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Rationale: Although type II alveolar epithelial cells (AEC2s) are chronically injured in idiopathic pulmonary fibrosis (IPF), they contribute to epithelial regeneration in IPF. Objectives: We hypothesized that Notch signaling may contribute to AEC2 proliferation, dedifferentiation characterized by loss of surfactant processing machinery, and lung fibrosis in IPF. Methods: We applied microarray analysis, kinome profiling, flow cytometry, immunofluorescence analysis, western blotting, quantitative PCR, and proliferation and surface activity analysis to study epithelial differentiation, proliferation, and matrix deposition in vitro (AEC2 lines, primary murine/human AEC2s), ex vivo (human IPF-derived precision-cut lung slices), and in vivo (bleomycin and pepstatin application, Notch1 [Notch receptor 1] intracellular domain overexpression). Measurements and Main Results: We document here extensive SP-B and -C (surfactant protein-B and -C) processing defects in IPF AEC2s, due to loss of Napsin A, resulting in increased intra-alveolar surface tension and alveolar collapse and induction of endoplasmic reticulum stress in AEC2s. In vivo pharmacological inhibition of Napsin A results in the development of AEC2 injury and overt lung fibrosis. We also demonstrate that Notch1 signaling is already activated early in IPF and determines AEC2 fate by inhibiting differentiation (reduced lamellar body compartment, reduced capacity to process hydrophobic SP) and by causing increased epithelial proliferation and development of lung fibrosis, putatively via altered JAK (Janus kinase)/Stat (signal transducer and activator of transcription) signaling in AEC2s. Conversely, inhibition of Notch signaling in IPF-derived precision-cut lung slices improved the surfactant processing capacity of AEC2s and reversed fibrosis. Conclusions: Notch1 is a central regulator of AEC2 fate in IPF. It induces alveolar epithelial proliferation and loss of Napsin A and of surfactant proprotein processing, and it contributes to fibroproliferation.

Alveolar type 2 (AT2) cells are heterogeneous cells, with specialised AT2 subpopulations within this lineage exhibiting stem cell properties. However, the existence of quiescent, immature cells within the AT2 lineage that are activated during lung regeneration is unknown. Sftpc CreERT2/+ ;tdTomato flox/flox mice were used for the labelling of AT2 cells and labelled subpopulations were analysed by flow cytometry, quantitative PCR, assay for transposase-accessible chromatin using sequencing (ATAC-seq), gene arrays, pneumonectomy and culture of precision-cut lung slices. Single-cell RNA-sequencing (scRNA-seq) data from human lungs were analysed.In mice, we detected two distinct AT2 subpopulations, with low tdTomato level (Tom Low ) and high tdTomato level (Tom High ). Tom Low cells express lower levels of the AT2 differentiation markers Fgfr2b and Etv5 , while Tom High , as bona fide mature AT2 cells, show higher levels of Sftpc , Sftpb , Sftpa1 , Fgfr2b and Etv5 expression. ATAC-seq analysis indicates that Tom Low and Tom High cells constitute two distinct cell populations, with specific silencing of Sftpc , Rosa26 and cell cycle gene loci in the Tom Low population. Upon pneumonectomy, the number of Tom Low but not Tom High cells increases and Tom Low cells show upregulated expression of Fgfr2b , Etv5 , Sftpc , Ccnd1 and Ccnd2 compared to Sham. Tom Low cells overexpress programmed cell death 1 ligand 1 (PD-L1), an immune inhibitory membrane receptor ligand, which is used by flow cytometry to differentially isolate these two subpopulations. In the human lung, data mining of a recent scRNA-seq AT2 data set demonstrates the existence of a PD-L1 Pos population. Therefore, we have identified a novel population of AT2 quiescent, immature progenitor cells in mouse that expand upon pneumonectomy and we have provided evidence for the existence of such cells in human., Competing Interests: Conflict of interest: N. Ahmadvand has nothing to disclose. Conflict of interest: F. Khosravi has nothing to disclose. Conflict of interest: A. Lingampally has nothing to disclose. Conflict of interest: R. Wasnick has nothing to disclose. Conflict of interest: I. Vasquez-Armendariz has nothing to disclose. Conflict of interest: G. Carraro has nothing to disclose. Conflict of interest: M. Heiner has nothing to disclose. Conflict of interest: S. Rivetti has nothing to disclose. Conflict of interest: Y. Lv has nothing to disclose. Conflict of interest: J. Wilhelm has nothing to disclose. Conflict of interest: A. Gunther has nothing to disclose. Conflict of interest: S. Herold has nothing to disclose. Conflict of interest: D. Al Alam has nothing to disclose. Conflict of interest: C. Chen has nothing to disclose. Conflict of interest: P. Minoo has nothing to disclose. Conflict of interest: J-S. Zhang has nothing to disclose. Conflict of interest: S. Bellusci has nothing to disclose., (Copyright ©The authors 2021.)

Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by type-II alveolar epithelial cell (AECII) injury and fibroblast hyperproliferation. Severe AECII endoplasmic reticulum (ER) stress is thought to underlie IPF, but is yet incompletely understood. We studied the regulation of C/EBP homologous protein (CHOP), a proapoptotic ER-stress-related transcription factor (TF) in AECII-like cells. Interestingly, single or combined overexpression of the active ER stress transducers activating transcription factor-4 (Atf4) and activating transcription factor-6 (p50Atf6) or spliced x-box-binding protein-1 (sXbp1) in MLE12 cells did not result in a substantial Chop induction, as compared to the ER stress inducer thapsigargin. Employing reporter gene assays of distinct CHOP promoter fragments, we could identify that, next to the conventional amino acid (AARE) and ER stress response elements (ERSE) within the CHOP promoter, activator protein-1 (AP-1) and c-Ets-1 TF binding sites are necessary for CHOP induction. Serial deletion and mutation analyses revealed that both AP-1 and c-Ets-1 motifs act in concert to induce CHOP expression. In agreement, CHOP promoter activity was greatly enhanced upon combined versus single overexpression of AP-1 and c-Ets-1. Moreover, combined overexpression of AP-1 and c-Ets-1 in MLE12 cells alone in the absence of any other ER stress inducer was sufficient to induce Chop protein expression. Further, AP-1 and c-Ets-1 were upregulated in AECII under ER stress conditions and in human IPF. Finally, Chop overexpression in vitro resulted in AECII apoptosis, lung fibroblast proliferation, and collagen-I production. We propose that CHOP activation by AP-1 and c-Ets-1 plays a key role in AECII maladaptive ER stress responses and consecutive fibrosis, offering new therapeutic prospects in IPF. KEY MESSAGES: Overexpression of active ER stress sensors Atf4, Atf6, and Xbp1 does not induce Chop. AP-1 and c-Ets-1 TFs are necessary for induction of the ER stress factor Chop. AP-1 and c-Ets-1 alone induce Chop expression in the absence of any ER stress inducers. AP-1 and c-Ets-1 are induced in AECII under ER stress conditions and in human IPF. Chop expression alone triggers AECII apoptosis and consecutive profibrotic responses.

Idiopathic pulmonary fibrosis is a common form of interstitial lung disease resulting in alveolar remodeling and progressive loss of pulmonary function because of chronic alveolar injury and failure to regenerate the respiratory epithelium. Histologically, fibrotic lesions and honeycomb structures expressing atypical proximal airway epithelial markers replace alveolar structures, the latter normally lined by alveolar type 1 (AT1) and AT2 cells. Bronchial epithelial stem cells (BESCs) can give rise to AT2 and AT1 cells or honeycomb cysts following bleomycin-mediated lung injury. However, little is known about what controls this binary decision or whether this decision can be reversed. Here we report that inactivation of Fgfr2b in BESCs impairs their contribution to both alveolar epithelial regeneration and honeycomb cysts after bleomycin injury. By contrast overexpression of Fgf10 in BESCs enhances fibrosis resolution by favoring the more desirable outcome of alveolar epithelial regeneration over the development of pathologic honeycomb cysts., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Whereas coronary aneurysms are commonly associated with Kawasaki disease, involvement of the renal vasculature is exceedingly rare. Genitourinary involvement in patients with Kawasaki disease is typically limited to sterile pyuria and proteinuria. In this case, a 13-year-old girl who presented with right flank pain and microhematuria was found to have an intraparenchymal hemorrhagic mass on computerized tomography scan. Renal arteriography confirmed the diagnosis of pseudoaneurysm in a lower pole segmental artery branch and complete occlusion was achieved with endovascular embolization., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Recent clinical studies show that tyrosine kinase inhibitors slow the rate of lung function decline and decrease the number of acute exacerbations in patients with Idiopathic Pulmonary Fibrosis (IPF). However, in the murine bleomycin model of fibrosis, not all tyrosine kinase signaling is detrimental. Exogenous ligands Fibroblast Growth Factor (FGF) 7 and 10 improve murine lung repair and increase survival after injury via tyrosine kinase FGF receptor 2b-signaling. Therefore, the level and location of FGF/FGFR expression as well as the exogenous effect of the most highly expressed FGFR2b ligand, FGF1, was analyzed on human lung fibroblasts., Methods: FGF ligand and receptor expression was evaluated in donor and IPF whole lung homogenates using western blotting and qPCR. Immunohistochemistry for FGF1 and FGFR1/2/3/4 were performed on human lung tissue. Lastly, the effects of FGF1, a potent, multi-FGFR ligand, were studied on primary cultures of IPF and non-IPF donor fibroblasts. Western blots for pro-fibrotic markers, proliferation, FACS for apoptosis, transwell assays and MetaMorph analyses on cell cultures were performed., Results: Whole lung homogenate analyses revealed decreased FGFR b-isoform expression, and an increase in FGFR c-isoform expression. Of the FGFR2b-ligands, FGF1 was the most significantly increased in IPF patients; downstream targets of FGF-signaling, p-ERK1/2 and p-AKT were also increased. Immunohistochemistry revealed FGF1 co-localization within basal cell sheets, myofibroblast foci, and Surfactant protein-C positive alveolar epithelial type-II cells as well as co-localization with FGFR1, FGFR2, FGFR3, FGFR4 and myofibroblasts expressing the migratory marker Fascin. Both alone and in the presence of heparin, FGF1 led to increased MAPK-signaling in primary lung fibroblasts. While smooth muscle actin was unchanged, heparin + FGF1 decreased collagen production in IPF fibroblasts. In addition, FGF1 + heparin increased apoptosis and cell migration. The FGFR inhibitor (PD173074) attenuated these effects., Conclusions: Strong expression of FGF1/FGFRs in pathogenic regions of IPF suggest that aberrant FGF1-FGFR signaling is increased in IPF patients and may contribute to the pathogenesis of lung fibrosis by supporting fibroblast migration and increased MAPK-signaling.

A 35-year-old white male presented with erectile dysfunction and areflexic bladder secondary to an intrathecal paraganglioma of the cauda equina. Erectile dysfunction has not been emphasized as a component of the cauda equina syndrome.

Clinical correlations have been made with the applied anatomy of the infradiphragmatic urethra. The entire urethra was removed en bloc and the infradiaphragmatic urethra was carefully dissected with metallic sounds in situ. The urethra immediately distal to the urogenital diaphragm is devoid of any corporal tissue anteriorly and constitutes the 'bare area' tha can easily be injured during rigid urethral instrumentation.

A case of neonatal urinary ascites resulting from a ureteropelvic junction obstruction in a solitary kidney is reported. This is an uncommon cause of urinary ascites in the newborn, reported but once heretofore.

The usage of the testicular scan to differentiate torsion from epididymo-orchitis in 33 patients is reported. Our results yielded a surgically confirmed accuracy rate of 77 per cent, and a clinical accuracy rate of 100 per cent. The entity of missed torsion has a characteristic appearance, which we have termed the "halo sign."

99mTechnetium-labeled dimercaptosuccinic acid (99mTc-DMSA) scanning provides superior quality images of renal parenchymal detail, which makes it highly sensitive for the diagnosis of pyelonephritic scarring. Unlike most other imaging techniques, radionuclide scanning is not affected by bowel gas or bony structures overlying the kidneys. This makes it particularly useful in children. Furthermore, renal scarring can be demonstrated by 99mTc-DMSA even before the classic gross anatomic and radiologic changes are present. The use of 99mTc-DMSA scanning in over 300 children has demonstrated its benefits and advantages over standard radiographic techniques.

We evaluated the anterior extravesical ureteroneocystostomy technique in 184 consecutive renal transplants done in 2 consecutive calendar years. Complications included 5 cases of ureteral and 1 of pelvic necrosis, and 2 of ureteral obstruction, with a ureteral complication rate of less than 4 per cent. All cases of pelvic or ureteral necrosis except 1 were seen in cadaver donor kidneys that were imported from other centers. No bladder complications were seen. Pelvioureteral obstruction, presumably of congenital origin in the cadaver donor, was discovered in the kidney after transplantation in 2 cases and was corrected successfully by pyeloureterostomy to the native ureter. The extraordinary simplicity of this technique, coupled with improvement in the complication rate, makes it our procedure of choice.

We reimplanted 121 ureters by the Cohen technique. A modification is introduced for difficult cases, making the Cohen technique more adaptable for dilated ureters and small bladders. Radiographic studies obtained at least 6 months after reimplantation revealed only 1 case of persistent reflux (grade I), no case of contralateral reflux and no obstruction. Even though the series included 35 ureters with grade V primary reflux and 7 primary obstructive megaureters, only 7 ureters were tapered. This finding suggests that the Cohen method might require tapering in a smaller percentage of cases compared to other reimplantation techniques.

The major difficulties encountered in the surgical correction of pediatric communicating hydroceles are separating the hernial sac from the spermatic vessels and vas, and identifying the anatomical location of the internal inguinal ring. The passage of a pediatric Foley catheter through the hernial sac via a high scrotal incision greatly expedites this surgery. Herein, we describe a new surgical technique and discuss its merits.