A Novel DC Therapy with Manipulation of MKK6 Gene on Nickel Allergy in Mice

BACKGROUND: Although the activation of dermal dendritic cells (DCs) or Langerhans cells (LCs) via p38 mitogen-activated protein kinase (MAPK) plays a crucial role in the pathogenesis of metal allergy, the in vivo molecular mechanisms have not been identified and a possible therapeutic strategy using the control of dermal DCs or LCs has not been established. In this study, we focused on dermal DCs to define the in vivo mechanisms of metal allergy pathogenesis in a mouse nickel (Ni) allergy model. The effects of DC therapy on Ni allergic responses were also investigated. METHODS AND FINDING: The activation of dermal DCs via p38 MAPK triggered a T cell-mediated allergic immune response in this model. In the MAPK signaling cascade in DCs, Ni potently phosphorylated MAP kinase kinase 6 (MKK6) following increased DC activation. Ni-stimulated DCs could prime T cell activation to induce Ni allergy. Interestingly, when MKK6 gene-transfected DCs were transferred into the model mice, a more pronounced allergic reaction was observed. In addition, injection of short interfering (si) RNA targeting the MKK6 gene protected against a hypersensitivity reaction after Ni immunization. The cooperative action between T cell activation and MKK6-mediated DC activation by Ni played an important role in the development of Ni allergy. CONCLUSIONS: DC activation by Ni played an important role in the development of Ni allergy. Manipulating the MKK6 gene in DCs may be a good therapeutic strategy for dermal Ni allergy

Clinical utility of multielectrode contact mapping for scar-related ventricular tachycardia ablation: A prospective single-center experience

Background: As with the use of circular catheters for pulmonary vein antral ablation, it may be favorable to use multipolar catheters for substrate mapping of the left ventricle (LV). The purpose of this study was to investigate the clinical feasibility of using multielectrode mapping combined with an impedance-based electroanatomic mapping system for scar-mediated ventricular tachycardia (VT). Methods: By using the multielectrode catheter in conjunction with the Velocity system, we obtained both geometric and electrogram data simultaneously, through transseptal and transsubxiphoid approaches. Higher-density mapping was performed in areas of dense scar (<0.5 mV) and border zones (0.5–1.5 mV). All late potentials (LPs) observed on the multipoles were tagged, and pace mapping was performed at those sites for comparison with the targeted VT morphology. Ablation was performed at target sites on the multipolar catheter that were identified by pace mapping, as well as at sites identified to have LPs and to be the origin of the premature ventricular complexes (PVCs) that triggered the VT. Results: Sixteen patients (8/8: ischemic/nonischemic cardiomyopathy) underwent endocardial (n=16) and epicardial (n=8) mapping. The mean number of endocardial and epicardial mapping points was 504±136 and 670±211, respectively, with an average mapping time of 21±6 min. LPs were seen in 13 patients (81%), and good (56%) and perfect (31%) pace maps were seen in 14 patients (88%). In two patients, sites with the earliest activation of PVCs that triggered VT were successfully identified with multipolar catheter mapping. A distinct geometric distortion of the endocardial LV was confirmed in two patients, and those were modified by dividing the LV into two chambers. After 10.0±3.7 months, 71% of the patients have remained free of VT episodes. Conclusion: Multipolar catheter mapping combined with the Velocity system results in a high-density delineation of the LV substrates in a relatively short time, suggesting that this is a feasible alternative mapping strategy for scar-related VT

Targeting the TGFβ signalling pathway in disease

Many drugs that target transforming growth factor-β (TGFβ) signalling have disease applications. Preclinical and clinical studies indicate the utility of these agents in fibrosis and oncology, particularly in augmentation of existing cancer therapies, such as radiation and chemotherapy, as well as in tumour vaccines. There are also reports of specialized applications, such as the reduction of vascular symptoms of Marfan syndrome. Here, we consider why the TGFβ signalling pathway is a drug target, the potential clinical applications of TGFβ inhibition, the issues arising with anti-TGFβ therapy and how these might be tackled using personalized approaches to dosing, monitoring of biomarkers as well as brief and/or localized drug-dosing regimens

Empagliflozin in Patients with Chronic Kidney Disease

Background The effects of empagliflozin in patients with chronic kidney disease who are at risk for disease progression are not well understood. The EMPA-KIDNEY trial was designed to assess the effects of treatment with empagliflozin in a broad range of such patients. Methods We enrolled patients with chronic kidney disease who had an estimated glomerular filtration rate (eGFR) of at least 20 but less than 45 ml per minute per 1.73 m(2) of body-surface area, or who had an eGFR of at least 45 but less than 90 ml per minute per 1.73 m(2) with a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 200. Patients were randomly assigned to receive empagliflozin (10 mg once daily) or matching placebo. The primary outcome was a composite of progression of kidney disease (defined as end-stage kidney disease, a sustained decrease in eGFR to &lt; 10 ml per minute per 1.73 m(2), a sustained decrease in eGFR of &amp; GE;40% from baseline, or death from renal causes) or death from cardiovascular causes. Results A total of 6609 patients underwent randomization. During a median of 2.0 years of follow-up, progression of kidney disease or death from cardiovascular causes occurred in 432 of 3304 patients (13.1%) in the empagliflozin group and in 558 of 3305 patients (16.9%) in the placebo group (hazard ratio, 0.72; 95% confidence interval [CI], 0.64 to 0.82; P &lt; 0.001). Results were consistent among patients with or without diabetes and across subgroups defined according to eGFR ranges. The rate of hospitalization from any cause was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.86; 95% CI, 0.78 to 0.95; P=0.003), but there were no significant between-group differences with respect to the composite outcome of hospitalization for heart failure or death from cardiovascular causes (which occurred in 4.0% in the empagliflozin group and 4.6% in the placebo group) or death from any cause (in 4.5% and 5.1%, respectively). The rates of serious adverse events were similar in the two groups. Conclusions Among a wide range of patients with chronic kidney disease who were at risk for disease progression, empagliflozin therapy led to a lower risk of progression of kidney disease or death from cardiovascular causes than placebo