Extratubular Polymerized Uromodulin Induces Leukocyte Recruitment and Inflammation In Vivo

Uromodulin (UMOD) is produced and secreted by tubular epithelial cells. Secreted UMOD polymerizes (pUMOD) in the tubular lumen, where it regulates salt transport and protects the kidney from bacteria and stone formation. Under various pathological conditions, pUMOD accumulates within the tubular lumen and reaches extratubular sites where it may interact with renal interstitial cells. Here, we investigated the potential of extratubular pUMOD to act as a damage associated molecular pattern (DAMP) molecule thereby creating local inflammation. We found that intrascrotal and intraperitoneal injection of pUMOD induced leukocyte recruitment in vivo and led to TNF-alpha secretion by F4/80 positive macrophages. Additionally, pUMOD directly affected vascular permeability and increased neutrophil extravasation independent of macrophage-released TNF-alpha. Interestingly, pUMOD displayed no chemotactic properties on neutrophils, did not directly activate beta 2 integrins and did not upregulate adhesion molecules on endothelial cells. In obstructed neonatal murine kidneys, we observed extratubular UMOD accumulation in the renal interstitium with tubular atrophy and leukocyte infiltrates. Finally, we found extratubular UMOD deposits associated with peritubular leukocyte infiltration in kidneys from patients with inflammatory kidney diseases. Taken together, we identified extratubular pUMOD as a strong inducer of leukocyte recruitment, underlining its critical role in mounting an inflammatory response in various kidneys pathologies

Radio haloes in nearby galaxies modelled with 1d cosmic ray transport using SPINNAKER

We present radio continuum maps of 12 nearby (D ≤ 27 Mpc), edge-on (i ≥ 76?), latetypespiral galaxies mostly at 1.4 and 5 GHz, observed with the Australia Telescope CompactArray, Very LargeArray, Westerbork Synthesis Radio Telescope, Effelsberg 100-m, and Parkes64-m telescopes. All galaxies show clear evidence of radio haloes, including the first detectionin the Magellanic-type galaxy NGC 55. In 11 galaxies, we find a thin and a thick discthat can be better fitted by exponential rather than Gaussian functions. We fit our SPINNAKER(SPectral INdex Numerical Analysis of K(c)osmic-ray Electron Radio-emission) 1D cosmicray transport models to the vertical model profiles of the non-thermal intensity and to thenon-thermal radio spectral index in the halo. We simultaneously fit for the advection speed (ordiffusion coefficient) and magnetic field scale height. In the thick disc, the magnetic field scaleheights range from 2 to 8 kpc with an average across the sample of 3.0 ± 1.7 kpc; they showno correlation with either star formation rate (SFR), SFR surface density (Σ SFR), or rotationspeed (Vrot). The advection speeds range from 100 to 700 km s-1 and display correlations ofV α SFR0.36±0.06 and V α Σ0.39±0.09SFR; they agree remarkably well with the escape velocities(0.5 ≤ V/Vesc ≤ 2), which can be explained by cosmic ray-driven winds. Radio haloes showthe presence of disc winds in galaxies with ΣSFR > 10-3Mo˙yr-1 kpc-2 that extend overseveral kpc and are driven by processes related to the distributed star formation in the disc

Rapid Response to Cyclosporin A and Favorable Renal Outcome in Nongenetic Versus Genetic Steroid-Resistant Nephrotic Syndrome

Background and objectives Treatment of congenital nephrotic syndrome (CNS) and steroid resistant nephrotic syndrome (SRNS) is demanding, and renal prognosis is poor. Numerous causative gene mutations have been identified in SRNS that affect the renal podocyte. In the era of high throughput sequencing techniques, patients with nongenetic SRNS frequently escape the scientific interest. We here present the long-term data of the German CNS/SRNS Follow-Up Study, focusing on the response to cyclosporin A (CsA) in patients with nongenetic versus genetic disease. Design, setting, participants, & measurements Cross sectional and longitudinal clinical data were collected from 231 patients with CNS/SRNS treated at eight university pediatric nephrology units with a median observation time of 113 months (interquartile range, 50-178). Genotyping was performed systematically in all patients. Results The overall mutation detection rate was high at 57% (97% in CNS and 41% in SRNS); 85% of all mutations were identified by the analysis of three single genes only (NPHS1, NPHS2, and WT1), accounting for 92% of all mutations in patients with CNS and 79% of all mutations in patients with SRNS. Remission of the disease in nongenetic SRNS was observed in 78% of patients after a median treatment period of 2.5 months; 82% of nongenetic patients responded within 6 months of therapy, and 98% of patients with nongenetic SRNS and CsA induced complete remission (normalbuminemia and no proteinuria) maintained a normal renal function. Genetic SRNS, on the contrary, is associated with a high rate of ESRD in 66% of patients. Only 3% of patients with genetic SRNS experienced a complete remission and 16% of patients with genetic SRNS experienced a partial remission after CsA therapy. Conclusions The efficacy of CsA is high in nonhereditary SRNS, with an excellent prognosis of renal function in the large majority of patients. CsA should be given for a minimum period of 6 months in these patients with nongenetic SRNS. In genetic SRNS, response to CsA was low and restricted to exceptional patients

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