive levels of TCR gammadelta were high in lepromatous patients. Thus, TCR bearing gammadelta appears to have a negligible regulatory role in peripheral blood of leprosy patients. The percentage of cells positive for CD4+ are increased in inducible state in all the three groups, while CD8+-positive cells were decreased in LL patients, thereby reconfirming the fact that priming of CD4+ cells are necessary for producing final effector functions. Lastly, intracellular cytokine staining experiment indicated that CD4+ cells are the major producers of IFN-gamma but not NK cells. The study highlights the reversal of T cell anergy especially in lepromatous patients through the modulation of costimulatory molecule expression under the influence of Th1 cytokines, i.e., IL-2 and IFNgamma.     

Successful use of topical cysteamine formulated from the oral preparation in a child with keratopathy secondary to cystinosis

PURPOSE: To report the successful use of topical cysteamine formulated from the oral preparation in the treatment of severe photophobia from corneal crystal deposition in cystinosis. DESIGN: Interventional case report. METHODS: Retrospective chart review. RESULTS: An 8-year-old boy with nephropathic cystinosis was experiencing debilitating and worsening photophobia from corneal crystal deposition. Because no parenteral cysteamine was available nationally, the oral capsule was used to formulate an ophthalmic preparation for compassionate use. After 8 months of topical application, the patient has marked improvement of his corneal disease, both subjectively and objectively. CONCLUSIONS: In situations of need, there is a role for the formulation of ophthalmic cysteamine from its oral preparation.     

Phosphodiesterase and thymidine phosphorylase-inhibiting salirepin derivatives from Symplocos racemosa

A re-investigation of the chemical constituents of the stem bark of Symplocos racemosa Roxb. led to the isolation of four new glycosides, symplocomoside (1), symponoside (2), symplososide (3) and symploveroside (4). Benzoylsalireposide (5) and salireposide (6) were re-isolated from this plant. The structures of the new compounds were determined by 1D and 2D-homonuclear and heteronuclear NMR spectroscopy, chemical evidence, and by comparison with the published data of the closely related compounds. The glycosides 1-4 displayed in vitro inhibitory activity against phosphodiesterase I with IC50 values of 122 +/- 0.017, 698 +/- 0.06, 722 +/- 0.03, 909 +/- 0.09 microM, respectively. The compounds 1-6 also showed in vitro inhibitory activity against thymidine phosphorylase with IC50 values of 189.96 +/- 1.02, 195.56 +/- 2.36, 207.61 +/- 1.06, 488.89 +/- 4.10, 427.20 +/- 5.36, 354.2 +/- 5.69 microM, respectively while 1 was also found to be a urease inhibitor with an IC50 value of 54.13 +/- 0.71 microM.     

Synthesis, characterization and cytotoxicity evaluation of some new platinum(II) complexes of tetrazolo[1,5-a]quinolines

Several new platinum(II) complexes of the general formulae cis-[PtCl(2)(DMSO)L], where L is a Schiff base or hydrazone derived from tetrazolo[1,5-a]quinoline-4-carboxaldehyde as carrier ligands, have been synthesized and characterized physicochemically and spectroscopically. These platinum complexes which are structurally analogues to what so called cisplatin [cis-[PtCl2(NH3)2]; the first generation anticancer agent] were evaluated for their cytotoxicity on HL-60 (human promyelocytic leukemia) cells. Two of the platinum complexes were almost similar in their activity to cisplatin, while the remaining three complexes have demonstrated higher efficacy than that of cisplatin. Based on our findings, these novel platinum complexes appear to be valuable leading compounds with high efficacy.     

A phase II trial of gefitinib (Iressa, ZD1839) in stage IV and recurrent renal cell carcinoma.

PURPOSE: The epidermal growth factor receptor (EGFR) is overexpressed in 75 to 90% of renal cell carcinomas and may play a role in tumor initiation and progression. Gefitinib (Iressa, ZD1839) is a potent, selective EGFR-tyrosine kinase inhibitor. This trial was undertaken to assess the efficacy and toxicity of gefitinib in advanced renal cell carcinoma. EXPERIMENTAL DESIGN: Oral gefitinib, 500 mg once daily, was given continuously. A single-dose reduction to 250 mg daily was allowed for toxicity. The primary end point was response rate (defined as complete remission + partial remission + stable disease). Secondary end points were progression-free survival, overall survival, toxicity, and correlation of response with EGFR status. RESULTS: Twenty-one patients were enrolled on this study, and all are evaluable for response and toxicity. Patient characteristics were median age 61 (range, 35-78 years); 17 males, 4 females; median performance status 0 (range 0-2); median number of prior systemic therapies 1 (range, 0-3). The median and mean number of cycles of therapy received was 3 and 4.7 (range, 1-14+). The best response was stable disease in eight patients (38%). Median progression-free survival was 2.7 months. Median overall survival was 8.3 months. The difference in overall survival was significantly different between patients with progressive disease versus stable disease (6.1 months versus 16+ months; Log-Rank test P value < 0.0001). Three patients required a dose reduction, all for grade 3 diarrhea. There was no apparent correlation between EGFR status and stability of disease or progression of disease. CONCLUSIONS: Gefitinib is without significant conventional activity in renal cell carcinoma. The relation of "stable disease" to treatment or to disease-related prognostic heterogeneity remains to be defined.     

Esophageal atresia and tracheo-esophageal fistula in a patient with Digeorge syndrome

DiGeorge Syndrome (DGS) is a congenital disorder that affects the thymus, parathyroid glands, and heart and brain. Thymus involvement in DGS may vary between absence/hypoplasia of thymus to various forms of reduced T cell function. TBX1 deficiency causes a number of distinct vascular and heart defects, suggesting multiple roles in cardiovascular development, specifically, formation and growth of the pharyngeal arch arteries, growth and septation of the outflow tract of the heart, interventricular septation, and conal alignment. Here the authors describe a case of DGS presenting with severe combined immunodeficiency, esophageal atresia, and tracheoesophageal fistula (TEF). DGS is an important differential diagnosis in TEF.     

Comparative study of 0.1% olopatadine hydrochloride and 0.5% ketorolac tromethamine in the treatment of seasonal allergic conjunctivitis

PURPOSE: To compare the therapeutic effects of two ophthalmic solutions (0.1% olopatadine hydrochloride and 0.5% ketorolac tromethamine) with different pharmacological mechanisms on the clinical signs and Symptoms of seasonal allergic conjunctivitis (SAC). METHODS: Forty patients with the signs and symptoms of SAC (i.e. hyperaemia, itching, mucus discharge, tearing) were included in this placebo-controlled, randomized, parallel group, single centre study. In group 1 (20 patients) one eye of each patient was treated with olopatadine and the other with placebo. In group 2 (20 patients) one eye of each patient was treated with ketorolac solution and the other with placebo. The principal signs and symptoms of SAC (hyperaemia and itching) were evaluated at 30 mins and at 2, 7 and 15 days. RESULTS: In group 1, both parameters improved significantly in eyes treated with olopatadine compared with those receiving placebo at all control examinations (all p < 0.05). Similarly, eyes treated with ketorolac showed significant reductions in signs and symptoms compared with those receiving placebo (all p < 0.05). When the clinical parameters of eyes treated with olopatadine were compared with those treated with ketorolac, the mean score of hyperaemia was found to be lower in the olopatadine group, but the difference was not statistically significant (all p > 0.05). However, the itching score was significantly lower in the olopatadine group from the second day through to the end of the study (p < 0.05). CONCLUSIONS: Both olopatadine and ketorolac ophthalmic solutions were found to be effective in alleviating the clinical signs and symptoms of SAC compared to placebo. However, olopatadine reduces ocular itching significantly more than ketorolac.