SPECIAL ISSUE PAPERS Pulmonary Nodule Detection in CT Images: False Positive Reduction Using Multi-View Convolutional Networks ...... .................................................................................... ..................... AAA Setio, F. Ciompi, G. Litjens, P. Gerke, C. Jacobs, SJ van Riel, MMW Wille, M. Naqibullah, CI Sánchez, and B. van Ginneken … Improving Computer-Aided Detection Using Convolutional Neural Networks and Random View Aggregation .......... ......................................... .. HR Roth, L. Lu, J. Liu, J. Yao, A. Seff, K. Cherry, L. Kim, and RM Summers … Automatic Detection of Cerebral Microbleeds From MR Images via 3D Convolutional Neural Networks ................. ..................................... Q. Dou, H. Chen, L. Yu, L. Zhao, J. Qin, D. Wang, VC Mok, L. Shi, and P.-A. Heng … Locality Sensitive Deep Learning for Detection and Classification of Nuclei in Routine Colon Cancer Histology Images . . .......................... K. Sirinukunwattana, SEA …

We propose a novel Computer-Aided Detection (CAD) system for pulmonary nodules using multi-view convolutional networks (ConvNets), for which discriminative features are automatically learnt from the training data. The network is fed with nodule candidates obtained by combining three candidate detectors specifically designed for solid, subsolid, and large nodules. For each candidate, a set of 2-D patches from differently oriented planes is extracted. The proposed architecture comprises multiple streams of 2-D ConvNets, for which the outputs are combined using a dedicated fusion method to get the final classification. Data augmentation and dropout are applied to avoid overfitting. On 888 scans of the publicly available LIDC-IDRI dataset, our method reaches high detection sensitivities of 85.4% and 90.1% at 1 and 4 false positives per scan, respectively. An additional evaluation on independent datasets from the ANODE09 challenge and DLCST is performed. We showed that the proposed multi-view ConvNets is highly suited to be used for false positive reduction of a CAD system.

Bluthochdruck und seine Folgen werden häufig von der Öffentlichkeit, Politik und den Medien unterschätzt, seine globale Bedeutung wird nicht wahrgenommen. Dabei sind bereits heute weltweit mehr als 1 Milliarde Menschen von Bluthochdruck betroffen und es sterben pro Jahr 7,5 Millionen Menschen an zu hohem Blutdruck – das entspricht 12,8 % aller weltweiten Todesfälle. Im Jahr 2025 werden bereits 1,5 Milliarden Menschen von Bluthochdruck betroffen sein. Am meisten betroffen werden mit 2 Dritteln der Patienten die ärmsten Länder der Welt sein. Bluthochdruck ist also schon lange keine Wohlstandserkrankung mehr. Auch in der Mongolei sind Erkrankungen des Herz-Kreislauf-Systems seit 1995 häufigste Todesursache. In dem bevölkerungsarmen Land sind große Entfernungen zu medizinischen Behandlungseinrichtungen ein großes Problem in der Entdeckung und Therapie der Hypertonie. Das beschriebene Projekt schildert die Situation in der Mongolei und stellt Wege vor, Menschen in ihrem direkten Umfeld zu erreichen (Arbeitsplatz, Wohnung) und dort das Screening nach Risikofaktoren sowie die Aufklärung über Vorbeugemöglichkeiten sowie Erfolgskontrollen durchzuführen. Anders als in vielen anderen Ländern ist der politische Wille zur Etablierung von Präventionsprogrammen gegeben, was sich in der Unterzeichnung eines Gesundheitsabkommens mit der Bundesrepublik mit Schwerpunkt der Prävention von Herz-Kreislauf-Erkrankungen zeigt. Hoffentlich erfolgt eine nachhaltige Umsetzung.

Introduction and Aims: Gadolinium chelate (GC)s using in magnetic resonance imaging (MRI) have been traditionally considered as non-nephrotoxic contrast materials.But, in some recent articles it has been suggested that GCs may have a nephrotoxic potential.Nevertheless, most of these reports are retrospective, and evaluated contrast agents and their doses were not homogenous.To investigate the effect of gadopentetate dimeglumine (GD) and magnetic field on renal function in patients with high-risk for acute kidney injury (AKI).Methods: We designed a prospective case control study, and age and sex-matched two groups of patients were included the study.Both of groups were consisted of the patients with high-risk for AKI (diabetes mellitus, hypotension, chronic renal failure, using nephrotoxic material, i.e.) (n=40, for each group).While contrast (gadopentetate dimeglumin)-enhanced non-vascular MRI was performed to group 1 patients, MRI without conrast agent was performed in goup 2 patients.Fixed dose of GD (0.2 mmol/kg) were administered to group 1 patients.All patients were followed up 72 hours.Before and at the 6, 24 and 72 hours after the MRI; biochemical markers, urinalysis, microalbumin/creatinine ratio in spot urine, serum creatinine, and glomerular filtration rate were measured.Results: Baseline serum creatinine, microalbumin/creatinine ratio, and GFR was not different between group 1 and group 2 ( p>0.05).We did not observe adverse effect related to procedures.There were no significant changes in renal functional tests (? serum creatinine, ?microalbumin/creatinin ratio, and ?GFR) in both groups after 6, 24 or 72 hours of the procedures ( p>0,05).Conclusions: Non-vascular contrast-enhanced (GD, 0.2 mmol/kg) MRI is a safe procedure for patients with high-risk for AKI.

Background. Optimal treatment of polyomavirus-induced allograft nephropathy (PVAN) with immunosuppressive and antiviral therapy is uncertain at present. Reduced immunosuppression is accompanied by increased risk of rejection, and antiviral agents are nephrotoxic. Leflunomide has immunosuppressive and antiviral properties and may be an alternative treatment agent. We report a two-center experience with use of leflunomide for treatment of PVAN.Patients and Methods. Thirteen renal allograft recipients were diagnosed with biopsy-proven PVAN. Treatment consisted of lowering the calcineurin-inhibitor trough level, discontinuing mycophenolate mofetil therapy, and initiating leflunomide therapy. In 8 of the 13 patients, the serum concentration of the leflunomide active metabolite A771726 was monitored.Results. Exchange of mycophenolate mofetil with leflunomide in patients with PVAN was well tolerated and safe, with no serious adverse effects or episodes of graft rejection. Mean follow-up after transplantation was 717 days, and after initiation of leflunomide therapy was 465 days. With the modified therapy, 12 patients cleared the virus at a mean of 109 days. One graft was lost due to refractory rejection accompanied by a decreasing viral load. In the other 12 patients, graft function stabilized or improved (mean [median] creatinine concentration at diagnosis, 2.39 [2.5] mg/mL, vs 2.27 [2.0] mg/dL at follow-up). Leflunomide concentration did not correlate with treatment efficiency.Conclusions. Treatment of PVAN with leflunomide, a low-dose calcineurin inhibitor, and prednisone seems to reduce viral load and stabilize renal graft function without increasing the risk of rejection. Even low serum concentrations of leflunomide support viral elimination and prevention of graft rejection.

Die Rekurrenz der Grundkrankheit zählt zu den wichtigsten Ursachen eines Nierentransplantatverlusts in den ersten 10 Jahren. Die klinischen Symptome ähneln denen der Grundkrankheit, können jedoch auch dezent sein oder als Teil einer chronischen Transplantatnephropathie imponieren. Ein hohes Risiko für eine klinisch relevante Rekurrenzen haben die primäre FSGS, das atypische HUS und die Amyloidose. Ein deutlich erhöhtes Risiko besteht für Patienten im Kindesalter, mit rasch fortschreitender Insuffizienz in den Eigennieren und solche, die bereits ein Transplantat durch Rekurrenz verloren haben. Da die Nierentransplantation das Patientenüberleben und die Lebensqualität gegenüber der Dialysebehandlung verbessert, ist sie selbst für Patienten mit häufig rekurrierenden Grundkrankheiten das Verfahren der Wahl. Der vorliegende Artikel diskutiert die Datenlage zu Häufigkeit, Risikofaktoren und Auswirkungen im Transplantat rekurrierender Nierenerkrankungen.

Nephrogenic systemic fibrosis (NSF) is a disease recently described in patients with kidney failure. It is characterized by scleroderma-like thickening of the skin, subcutaneous edema and ensuing joint contractures leading to profound disability. Furthermore, involvement of internal organs has been described. Whereas the pathogenesis is not known to date, recent reports have linked NSF to high doses of gadolinium-containing contrast agents given at magnetic resonance angiography (MRA). We describe a patient with severe NSF. The patient had received erythropoietin and had undergone vascular interventions which are suspected risk factors for this disease. Notably, the disease developed shortly after the application of gadolinium at an MRA, giving support to the recently published hypothesis that gadolinium-containing contrast agents are among the causative factors. We provide a short overview and hope to raise overall awareness towards this entity and the use of MRA contrast agents in renal patients.

Nephrin and NEPH1, the gene products of NPHS1 and NEPH1, are podocyte membrane proteins of the Ig superfamily. Similar to the nephrin knockout, mice lacking NEPH1 show severe proteinuria leading to perinatal death. To identify the ligand of NEPH1, the extracellular domain of NEPH1 was fused to human IgG. This NEPH1-Ig fusion protein labeled the glomerular capillary wall of mouse kidneys in a staining pattern identical to NEPH1 and nephrin, prompting speculation that that NEPH1 might form homodimers and/or heterodimers with nephrin. In coimmunoprecipitation and pull-down assays, the NEPH1-Ig fusion protein precipitated wild-type NEPH1 from overexpressing HEK 293T cells. Truncational analysis revealed that the adhesive properties were not confined to a single Ig domain of NEPH1. Fusion proteins containing two Ig domains of NEPH1 were sufficient to immobilize NEPH1, but they failed to interact with control protein containing the phylogenetically related PKD repeats of polycystin-1. NEPH1 also precipitated nephrin, a protein with eight Ig domains and a fibronectin-like domain. Truncational analysis of nephrin revealed a very similar mode of interaction, i.e., two nephrin Ig domains fused to human IgG precipitated either nephrin or NEPH1, but not the control protein. Both NEPH1 and nephrin interactions were strictly dependent upon posttranslational glycosylation, and bacterially expressed protein failed to bind NEPH1. These findings demonstrate that the Ig domains of NEPH1 and nephrin form promiscuous homodimeric and heterodimeric interactions that may facilitate cis- and trans- homodimerizations and heterodimerizations of these molecules at the glomerular slit diaphragm.

Leptospirosis is an infectious disease of variable severity characterized by sudden onset of headache, myalgia and prostration. Although most common in the tropics, an increasing number of cases is reported in Europe and Northern America. Severe forms referred to as Weil's disease commonly involve kidneys, liver, lungs, CNS and heart and require early recognition and immediate initiation of adequate therapy. We describe 3 patients with Weil's syndrome from an urbanized region in Southern Germany, who developed renal and respiratory failure. PCR facilitated early diagnosis, and therefore, specific treatment before serological tests were positive. Illustrating the case histories, initial presentations and clinical courses, we point out difficulties with early diagnosis and treatment. Furthermore, we offer a comprehensive overview on leptospirosis with emphasis on renal involvement, current diagnostic tools and evidence-based therapy.

The PSD95/Dlg/ZO-1 (PDZ) domain-containing protein zonula occludens-1 (ZO-1) selectively localizes to the cytoplasmic basis of the slit diaphragm, a specialized cell-cell contact in between glomerular podocytes necessary to prevent the loss of protein in the urine. However, the function of ZO-1 at the slit diaphragm has remained elusive. Deletion of Neph1, a slit diaphragm protein of the immunoglobulin superfamily with a cytoplasmic PDZ binding site, causes proteinuria in mice. We demonstrate now that Neph1 binds ZO-1. This interaction was mediated by the first PDZ domain of ZO-1 and involved the conserved PDZ domain binding motif present in the carboxyl terminus of the three known Neph family members. Furthermore, Neph1 co-immunoprecipitates with ZO-1 from lysates of mouse kidneys, demonstrating that this interaction occurs in vivo. Both deletion of the PDZ binding motif of Neph1 as well as threonine-to-glutamate mutation of the threonine within the binding motif abrogated binding of ZO-1, suggesting that phosphorylation may regulate this interaction. ZO-1 binding was associated with a strong increase in tyrosine phosphorylation of the cytoplasmic tail of Neph1 and dramatically accelerated the ability of Neph1 to induce signal transduction. Thus, our data suggest that ZO-1 may organize Neph proteins and recruit signal transduction components to the slit diaphragm of podocytes.

Mutations of NPHS1 or NPHS2, the genes encoding for the glomerular podocyte proteins nephrin and podocin, cause steroid-resistant proteinuria. In addition, mice lacking NEPH1 develop a nephrotic syndrome that resembles NPHS mutations, suggesting that all three proteins are essential for the integrity of glomerular podocytes. Podocin interacts with the C-terminal domain of nephrin and facilitates nephrin-dependent signaling. NEPH1, a member of the immunoglobulin superfamily, is structurally related to nephrin. We report now that NEPH1 belongs to a family of three closely related proteins that interact with the C-terminal domain of podocin. All three NEPH proteins share a conserved podocin-binding motif; mutation of a centrally located tyrosine residue dramatically lowers the affinity of NEPH1 for podocin. NEPH1 triggers AP-1 activation similarly to nephrin but requires the presence of Tec family kinases for efficient transactivation. We conclude that NEPH1 defines a new family of podocin-binding molecules that are potential candidates for hereditary nephrotic syndromes not linked to either NPHS1 or NPHS2.

There is increasing evidence that Dobrava (DOBV) but not Hantaan (HTNV) hantavirus is a hemorrhagic fever with renal syndrome (HFRS) causing agent in Central Europe. However, only single clinical cases of HFRS due to acute DOBV infection have been described so far. We report on three male patients from a non-endemic hantavirus focus in Northern Germany who suffered from mild to moderate HFRS strongly resembling nephropathia epidemica. Serotyping by detection of hantavirus species-specific neutralizing antibodies revealed acute infections by the HTNV-related hantavirus DOBV in all three cases. Since DOBV infections in the Balkans frequently present as severe HFRS, our cases suggest that Central-European DOBV infections have a different, less severe clinical outcome. These differences in DOBV virulence towards humans might be due to the existence of different genetic lineages of DOBV.

Juvenile nephronophthisis type 1 is caused by mutations of NPHP1, the gene encoding for nephrocystin. The function of nephrocystin is presently unknown, but the presence of a Src homology 3 domain and its recently described interaction with p130Cas suggest that nephrocystin is part of the focal adhesion signaling complex. We generated a nephrocystin-specific antiserum and analyzed the interaction of native nephrocystin with endogenous proteins. Immunoprecipitation of nephrocystin revealed that nephrocystin forms protein complexes with p130Cas, proline-rich tyrosine kinase 2 (Pyk2), and tensin, indicating that these proteins participate in a common signaling pathway. Expression of nephrocystin resulted in phosphorylation of Pyk2 on tyrosine 402 as well as activation of downstream mitogen-activated protein kinases, such as ERK1 and ERK2. Our findings suggest that nephrocystin helps to recruit Pyk2 to cell matrix adhesions, thereby initiating phosphorylation of Pyk2 and Pyk2-dependent signaling. A lack of functional nephrocystin may compromise Pyk2 signaling in a subset of renal epithelial cells.