Fibrosis and Immune Cell Infiltration Are Separate Events Regulated by Cell-Specific Receptor Notch3 Expression.

BACKGROUND: Kidney injuries that result in chronic inflammation initiate crosstalk between stressed resident cells and infiltrating immune cells. In animal models, whole-body receptor Notch3 deficiency protects from leukocyte infiltration and organ fibrosis. However, the relative contribution of Notch3 expression in tissue versus infiltrating immune cells is unknown. METHODS: Chimeric mice deficient for Notch3 in hematopoietic cells and/or resident tissue cells were generated, and kidney fibrosis and inflammation after unilateral ureteral obstruction (UUO) were analyzed. Adoptive transfer of labeled bone marrow-derived cells validated the results in a murine Leishmania ear infection model. In vitro adhesion assays, integrin activation, and extracellular matrix production were analyzed. RESULTS: Fibrosis follows UUO, but inflammatory cell infiltration mostly depends upon Notch3 expression in hematopoietic cells, which coincides with an enhanced proinflammatory milieu (e.g., CCL2 and CCL5 upregulation). Notch3 expression on CD45+ leukocytes plays a prominent role in efficient cell transmigration. Functionally, leukocyte adhesion and integrin activation are abrogated in the absence of receptor Notch3. Chimeric animal models also reveal that tubulointerstitial fibrosis develops, even in the absence of prominent leukocyte infiltrates after ureteral obstruction. Deleting Notch3 receptors on resident cells blunts kidney fibrosis, ablates NF-κB signaling, and lessens matrix deposition. CONCLUSIONS: Cell-specific receptor Notch3 signaling independently orchestrates leukocyte infiltration and organ fibrosis. Interference with Notch3 signaling may present a novel therapeutic approach in inflammatory as well as fibrotic diseases.

DNA-Binding Protein A Is Actively Secreted in a Calcium-and Inflammasome-Dependent Manner and Negatively Influences Tubular Cell Survival.

DNA-binding protein A (DbpA) belongs to the Y-box family of cold shock domain (CSD) proteins that bind RNA/DNA and exert intracellular functions in cell stress, proliferation, and differentiation. Given the pattern of DbpA staining in inflammatory glomerular diseases, without adherence to cell boundaries, we hypothesized extracellular protein occurrence and specific functions. Lipopolysaccharide and ionomycin induce DbpA expression and secretion from melanoma and mesangial cells. Unlike its homologue Y-box-binding protein 1 (YB-1), DbpA secretion requires inflammasome activation, as secretion is blocked upon the addition of a NOD-like receptor protein-3 (NLRP3) inhibitor. The addition of recombinant DbpA enhances melanoma cell proliferation, migration, and competes with tumor necrosis factor (TNF) binding to its receptor (TNFR1). In TNF-induced cell death assays, rDbpA initially blocks TNF-induced apoptosis, whereas at later time points (>24 h), cells are more prone to die. Given that CSD proteins YB-1 and DbpA fulfill the criteria of alarmins, we propose that their release signals an inherent danger to the host. Some data hint at an extracellular complex formation at a ratio of 10:1 (DbpA:YB-1) of both proteins.

Elevated Mitral Valve Pressure Gradient Is Predictive of Long-Term Outcome After Percutaneous Edge-to-Edge Mitral Valve Repair in Patients With Degenerative Mitral Regurgitation ( MR ), But Not in Functional MR.

Background This study analyzed the effects on long-term outcome of residual mitral regurgitation ( MR ) and mean mitral valve pressure gradient ( MVPG ) after percutaneous edge-to-edge mitral valve repair using the MitraClip system. Methods and Results Two hundred fifty-five patients who underwent percutaneous edge-to-edge mitral valve repair were analyzed. Kaplan-Meier and Cox regression analyses were performed to evaluate the impact of residual MR and MVPG on clinical outcome. A combined clinical end point (all-cause mortality, MV surgery, redo procedure, implantation of a left ventricular assist device) was used. After percutaneous edge-to-edge mitral valve repair, mean MVPG increased from 1.6±1.0 to 3.1±1.5 mm Hg ( P<0.001). Reduction of MR severity to ≤2+ postintervention was achieved in 98.4% of all patients. In the overall patient cohort, residual MR was predictive of the combined end point while elevated MVPG >4.4 mm Hg was not according to Kaplan-Meier and Cox regression analyses. We then analyzed the cohort with degenerative and that with functional MR separately to account for these different entities. In the cohort with degenerative MR , elevated MVPG was associated with increased occurrence of the primary end point, whereas this was not observed in the cohort with functional MR . Conclusions MVPG >4.4 mm Hg after MitraClip implantation was predictive of clinical outcome in the patient cohort with degenerative MR . In the patient cohort with functional MR , MVPG >4.4 mm Hg was not associated with increased clinical events.

(3R,4S,5S)-4-Hydr-oxy-3-methyl-5-[(2S,3R)-3-methyl-pent-4-en-2-yl]tetra-hydro-furan-2-one.

The title compound, C(11)H(18)O(3), was synthesized to prove the relative configuration of the corresponding acyclic C1-C8 stereopentade. It crystallizes with two mol-ecules in the asymmetric unit, which show only slight differences. The mol-ecules are linked via O-H⋯O hydrogen bonds, resulting in two crystallographically independent chains of mol-ecules propagating in the a-axis direction. The absolute configuration was known from the synthesis.

Previous TAVR in patients undergoing percutaneous edge-to-edge mitral valve repair (PMVR) affects improvement of MR.

BACKGROUND: Patients after transcatheter aortic valve replacement (TAVR) and persistent severe mitral regurgitation (MR) are increasingly treated with percutaneous edge-to-edge mitral valve repair (PMVR). The impact of a former TAVR on PMVR procedures is not clear. METHODS AND RESULTS: We retrospectively analyzed 332 patients undergoing PMVR using the MitraClip system with respect to procedural and clinical outcome. 21 of these 332 patients underwent TAVR before PMVR. Intra-procedural transthoracic (TTE) and transesophageal echocardiograms (TEE) immediately before and after clip implantation as well as invasive hemodynamic measurements were evaluated. At baseline, we found a significantly smaller mitral valve anterior-posterior diameter in the TAVR cohort (p < 0.001). A reduction of MR by at least three grades was achieved in a smaller fraction in the TAVR cohort as compared to the cohort with a native aortic valve (p = 0.02). Accordingly, we observed a smaller post-procedural cardiac output in the TAVR cohort (p = 0.02). CONCLUSION: PMVR in patients who had a TAVR before, is associated with altered MR anatomy before and a reduced improvement of MR after the procedure. Future larger and prospective studies will have to determine, whether a previous TAVR influences long-term clinical outcome of patients undergoing PMVR.

Comparison of Deep Sedation With General Anesthesia in Patients Undergoing Percutaneous Mitral Valve Repair.

BACKGROUND: Percutaneous edge-to-edge mitral valve repair (PMVR) has become an established treatment option for mitral regurgitation in patients not eligible for surgical repair. Currently, most procedures are performed under general anesthesia (GA). An increasing number of centers, however, are performing the procedure under deep sedation (DS). Here, we compared patients undergoing PMVR with GA or DS. METHODS AND RESULTS: A total of 271 consecutive patients underwent PMVR at our institution between May 2014 and December 2016. Seventy-two procedures were performed under GA and 199 procedures under DS. We observed that in the DS group, doses of propofol (743±228 mg for GA versus 369±230 mg for DS, P<0.001) and norepinephrine (1.1±1.6 mg for GA versus 0.2±0.3 mg for DS, P<0.001) were significantly lower. Procedure time, fluoroscopy time, and dose area product were significantly higher in the GA group. There was no significant difference between GA and DS with respect to overall bleeding complications, postinterventional pneumonia (4% for GA versus 5% for DS), or C-reactive protein levels (361±351 nmol/L for GA versus 278±239 nmol/L for DS). Significantly fewer patients with DS needed a postinterventional stay in the intensive care unit (96% for GA versus 19% for DS, P<0.001). Importantly, there was no significant difference between DS and GA regarding intrahospital or 6-month mortality. CONCLUSIONS: DS for PMVR is safe and feasible. No disadvantages with respect to procedural outcome or complications in comparison to GA were observed. Applying DS may simplify the PMVR procedure.