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Background and Purpose
Kv1.3 potassium channels are promising pharmaceutical targets for treating immune diseases as they modulate Ca2+ signalling in T cells by regulating the membrane potential and with it the driving force for Ca2+ influx. The antimycobacterial drug clofazimine has been demonstrated to attenuate antigen‐induced Ca2+ oscillations, suppress cytokine release and prevent skin graft rejection by inhibiting Kv1.3 channels with high potency and selectivity.Experimental Approach
We used patch‐clamp methodology to investigate clofazimine''s mechanism of action in Kv1.3 channels expressed in HEK293 cells.Key Results
Clofazimine blocked Kv1.3 channels by involving two discrete mechanisms, both of which contribute to effective suppression of channels: (i) a use‐dependent open‐channel block during long depolarizations, resulting in accelerated K+ current inactivation and (ii) a block of closed deactivated channels after channels were opened by brief depolarizations. Both modes of block were use‐dependent and state‐dependent in that they clearly required prior channel opening. The clofazimine‐sensitive closed‐deactivated state of the channel was distinct from the resting closed state because channels at hyperpolarized voltages were not inhibited by clofazimine. Neither were channels in the C‐type inactivated state significantly affected. Kv1.3 channels carrying the H399T mutation and lacking C‐type inactivation were insensitive to clofazimine block of the closed‐deactivated state, but retained their susceptibility to open‐channel block.Conclusions and Implications
Given the prominent role of Kv1.3 in shaping Ca2+ oscillations, the use‐dependent and state‐dependent block of Kv1.3 channels by clofazimine offers therapeutic potential for selective immunosuppression in the context of autoimmune diseases in which Kv1.3‐expressing T cells play a significant role.Abbreviations
- CLF
- clofazimine
- FDA
- Food and Drug Administration
- IPI
- interpulse intervals
- WT
- wild type
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Pneumocystis carinii pneumonia in patients with hematologic malignancies: a descriptive study 总被引:3,自引:0,他引:3
Roblot F Le Moal G Godet C Hutin P Texereau M Boyer E Prazuck T Lacroix C Souala MF Raffi F Weinbreck P Besnier JM Garo B de Gentile L Becq-Giraudon B 《The Journal of infection》2003,47(1):19-27
Objectives. A retrospective multicentric study was conducted over a five-year period to evaluate the clinical and laboratory characteristics and outcome of patients with proven Pneumocystis carinii pneumonia (PCP) complicating hematologic malignancies.Results. The study included 60 HIV-negative patients with 18 non-Hodgkin's malignant lymphoma (30%), 13 chronic lymphocytic leukaemia (21.7%), 10 acute leukemia (16.6%), 5 multiple myeloma (8.3%), 4 Waldenstr?m's diseases (6.6%), 4 chronic myeloid leukemia (6.6%), 3 myelodysplasia (5%), 2 Hodgkin's diseases (3.3%) and 1 thrombopenia. Bronchoalveolar lavage was diagnostic in all patients. Forty-nine patients received cytotoxic drugs (81.7%), 25 (41.7%) a long-term corticotherapy and 15 (25%) underwent bone marrow transplantation. Twenty-seven patients (45%) required admission in the intensive care unit, 35 (58.3%) received an adjunctive corticotherapy and 18 mechanical ventilation (30%). Twenty patients (33.3%) died of PCP. A previous long-term corticotherapy (p=0.04), high respiratory (p=0.05) and pulse rates (p=0.02), elevated C reactive protein (p=0.01) and mechanical ventilation (OR=13.37; IC: 1.9-50) were associated with a poor prognosis. Adjunctive corticotherapy did not modify the prognosis.Conclusions. These results suggest that PCP can occur during the course of various hematologic malignancies, not only lymphoproliferative disorders. Prognosis remains poor. The diagnosis should be advocated more frequently and earlier to improve the prognosis. 相似文献
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Michaud Katarzyna Magnin Virginie Faouzi Mohamed Fracasso Tony Aguiar Diego Dedouit Fabrice Grabherr Silke 《International journal of legal medicine》2021,135(5):1829-1836
International Journal of Legal Medicine - Sudden cardiac death (SCD) related to atherosclerotic coronary artery disease (ACAD) resulting in myocardial infarction is the most prevalent cause of... 相似文献
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Tonet J De Sisti A Pardo Restrepo N Raguin D Amara W Márquez MF Aouate P Waintraub X Touil F Hidden-Lucet F 《Journal of interventional cardiac electrophysiology》2012,35(1):63-69
Purpose
A residual slow pathway after successful cryoablation for atrioventricular nodal reentrant tachycardia (AVNRT) is correlated with a higher recurrence rate. We described determinants of recurrence in subjects with a residual jump.Methods
We analyzed the data of subjects with acute successful slow pathway cryoablation for AVNRT using a 6-mm-tip cryocatheter. Success was defined as AVNRT non-inducibility. Patients with no baseline elicitable jump, no inducible AVNRT, and transient first atrioventricular (AV) block at the last site were excluded.Results
From 371 patients who underwent cryoablation from May 2002 to March 2011, 303 fulfilled the entry criteria (mean age, 41?±?16; 222 women). Baseline AV nodal effective refractory period (ERP) was 272?±?57?ms, postprocedural 331?±?64 (P?0.001), and the mean of the difference (?? ERP) 60?±?41. At the end of the procedure, 64 patients (21?%) had a residual jump, of whom 22 with a single echo. At 12?months follow-up, the actuarial recurrence-free rate was 70.3?% in patients with a residual jump and 86?% in those without (P?=?0.01). In patients with a jump, only ?? AV nodal ERP was correlated with recurrence (37?±?41 vs. 68?±?47?ms; P?0.04) while a single echo was not. The actuarial rate of recurrence was 60.8?% in patients with a ?? AV nodal ERP????30?ms and 18.8?% in those with a ?? AV nodal ERP >30?ms (P?0.01).Conclusions
Suppression of slow pathway conduction is the optimal endpoint for AVNRT cryoablation. A residual jump can be tolerated if AV nodal ERP postcryoablation is prolonged >30?ms. 相似文献8.
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TSP1 and MMP9 genetic variants in sporadic prostate cancer 总被引:2,自引:0,他引:2
Angiogenesis plays an important role in the initiation and progression of many malignancies including prostate cancer (PCa). Therefore, genes implicated in angiogenic pathways could be susceptibility candidate genes for this malignancy. In this respect, we investigated the impact of functional genetic variants of TSP1 (N700S) and MMP9 (-1562 C/T) genes on the development and progression of PCa. This case-control study included 101 PCa patients and 106 healthy controls analyzed by polymerase chain reaction -restriction fragment length polymorphism assay. No association was observed between any of the TSP1 genotypes and PCa risk or severity; however, subjects carrying one copy of the MMP9 T allele exhibited threefold higher risk of developing PCa (OR = 2.86; P = 0.004). Regarding prognostic value, a significant association was found between the occurrence of the MMP9 T allele and the high-grade tumor (OR = 3.21; P = 0.004) and the advanced disease (OR = 2.47; P = 0.026). We also analyzed the effect of the combined genotypes on PCa risk. The patients with two high-risk genotypes exhibited 2.8-fold higher risk of developing PCa than those with only low-risk genotypes, but the association was not statistically significant. These findings suggest that MMP9 polymorphism is an independent risk factor of PCa development and aggressiveness. 相似文献
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