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The measurement of nuclear neutrinoless double-beta decay would be a revolutionary result in particle physics. The observation of such a decay would prove that the neutrinos are their own antiparticles, help to study the absolute mass of neutrinos, explore the origin of their mass, and may explain the matter-antimatter asymmetry in our universe by the violation of lepton number. We propose to develop a time projection chamber (TPC) using high-pressure 82SeF6 gas and the top-metal silicon sensors for read-out in the China Jinping Underground Laboratory (CJPL), to search for neutrinoless double-beta decay of 82Se, called the NvDEx experiment. Besides located at CJPL with world's deepest rock shielding, NvDEx combines the advantages of the high Q value (2.996 MeV) of 82Se and TPC's ability to distinguish signal and background events using their different topological characteristics. These give NvDEx unique and great potential for low background and high sensitivity. NvDEx-100, the NvDEx experiment phase with 100 kg of SeF6 gas, is being built and planned to complete with installation at CJPL around year 2025. This report will introduce the neutrinoless double-beta decay physics, NvDEx concept and its advantages, the schematic design of NvDEx-100 and its sub-systems, as well as the background and sensitivity estimation for it.

Billions of COVID-19 vaccine doses have been administered to combat the ongoing global pandemic caused by severe acute respiratory syndrome coronavirus-2. While these vaccines are considered safe, with most adverse events being mild to moderate and transient, uncommon systemic side effects of the vaccines, including de novo or re-activation of various glomerular diseases have recently been observed. We report 6 patients who developed glomerular or acute tubulointerstitial disease shortly after receiving COVID-19 vaccinations. Five of these patients received mRNA vaccines (3 Moderna, 2 Pfizer-BioNTech) and 1 received adenovirus-26 vector vaccine (Johnson and Johnson/Janssen). Four of our patients developed de novo glomerulonephritis or acute tubulointerstitial nephritis (ATIN), while the other 2 had re-activation of prior glomerulonephritis. Two patients presented with acute kidney injury (AKI) characterized by severe ATIN. While both of them also had evidence of immune complex glomerular disease, ATIN was the dominant feature on the biopsies. Two other patients presented with high-grade proteinuria and AKI. Like the aforementioned patients, these patients had evidence of immune complex glomerular disease, but acute onset nephrotic syndrome was the leading clinical feature. Another patient presented with de novo myeloperoxidase-anti-neutrophil-cytoplasmic-antibody-associated pauci-immune crescentic glomerulonephritis. Yet another patient had re-activation of immunoglobulin-A glomerulonephritis that had been quiescent for several years prior to the vaccination. It is difficult to ascertain any causal relationship between COVID-19 vaccination and onset/recurrence of kidney diseases. However, vigilance about occurrence of such complications is imperative. Importantly, all our cases responded well to the immunosuppressive treatment.

Data for the article: The Levels and Sources of Nitrous Acid (HONO) in Winter of Beijing and SanmenxiaThe Levels and Sources of Nitrous Acid (HONO) in Winter of Beijing and Sanmenxia.

Background Obesity is associated with a higher incidence of atrial fibrillation (AF). Weight reduction improves outcomes in patients known to have AF. Objective The purpose of this study was to compare the incidence of heart failure (HF) or first-time AF hospitalization in obese patients undergoing bariatric surgery (BAS) vs other abdominal surgeries. Methods A retrospective cohort study was conducted using linked hospital discharge records from 1994–2014. Obese patients without known AF or atrial flutter (AFL) who had undergone abdominal hernia or laparoscopic cholecystectomy surgery were identified for each case that underwent BAS (2:1). Clinical outcomes were HF, first-time hospitalization for AF, AFL, gastrointestinal bleeding (GIB), and ischemic or hemorrhagic stroke. Outcomes were analyzed using conditional proportional hazard modeling accounting for the competing risk of death, adjusting for demographics and comorbidities. Results There were 1581 BAS cases and 3162 controls (48% age, Graphical abstract

A novel QTL (qSCN-PL10) for SCN resistance and related candidate genes were identified in the soybean variety Pingliang xiaoheidou, and plant basal immunity seems to contribute to the SCN resistance. Soybean cyst nematode (SCN, Heterodera glycines Ichinohe) is one of the most devastating soybean pests worldwide. The development of host plant resistance represents an effective strategy to control SCN. However, owing to the lack of diversity of resistance genes in soybean varieties, further investigation is necessary to identify new SCN resistance genes. By analyzing the resistance phenotypes of soybean variety Pingliang xiaoheidou (Pingliang, ZDD 11047), we found that it exhibited the different resistance phenotypes from PI 88788 and Peking varieties. Because Pingliang variety contains the Rhg1-a (low copy) haplotype and lacks the resistant Rhg4 haplotype, novel quantitative trait locus might account for their SCN resistance. After sequencing parental lines (Magellan and Pingliang) and 200 F2:3 progenies, a high-density genetic map was constructed using the specific length amplified fragment sequencing method and qSCN-PL10 was identified as a novel locus for SCN resistance. Candidate genes were predicted by RNA sequencing (RNA-seq) in the qSCN-PL10 locus region. The RNA-seq analysis performed also indicated that plant basal immunity plays an important role in the resistance of Pingliang to SCN. These results lay a foundation for the use of marker-assisted breeding to enhance the resistance to SCN.

Implantable Cardioverter Defibrillators (ICDs) are used in the management of sudden cardiac arrest. Compared with clinic visits, remote interrogation of these devices has shown clinical benefit and lower cost. We hypothesize that demographic and socioeconomic factors influence patient satisfaction with remote monitoring and therefore the choice of a pathway for follow-up. Questionnaires were mailed to 85 patients (mean age 63 ± 13.5 years, 73% male), with ICDs implanted for primary prevention of sudden cardiac arrest. Information regarding education, social support, employment, and income was collected. To compare clinic and remote monitoring, patients were given questionnaires to assess which parameters they consider important: convenience, accuracy, human contact, scheduling, and cost. Of the 34 responders, patients rated clinic visit to be as accurate with better opportunity to ask questions and better human contact, but there was no difference in perception of convenience, scheduling, or cost between the 2 groups. Significant number of patients dropped from the labor market after ICD implantation; however labor status, education, or income did not influence the preference of clinic appointment. Survey respondents preferred clinic to remote interrogation because they believe clinic appointments allow better interaction. Educating patients about the benefits of remote interrogation and improved communication will enhance utilization of this sophisticated technology for superior patient care.

Supplemental Digital Content is Available in the Text. This study evaluates the effectiveness of Healaflow as a retinal patch in primary rhegmatogenous retinal detachment repaired by 27-G pars plana vitrectomy combined with air tamponade. This protocol results in a high reattachment rate in the treatment of rhegmatogenous retinal detachment., Purpose: To report the surgical outcomes of primary rhegmatogenous retinal detachment (RRD) repaired by 27-gauge pars plana vitrectomy combined with Healaflow patch and air tamponade. Methods: In an initial vitro experiment, we observed and compared the dissolution and displacement of the dispersion spots of 0.05-mL Healaflow and sodium hyaluronate. We then performed a prospective, interventional cohort study on 38 eyes in 37 consecutive patients with primary rhegmatogenous retinal detachment. All eyes underwent pars plana vitrectomy combined with Healaflow patch and air tamponade; the postoperative period did not involve prone positioning. The primary and final anatomical attachment rate, best-corrected visual acuity, and intraoperative and postoperative complications were evaluated. Results: In the in vitro experiment, the viscoelastic Healaflow remained adherent with no change in the size of the area; however, the control dissolved completely in the balance solution. The patient study included 16 women (43.2%) and 21 men (56.8%) (mean age, 59.5 ± 9.5 years; mean follow-up period, 8.9 ± 3.8 months). A single break was present in 21 (55.3%) and 2 to 5 breaks in 17 cases (44.8%). The macula was involved in 25 (65.8%) and attached in 13 cases (34.2%) intraoperatively. Initial reattachment was achieved in 37 (97.4%) and final reattachment in 38 cases (100%). In one case (2.6%), the macula redetached because of failure of the chorioretinal scar to develop around the treated break. Mean preoperative and postoperative best-corrected visual acuities were 1.02 ± 0.82 logarithm of the minimum angle of resolution (median Snellen acuity: 20/125, range: 20/20,000–20/20) and 0.23 ± 0.17 logarithm of the minimum angle of resolution (median Snellen acuity: 20/32, range: 20/100–20/20), respectively (P < 0.001). Intraocular pressure was elevated transiently in 28 eyes (73.7%). There were no other intraoperative complications or postoperative scleral incision leakage. Conclusion: A 27-gauge pars plana vitrectomy combined with Healaflow patch, and air tamponade results in a high reattachment rate in the treatment of rhegmatogenous retinal detachment. Thus, patients can benefit from early visual recovery and less complications.

Research on low-temperature electron transport materials in perovskite solar cells has been pursued to expand their application on flexible and tandem device architectures. The traditional TiO2 electron transport material has low electron mobility, resulting in sever charge accumulation at the interface. Here, PCBM is applied as buffer layer to increase the electron extraction rate and suppress charge accumulation, as well as modify the interface of the electron transport layer. The authors find that perovskite layer exhibits better morphology with PCBM buffer layer, and the solar cell presents improved performance, which makes the low-temperature prepared TiO2 film a promising electron transport material for perovskite solar cells.

Although 2-hydroxybenzaldehyde acylhydrazones, such as salicylaldehyde acylhydrazones, are intriguing bioactive molecules, few of their N-alkylated derivatives are known, and only methyl analogues have been reported previously. We achieved selective N-alkylation of 2-hydroxybenzaldehyde acylhydrazones, as their Fe(III) complexes, by using combinations of alkylating agents (for example, an alkyl bromide and a dialkyl sulfate). Fifteen substrates were examined, and 45 new 2-hydroxybenzaldehyde acyl(alkyl)hydrazones were synthesized in moderate to good yields. In all cases, the target products were obtained exclusively, and no O-alkylation byproducts were produced. The method provides an efficient way of preparing 2-hydroxybenzaldehyde acyl(alkyl)hydrazones.

BackgroundObesity is associated with a higher incidence of atrial fibrillation (AF). Weight reduction improves outcomes in patients known to have AF.ObjectiveThe purpose of this study was to compare the incidence of heart failure (HF) or first-time AF hospitalization in obese patients undergoing bariatric surgery (BAS) vs other abdominal surgeries.MethodsA retrospective cohort study was conducted using linked hospital discharge records from 1994-2014. Obese patients without known AF or atrial flutter (AFL) who had undergone abdominal hernia or laparoscopic cholecystectomy surgery were identified for each case that underwent BAS (2:1). Clinical outcomes were HF, first-time hospitalization for AF, AFL, gastrointestinal bleeding (GIB), and ischemic or hemorrhagic stroke. Outcomes were analyzed using conditional proportional hazard modeling accounting for the competing risk of death, adjusting for demographics and comorbidities.ResultsThere were 1581 BAS cases and 3162 controls (48%age&nbsp

Chronic kidney diseases have become a major issue worldwide. The spectrum of biopsy proven renal diseases differs between locations and changes over time. It is therefore essential to describe the local epidemiological trends and the prevalence of renal biopsy in various regions to shine new light on the pathogenesis of various renal diseases and provide a basis for further hypothesis-driven research. We retrospectively analyzed 34,630 hospitalized patients undergoing native renal biopsy between January 1, 2009 and December 31, 2018. Indications for renal biopsy and histological diagnosis were analyzed to describe the prevalence of renal biopsy, and changing prevalence between period 1 (2009–2013) and period 2 (2014–2018) were further analyzed. Nephrotic syndrome (NS) was the most common indication for biopsy. Membranous nephropathy (MN, 24.96%) and IgA nephropathy (IgAN, 24.09%) were the most common primary glomerulonephritis (PGN). MN was most common in adults, with IgAN more prevalent in children. Lupus nephritis (LN) was the most common secondary glomerulonephritis (SGN) in adults, while Henöch–Schönlein purpura nephritis (HSPN) in children. The prevalence of MN increased significantly and nearly doubled from period 1 (15.98%) to period 2 (30.81%) (P = 0.0004). The same trend appeared with membranoproliferative glomerulonephritis (MPGN), diabetic nephropathy (DN) and obesity-related glomerulopathy (ORG), while the frequencies of minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), LN and hepatitis B associated glomerulonephritis (HBV-GN) significantly decreased between the two intervals. NS was the most common indication for biopsy across all age groups and genders. MN has overtaken IgAN to become the most common PGN in adults, while IgAN was the most common PGN in children. LN was the most common SGN in adults, and HSPN the most common in children.

Background and Purpose— Selection of patients with acute ischemic stroke for endovascular treatment generally relies on dynamic susceptibility contrast magnetic resonance imaging or computed tomography perfusion. Dynamic susceptibility contrast magnetic resonance imaging requires injection of contrast, whereas computed tomography perfusion requires high doses of ionizing radiation. The purpose of this work was to develop and evaluate a deep learning (DL)–based algorithm for assisting the selection of suitable patients with acute ischemic stroke for endovascular treatment based on 3-dimensional pseudo-continuous arterial spin labeling (pCASL). Methods— A total of 167 image sets of 3-dimensional pCASL data from 137 patients with acute ischemic stroke scanned on 1.5T and 3.0T Siemens MR systems were included for neural network training. The concurrently acquired dynamic susceptibility contrast magnetic resonance imaging was used to produce labels of hypoperfused brain regions, analyzed using commercial software. The DL and 6 machine learning (ML) algorithms were trained with 10-fold cross-validation. The eligibility for endovascular treatment was determined retrospectively based on the criteria of perfusion/diffusion mismatch in the DEFUSE 3 trial (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke). The trained DL algorithm was further applied on twelve 3-dimensional pCASL data sets acquired on 1.5T and 3T General Electric MR systems, without fine-tuning of parameters. Results— The DL algorithm can predict the dynamic susceptibility contrast–defined hypoperfusion region in pCASL with a voxel-wise area under the curve of 0.958, while the 6 ML algorithms ranged from 0.897 to 0.933. For retrospective determination for subject-level endovascular treatment eligibility, the DL algorithm achieved an accuracy of 92%, with a sensitivity of 0.89 and specificity of 0.95. When applied to the GE pCASL data, the DL algorithm achieved a voxel-wise area under the curve of 0.94 and a subject-level accuracy of 92% for endovascular treatment eligibility. Conclusions— pCASL perfusion magnetic resonance imaging in conjunction with the DL algorithm provides a promising approach for assisting decision-making for endovascular treatment in patients with acute ischemic stroke.

Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) has been recognized as a distinct entity in recent years. To the best of our knowledge, all patients with PGNMID reported thus far were older than 20 years of age. We now report five cases of PGNMID in patients under 20 years of age. The clinical database was searched for patients with native kidney biopsies from 9/2011 to 8/2017, and cases with a diagnosis of PGNMID were retrieved. Light microscopy specimens and immunofluorescence and electron microscopy images were revisited. Clinical data and kidney biopsy findings for patients under the age of 20 were recorded. Five (0.78%) of a total of 637 patients younger than 20 with native renal biopsies had a diagnosis of PGNMID, including three males and two females with an average age of 14 years old (range 10–19). All five patients presented with microscopic hematuria and proteinuria. Three patients were nephrotic and their C3 levels were low. All five cases showed a membranoproliferative pattern with abundant mesangial and subendothelial monoclonal IgG3 deposits (3 κ and 2 λ light chain, respectively). The patients were followed up to 56 months. Two patients had re-biopsies 28 and 18 months after initial diagnosis and both showed similar morphologic changes. Various treatments were attempted including prednisone, mycophenolate mofetil, tacrolimus, rituximab, and eculizmab, with mixed responses. PGNMID does occur in children and young adults. Membranoproliferative glomerulonephritis pattern with monoclonal IgG3 deposits is a common feature. Despite various immunosuppressive treatments, the disease appears slowly progressive.

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related deaths worldwide. Most CRC deaths are the result of progression of metastases. The assessment of metastases is done using the RECIST criterion, which is time consuming and subjective, as clinicians need to manually measure anatomical tumor sizes. AI has many successes in image object detection, but often suffers because the models used are not interpretable, leading to issues in trust and implementation in the clinical setting. We propose a framework for an AI-augmented system in which an interactive AI system assists clinicians in the metastasis assessment. We include model interpretability to give explanations of the reasoning of the underlying models., Comment: 4 pages, 2 figures, 2019 KDD Workshop on Applied Data Science for Healthcare

Background Cavernous sinus hemangioma (CSH) is a rare type of benign vascular tumor. Microsurgery for CSH treatment usually results in profuse bleeding and cranial nerve injury. Radiosurgery is an alternative treatment for CSH. The objective of this study was to elucidate the efficacy and safety of gamma knife surgery (GKS) for the treatment of CSH. Methods A total of 32 patients with CSH underwent 34 times of GKS as a primary and exclusive treatment from 2009 to 2015 at West China Hospital. The diagnosis was mainly based on findings of magnetic resonance imaging. The treatment was performed with the Leksell Gamma Knife model C. The follow-up period was from 12–67 months. Changes in imaging results and signs or symptoms were analyzed. Studies of patients who had undergone radiosurgery and microsurgery were compared. Results Clinical improvement was observed after GKS in 26 of 27 patients who presented with signs or symptoms of CSH. Tumor shrinkage was detected in all cases. A reduction in tumor volume of 0–25%, 26%–50%, 51%–75%, and 76%–100% was observed in 3, 2, 8, and 19 cases, respectively. Remarkable tumor shrinkage occurred within 6–12 months after GKS. According to a retrospective analysis of 151 patients diagnosed with CSH, 77 patients underwent GKS without any complications, 17 of 74 patients were treated with microsurgery and exhibited persistent complications, and 1 patient died. Conclusions GKS is a safe and effective treatment for most cases of CSH. The concept of GKS as an adjuvant treatment for CSH requires reconsideration.

Sanya Bay, a tropical open coral-reef bay in the northern South China Sea, is undergoing great changes in environmental conditions due to the rapid increase in human activities. This study assessed spatial and temporal variation in copepod species composition, abundance, and distribution in relation to environmental variables in Sanya Bay. A total of 63 copepod species were identified. The annual average abundance of copepods was 4707.1 ± 2763.8 ind m – 3 , with the highest densities observed in winter and the lowest densities observed in summer. The number of copepod species increased from nearshore to offshore waters of the bay, whereas their abundance decreased seaward, with highest values being recorded in nearshore waters. Approximately 90% of copepod recorded in this study belonged to 11 dominant species.Parvocalanus crassirostriswas the most common and abundant species in Sanya Bay. Abundances of total copepods and P. crassirostris were negatively correlated with temperature and positively correlated with chlorophyll a concentration, but no significant correlation between them was found in spring, summer or fall. High abundances of copepods were mainly concentrated near the mouth of the Sanya River. The seasonal and regional patterns of copepod variation in Sanya Bay were characterized by low diversity and high abundance in winter, and by highest abundance in the nearshore waters during the four sampling periods. Copepod abundance distribution in winter was enhanced by low temperature and high chlorophyll a concentration, and was driven by the dominant species P. crassirostris.

Thrombotic microangiopathy (TMA) is a disorder characterized by microvascular occlusion that can lead to thrombocytopenia, hemolytic anemia, and glomerular damage. Complement activation is the central event in most cases of TMA. Primary forms of TMA are caused by mutations in genes encoding components of the complement or regulators of the complement cascade. Recently, we and others have described a genetic form of TMA caused by mutations in the gene diacylglycerol kinase-ε ( DGKE) that encodes the lipid kinase DGKε(Lemaire M, Fremeaux-Bacchi V, Schaefer F, Choi MR, Tang WH, Le Quintrec M, Fakhouri F, Taque S, Nobili F, Martinez F, Ji WZ, Overton JD, Mane SM, Nurnberg G, Altmuller J, Thiele H, Morin D, Deschenes G, Baudouin V, Llanas B, Collard L, Majid MA, Simkova E, Nurnberg P, Rioux-Leclerc N, Moeckel GW, Gubler MC, Hwa J, Loirat C, Lifton RP. Nat Genet 45: 531–536, 2013; Ozaltin F, Li BH, Rauhauser A, An SW, Soylemezoglu O, Gonul II, Taskiran EZ, Ibsirlioglu T, Korkmaz E, Bilginer Y, Duzova A, Ozen S, Topaloglu R, Besbas N, Ashraf S, Du Y, Liang CY, Chen P, Lu DM, Vadnagara K, Arbuckle S, Lewis D, Wakeland B, Quigg RJ, Ransom RF, Wakeland EK, Topham MK, Bazan NG, Mohan C, Hildebrandt F, Bakkaloglu A, Huang CL, Attanasio M. J Am Soc Nephrol 24: 377–384, 2013). DGKεis unrelated to the complement pathway, which suggests that unidentified pathogenic mechanisms independent of complement dysregulation may result in TMA. Studying Dgke knockout mice may help to understand the pathogenesis of this disease, but no glomerular phenotype has been described in these animals so far. Here we report that Dgke null mice present subclinical microscopic anomalies of the glomerular endothelium and basal membrane that worsen with age and develop glomerular capillary occlusion when exposed to nephrotoxic serum. We found that induction of cyclooxygenase-2 and of the proangiogenic prostaglandin E2are impaired in Dgke null kidneys and are associated with reduced expression of the antithrombotic cell adhesion molecule platelet endothelial cell adhesion molecule-1/CD31 in the glomerular endothelium. Notably, prostaglandin E2supplementation was able to rescue motility defects of Dgke knockdown cells in vitro and to restore angiogenesis in a test in vivo. Our results unveil an unexpected role of Dgke in the induction of cyclooxygenase-2 and in the regulation of glomerular prostanoids synthesis under stress.

The purpose of this study was to develop and evaluate a scoring system for assessing reperfusion status based on arterial spin labeled (ASL) perfusion MRI in acute ischemic stroke (AIS) patients receiving thrombolysis and/or endovascular treatment. Pseudo-continuous ASL with background suppressed 3D GRASE was acquired along with DWI in 90 patients within 24 h post-treatment. An automatic reperfusion scoring system (auto-RPS) was devised based on the Alberta Stroke Program Early CT Score (ASPECTS) template, and compared with manual RPS and DWI-ASPECTS. TICI (thrombolysis in cerebral infarction) scores were graded in 48 patients who received endovascular treatment. Favorable outcomes were defined by a modified Rankin Scale score of 0-2 at three months. Auto-RPS was positively correlated with DWI-ASPECTS (ρ = 0.6, P

Multi-task learning is a type of transfer learning that trains multiple tasks simultaneously and leverages the shared information between related tasks to improve the generalization performance. However, missing features in the input matrix is a much more difficult problem which needs to be carefully addressed. Removing records with missing values can significantly reduce the sample size, which is impractical for datasets with large percentage of missing values. Popular imputation methods often distort the covariance structure of the data, which causes inaccurate inference. In this paper we propose using plug-in covariance matrix estimators to tackle the challenge of missing features. Specifically, we analyze the plug-in estimators under the framework of robust multi-task learning with LASSO and graph regularization, which captures the relatedness between tasks via graph regularization. We use the Alzheimer's disease progression dataset as an example to show how the proposed framework is effective for prediction and model estimation when missing data is present., Comment: 4 pages, 3 figures, 1 table, 2018 KDD Workshop on Machine Learning for Medicine and Healthcare

PurposeDifferentiating WHO grade I-III of meningioma by non-invasive imaging is challenging. This study investigated the potential of MR arterial spin labeling (ASL) to establish tumor grade in meningioma patients.Material and methodsPseudo-continuous ASL with 3D background suppressed gradient and spin echo (GRASE) was acquired on 54 patients with newly diagnosed or recurrent intracranial meningioma. Perfusion patterns characterized in CBF color maps were independently evaluated by three neuroradiologists blinded to patient history, and correlated with tumor grade from histo-pathological review.ResultsThree perfusion patterns could be discerned by visual evaluation of CBF maps. Pattern 1 consisted of homogeneous hyper-perfusion of the entire tumor; pattern 2 demonstrated heterogeneous hyper-perfusion; pattern 3 showed no substantial hyper-perfusion. Evaluation of the perfusion patterns was highly concordant among the three readers (Kendall W=0.9458, P

BACKGROUND AND PURPOSE: Glioblastoma is a common primary brain tumor with a poor but variable prognosis. Our aim was to investigate the feasibility of MR perfusion imaging by using arterial spin-labeling for determining the prognosis of patients with glioblastoma. MATERIALS AND METHODS: Pseudocontinuous arterial spin-labeling with 3D background-suppressed gradient and spin-echo was acquired before surgery on 53 patients subsequently diagnosed with glioblastoma. The calculated CBF color maps were visually evaluated by 3 independent readers blinded to patient history. Pathologic and survival data were correlated with CBF map findings. Arterial spin-labeling values in tumor tissue were also quantified by using manual fixed-size ROIs. RESULTS: Two perfusion patterns were characterized by visual evaluation of CBF maps on the basis of either the presence (pattern 1) or absence (pattern 2) of substantial hyperperfused tumor tissue. Evaluation of the perfusion patterns was highly concordant among the 3 readers ( 0.898, P .001). Pattern 1 (versus pattern 2) was associated with significantly shorter progression-free survival by Kaplan-Meier analysis (median progression-free survival of 182 days versus 485 days, P .01) and trended with shorter overall survival (P .079). There was a significant association between pattern 1 and epidermal growth factor receptor variant III expression (P .01). CONCLUSIONS: Qualitative evaluation of arterial spin-labeling CBF maps can be used to stratify survival and predict epidermal growth factor receptor variant III expression in patients with glioblastoma. ABBREVIATIONS: ASL arterial spin-labeling; EGFR epidermal growth factor receptor; EGFRvIII epidermal growth factor receptor variant III; GBM glioblastoma; HR hazard ratio; OS overall survival; PFS progression-free survival

The purpose of this study was to develop and evaluate a scoring system for assessing reperfusion status based on arterial spin labeled (ASL) perfusion MRI in acute ischemic stroke (AIS) patients receiving thrombolysis and/or endovascular treatment. Pseudo-continuous ASL with background suppressed 3D GRASE was acquired along with DWI in 90 patients within 24 h post-treatment. An automatic reperfusion scoring system (auto-RPS) was devised based on the Alberta Stroke Program Early CT Score (ASPECTS) template, and compared with manual RPS and DWI-ASPECTS. TICI (thrombolysis in cerebral infarction) scores were graded in 48 patients who received endovascular treatment. Favorable outcomes were defined by a modified Rankin Scale score of 0–2 at three months. Auto-RPS was positively correlated with DWI-ASPECTS (ρ = 0.6, P

Objective Current treatment options for lupus are far from optimal. Previously, we reported that PI3K/AKT/mTOR, MEK1/Erk1,2, p38, STAT3, STAT5, NF-κB, multiple Bcl-2 family members, and various cell cycle molecules were over-expressed in splenic B-cells in an age-dependent and gene-dose-dependent manner in mouse strains with spontaneous lupus. As the synthetic triterpenoid methyl-2-cyano-3,12-dioxooleana-1,9-dien-28-oate (CDDO-Me) has been shown to inhibit AKT, MEK1/2, and NF-κB, and to induce caspase-mediated apoptosis, we tested the therapeutic potential of this agent in murine lupus nephritis.

NVP-BEZ235 is a newly developed dual PI3K/mTOR inhibitor, being tested in multiple clinical trials, including breast cancer. NVP-BEZ235 selectively induces cell growth inhibition in a subset, but not all, breast cancer cell lines. However, it remains a challenge to distinguish between sensitive and resistant tumors, particularly in the pretreatment setting. Here, we used ten breast cancer cell lines to compare NVP-BEZ235 sensitivity and in the context of androgen receptor (AR) activation during NVP-BEZ235 treatment. We also used female SCID mice bearing breast tumor xenografts to investigate the beneficial effect of dihydrotestosterone/NVP-BEZ235 combination treatment compared with each alone. We found that AR-positive breast cancer cell lines are much more sensitive to NVP-BEZ235 compared with AR-negative cells, regardless of PTEN or PI3KCA status. Reintroducing AR expression in NVP-BEZ235 nonresponsive AR-negative cells restored the response. DHT/NVP-BEZ235 combination not only resulted in a more significant growth inhibition than either drug alone, but also achieved tumor regression and complete responses for AR+/ER+ tumors. This beneficial effect was mediated by dihydrotestosterone (DHT)-induced PTEN and KLLN expression. Furthermore, DHT could also reverse NVP-BEZ235–induced side effects such as skin rash and weight loss. Our data suggest that AR expression may be an independent predictive biomarker for response to NVP-BEZ235. AR induction could add benefit during NVP-BEZ235 treatment in patients, especially with AR+/ER+ breast carcinomas. Mol Cancer Ther; 13(2); 517–27. ©2013 AACR . This article is featured in Highlights of This Issue, [p. 273][1] [1]: /lookup/volpage/13/273?iss=2

We previously reported that expression of the transcription factor interferon regulatory factor 1 (IRF1) is an early, critical maladaptive signal expressed by renal tubules during murine ischemic acute kidney injury (AKI). We now show that IRF1 mediates signals from reactive oxygen species (ROS) generated during ischemic AKI and that these signals ultimately result in production of α-subtypes of type I interferons (IFNαs). We found that genetic knockout of the common type I IFN receptor (IFNARI−/−) improved kidney function and histology during AKI. There are major differences in the spatial-temporal production of the two major IFN subtypes, IFNβ and IFNαs: IFNβ expression peaks at 4 h, earlier than IFNαs, and continues at the same level at 24 h; expression of IFNαs also increases at 4 h but continues to increase through 24 h. The magnitude of the increase in IFNαs relative to baseline is much greater than that of IFNβ. We show by immunohistology and study of isolated cells that IFNβ is produced by renal leukocytes and IFNαs are produced by renal tubules. IRF1, IFNαs, and IFNARI were found on the same renal tubules during ischemic AKI. Furthermore, we found that ROS induced IFNα expression by renal tubules in vitro. This expression was inhibited by small interfering RNA knockdown of IRF1. Overexpression of IRF1 resulted in the production of IFNαs. Furthermore, we found that IFNα stimulated production of maladaptive proinflammatory CXCL2 by renal tubular cells. Altogether our data support the following autocrine pathway in renal tubular cells: ROS > IRF1 > IFNα > IFNARI > CXCL2.

BACKGROUND AND PURPOSE: A substantial portion of clinically diagnosed TIA cases is imaging-negative. The purpose of the current study is to determine if arterial spin-labeling is helpful in detecting perfusion abnormalities in patients presenting clinically with TIA. MATERIALS AND METHODS: Pseudocontinuous arterial spin-labeling with 3D background-suppressed gradient and spin-echo was acquired on 49 patients suspected of TIA within 24 hours of symptom onset. All patients were free of stroke history and had no lesion-specific findings on general MR, DWI, and MRA sequences. The calculated arterial spin-labeling CBF maps were scored from 1–3 on the basis of presence and severity of perfusion disturbance by 3 independent observers blinded to patient history. An age-matched cohort of 36 patients diagnosed with no cerebrovascular events was evaluated as a control. Interobserver agreement was assessed by use of the Kendall concordance test. RESULTS: Scoring of perfusion abnormalities on arterial spin-labeling scans of the TIA cohort was highly concordant among the 3 observers (W 0.812). The sensitivity and specificity of arterial spin-labeling in the diagnosis of perfusion abnormalities in TIA was 55.8% and 90.7%, respectively. In 93.3% (70/75) of the arterial spin-labeling CBF map readings with positive scores (2), the brain regions where perfusion abnormalities were identified by 3 observers matched with the neurologic deficits at TIA onset. CONCLUSIONS: In this preliminary study, arterial spin-labeling showed promise in the detection of perfusion abnormalities that correlated with clinically diagnosed TIA in patients with otherwise normal neuroimaging results. ABBREVIATIONS: ASL arterial spin-labeling; ATT arterial transit time; PCT contrast-enhanced perfusion CT; PLD postlabel delay

The use of digital whole slide images (WSI) in the field of pathology has become feasible for routine diagnostic purposes and has become more prevalent in recent years. This type of technology offers many advantages but must show the same degree of diagnostic reliability as conventional glass slides. Several studies have examined this issue in various settings and indicate that WSI are a reliable method for diagnostic pathology. Since transplant pathology is a highly specialized field that requires not only accurate but rapid diagnostic evaluation of biopsy materials, this field may greatly benefit from the use of WSI. In this study, we assessed the reliability of using WSI compared to conventional glass slides in renal allograft biopsies. We examined morphologic features and diagnostic categories defined by the Banff 07 Classification of Renal Allograft Pathology as well as additional morphologic features not included in this classification scheme. We found that intraobserver scores, when comparing the use of glass slides versus WSI, showed substantial agreement for both morphologic features (κ = 0.68) and acute rejection diagnostic categories (κ = 0.74). Furthermore, interobserver reliability was comparable for morphologic features (κ = 0.44 [glass] vs 0.42 [WSI]) and acute rejection diagnostic categories (κ = 0.49 [glass] vs 0.51 [WSI]). These data indicate that WSI are as reliable as glass slides for the evaluation of renal allograft biopsies.

There is a critical need to identify biomarkers for Systemic Lupus Erythematosus (SLE) which has a high prevalence of renal failure. When urine from patients with lupus nephritis was recently screened for the levels of ∼280 molecules using an exploratory array-based proteomic platform, elevated angiostatin levels were noted. Angiostatin is a bioactive fragment of plasminogen, and has been known to have modulatory function in angiogenesis and inflammation. The significant elevation in urinary angiostatin was next validated in an independent cohort of SLE patients (n = 100) using ELISA. Among patients with SLE, urine angiostatin was significantly increased in active SLE compared with inactive SLE, correlating well with the SLEDAI disease activity index and SLICC renal activity score (r = 0.66, p < 0.0001). ROC curve analysis further confirmed that urinary angiostatin had the capacity to discriminate patients with active SLE from those with inactive disease. Patients with Class IV lupus nephritis exhibited the highest levels of urinary angiostatin. Immunohistochemistry staining localized angiostatin expression to the renal tubular cells in these patients. Finally, when paired urine-kidney samples procured concurrently from patients with LN were next examined, urine angiostatin levels correlated strongly with the renal pathology chronicity index, but not with the activity index. Given that Class IV lupus nephritis and renal pathology chronicity changes forebode poor renal and patient survival, urinary angiostatin emerges as a novel noninvasive marker of renal disease in SLE. Longitudinal studies are in progress to further assess the disease-predictive potential of urinary angiostatin.

Renal involvement is the major cause of morbidity and mortality in lupus. Besides autoantibodies, intrinsic renal factors may contribute to the susceptibility to lupus nephritis. To determine how different mouse strains that develop spontaneous lupus fare in their susceptibility to immune mediated nephritis, mice from six lupus-prone strains and two non-lupus control strains (B6 and BALB/c) were challenged with rabbit anti-GBM sera. Among the strains tested, NZM2410 (or NZM) mice developed severe glomerulonephritis (GN), whereas BXSB and B6.lpr, NZB mice were relatively resistant to anti-GBM disease, as were the BALB/c controls. BWF1 and B6.Yaa mice exhibited intermediate degrees of GN that was comparable to the B6 controls. The severity of the renal disease in these strains did not appear to be related to the degree of the systemic immune response to the administered rabbit Ig. In addition, cytokine profiling demonstrated differential urinary excretion of several molecules in the NZM mice, compared with the controls. Together with our previous reports, our studies demonstrate that lupus-prone strains vary in their susceptibility to immune mediated nephritis, despite similar levels of circulating autoantibodies and comparable degrees of immune complex deposition in the kidneys.

The autoimmune disease systemic lupus erythematosus is characterized by loss of tolerance to nuclear Ags and a heightened inflammatory environment, which together result in end organ damage. Lyn-deficient mice, a model of systemic lupus erythematosus, lack an inhibitor of B-cell and myeloid cell activation. This results in B-cell hyper-responsiveness, plasma cell accumulation, autoantibodies, and glomerulonephritis (GN). IL-21 is associated with autoimmunity in mice and humans and promotes B-cell differentiation and class switching. Here, we explore the role of IL-21 in the autoimmune phenotypes of lyn–/– mice. We find that IL-21 mRNA is reduced in the spleens of lyn–/–IL-6–/– and lyn–/–Btklo mice, neither of which produce pathogenic autoantibodies or develop significant GN. While IL-21 is dispensable for plasma cell accumulation and IgM autoantibodies in lyn–/– mice, it is required for anti-DNA IgG antibodies and some aspects of T-cell activation. Surprisingly, GN still develops in lyn–/–IL-21–/– mice. This likely results from the presence of IgG autoantibodies against a limited set of non-DNA Ags. These studies identify a specific role for IL-21 in the class switching of anti-DNA B cells and demonstrate that neither IL-21 nor anti-DNA IgG is required for kidney damage in lyn–/– mice.

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease characterized by the production of antinuclear autoantibodies. Antinuclear autoantibody development is recognized as one of the initial stages of disease that often results in systemic inflammation, kidney disease, and death. The etiology is complex, but it is clear that innate pathways may play an important role in disease progression. Recent data have highlighted an important role for the TLR family, particularly TLR7, in both human disease and murine models. In this study, we have presented a low copy conditional TLR7 transgenic (Tg7) mouse strain that does not develop spontaneous autoimmunity. When we combine Tg7 with the Sle1 lupus susceptibility locus, the mice develop severe disease. Using the CD19Cre recombinase system, we normalized expression of TLR7 solely within the B cells. Using this method we demonstrated that overexpression of TLR7 within the B cell compartment reduces the marginal zone B cell compartment and increases B and T cell activation but not T follicular helper cell development. Moreover, this enhanced B cell TLR7 expression permits the specific development of Abs to RNA/protein complexes and exacerbates SLE disease.

Introduction Lupus nephritis (LN) is an ominous complication of systemic lupus erythematosus, and the risk factors for the disease progression are not well characterized. Methods In a retrospective study, the authors evaluated the mode of presentation and outcomes of 163 consecutive patients with biopsy-proven LN, who presented to the center between January 1999 and September 2008. Using stepwise logistic regression analysis, the authors assessed risk factors independently associated with response to treatment and to progression to end-stage renal disease (ESRD) in proliferative LN (PLN). Results Ninety percent of the patients belonged to minority population. Among 122 patients with class III and IV LN (PLN), 76 patients received intravenous cyclophosphamide and 38 patients received mycophenolate for induction, whereas 34 patients received intravenous cyclophosphamide and 63 patients received mycophenolate for maintenance. Thirty-six (30%) patients with PLN progressed to ESRD, and 3 patients died over a mean follow-up of 37.5months. In multivariate analysis, chronicity index (CI) ( P =0.0007) and hypertension ( P =0.042) positively correlated with progression to ESRD and death, and CI was associated with increased probability of nonresponse to treatment ( P =0.001). In addition, mycophenolate as maintenance agent was associated with increased likelihood of sustained complete remission and partial remission ( P =0.045). Conclusions In patients with LN, hypertension and a high CI are independent risk factors for progression to ESRD or death. Furthermore, a high CI is associated with poor response, and mycophenolate as a maintenance agent may improve the response to treatment.

The unchecked overproduction of reactive oxygen and nitrogen species by inflammatory cells can cause tissue damage, intensify inflammation, promote apoptosis, and accelerate the progression of immune-mediated glomerulonephritis (GN). Here we tested whether the anti-inflammatory and antioxidant properties of the green tea polyphenol (−)-epigallocatechin-3-gallate (EGCG) favorably affect the development of immune-mediated GN. Pretreatment of 129/svJ mice with EGCG from 2 days before to 2 weeks after the induction of GN led to reduced proteinuria and serum creatinine, and marked improvement in renal histology when compared with vehicle-pretreated diseased mice. This pretreatment reduced oxidative stress, and normalized osteopontin, p65/nuclear factor-κB, inducible nitric oxide synthase, nitric oxide metabolites, p-Akt, phosphorylated extracellular signal-regulated kinases 1 and 2, p47phox, and myeloperoxidase, all of which were elevated in vehicle-pretreated diseased mice. Levels of glutathione peroxidase and peroxisome proliferator-activated receptor-γ (PPARγ), both reduced in the vehicle-pretreated diseased mice, were normalized. This renoprotective effect was reversed by concomitant administration of the PPARγ antagonist GW9662 throughout the EGCG pretreatment period. Importantly, mortality and renal dysfunction were significantly attenuated even when the polyphenol treatment was initiated 1 week after the onset of GN. Thus, EGCG reversed the progression of immune-mediated GN in mice by targeting redox and inflammatory pathways.

Suppressive subtractive hybridization (SSH) was employed to identify differentially expressed genes in ayu (Plecoglossus altivelis) associated with Listonella anguillarum infection. 800 random clones were selected from forward and reverse subtractive libraries and 787 were successfully sequenced. After assembling, 105 contigs and 414 singletons were finally obtained, some of which were immune-related genes. A real-time quantitative PCR (RT-qPCR) analysis of the expression patterns of 28 transcripts showed that the false-positive rate was approximately 7.1%. Furthermore, Wap65-2 was overexpressed in Escherichia coli, purified and used for antiserum preparation. Western blot analysis revealed that serum Wap65-2 of ayu significantly increased after bacterial infection, suggesting that it was a positive acute-phase protein (APP).

Ischemic acute kidney injury (AKI) triggers expression of adaptive (protective) and maladaptive genes. Agents that increase expression of protective genes should provide a therapeutic benefit. We now report that bardoxolone methyl (BARD) ameliorates ischemic murine AKI as assessed by both renal function and pathology. BARD may exert its beneficial effect by increasing expression of genes previously shown to protect against ischemic AKI, NF-E2-related factor 2 (Nrf2), peroxisome proliferator-activated receptor-γ (PPARγ), and heme oxygenase 1 (HO-1). Although we found that BARD alone or ischemia-reperfusion alone increased expression of these genes, the greatest increase occurred after the combination of both ischemia-reperfusion and BARD. BARD had a different mode of action than other agents that regulate PPARγ and Nrf2. Thus we report that BARD regulates PPARγ, not by acting as a ligand but by increasing the amount of PPARγ mRNA and protein. This should increase ligand-independent effects of PPARγ. Similarly, BARD increased Nrf2 mRNA; this increased Nrf2 protein by mechanisms in addition to the prolongation of Nrf2 protein half-life previously reported. Finally, we localized expression of these protective genes after ischemia and BARD treatment. Using double-immunofluorescence staining for CD31 and Nrf2 or PPARγ, we found increased Nrf2 and PPARγ on glomerular endothelia in the cortex; Nrf2 was also present on cortical peritubular capillaries. In contrast, HO-1 was localized to different cells, i.e., tubules and interstitial leukocytes. Although Nrf2-dependent increases in HO-1 have been described, our data suggest that BARD's effects on tubular and leukocyte HO-1 during ischemic AKI may be Nrf2 independent. We also found that BARD ameliorated cisplatin nephrotoxicity.

Knowledge of specific protein-protein interaction (PPI) is an important component in understanding biological processes and regulatory mechanisms. A library to library screening method (LLS) was established based on yeast two-hybrid (YTH) system in this research, and applied to study the PPIs in ayu liver. In total, 23 out of 55 interaction pairs were found positive through phenotypic identification, with a positive rate of 41.8%. Of the 11 unique PPIs, 9 interactions including FGB/FGG, CaM/Spna2, C9/Apo-AI-1, α₂M/Ft, RPL10/RPL5, C8α/C9, FGG/Apo-AI-1, LECT2/Tf, and Apo-AI-2/C9 were previously reported. The other two PPIs including FGG/CLR and Wap65/C3 are novel, and in vitro co-immunoprecipitation (co-IP) experiments further confirmed these interactions. FGG/CLR interaction might play a role in regulating the inflammatory response. The interaction between Wap65 and C3 hints that Wap65 might function through the complement activation pathways when microbial infection occurs.

Ischemic acute kidney injury (AKI) triggers an inflammatory response which exacerbates injury that requires increased expression of endothelial adhesion molecules. To study this further, we used in situ hybridization, immunohistology, and isolated endothelial cells, and found increased Toll-like receptor 4 (TLR4) expression on endothelial cells of the vasa rectae of the inner stripe of the outer medulla of the kidney 4h after reperfusion. This increase was probably due to reactive oxygen species, known to be generated early during ischemic AKI, because the addition of hydrogen peroxide increased TLR4 expression in MS1 microvascular endothelial cells in vitro . Endothelial TLR4 may regulate adhesion molecule (CD54 and CD62E) expression as they were increased on endothelia of wild-type but not TLR4 knockout mice in vivo . Further, the addition of high-mobility group protein B1, a TLR4 ligand released by injured cells, increased adhesion molecule expression on endothelia isolated from wild-type but not TLR4 knockout mice. TLR4 was localized to proximal tubules in the cortex and outer medulla after 24h of reperfusion. Thus, at least two different cell types express TLR4, each of which contributes to renal injury by temporally different mechanisms during ischemic AKI.

Malignant rhabdoid tumors (MRT) of the kidney are rare in children and even less common in adults, with only six previously reported adult cases. We present the case of a 60-year-old man with an MRT arising in the left kidney with extensive pulmonary micrometastases and thromboembolism resulting in thrombotic pulmonary microangiopathy (pulmonary tumor embolism syndrome). MRT is an extremely aggressive neoplasm with a short survival time.

Experimental autoimmune nephritis in mice and spontaneous lupus nephritis are both associated with elevated expression of several chemokines in the kidneys. Nevertheless, the role that different chemokines play in mediating renal inflammation is far from complete. This study focuses on elucidating the functional role of RANTES, a chemokine that has been noted to be hyper-expressed within the kidneys, both in experimental renal disease as well as in spontaneous lupus nephritis. To elucidate if RANTES was essential for immune-mediated glomerulonephritis, DBA/1 mice that are highly sensitive to nephrotoxic serum nephritis were rendered RANTES-deficient and then tested for disease susceptibility. Nephritis-sensitive DBA/1 mice expressed more RANTES within the diseased kidneys. Compared to wild-type DBA/1 mice, RANTES-deficient DBA/1 mice developed significantly less proteinuria, azotemia, and renal inflammation, with reduced crescent formation and tubulo-interstitial nephritis. These findings indicate that RANTES ablation attenuates immune-mediated nephritis and suggest that this chemokine could be a potential therapeutic target in these diseases.

Oxidative stress plays an important role in the pathogenesis of anti-glomerular basement membrane antibody-induced glomerulonephritis (anti-GBM-GN). Superoxide dismutase (SOD) is the first line of defense against oxidative stress by converting superoxide to hydrogen peroxide (H2O2). We investigated the effect of the SOD mimetic drug tempol on anti-GBM-GN in mice. 129/svJ mice were challenged with rabbit anti-mouse-GBM sera to induce GN and subsequently divided into tempol (200 mg·kg−1·day−1, orally) and vehicle-treated groups. Routine histology, SOD and catalase activities, malondialdehyde (MDA), H2O2, and immunohistochemical staining for neutrophils, lymphocytes, macrophages, p65-NF-κB, and osteopontin were performed. Mice with anti-GBM-GN had significantly reduced renal SOD and catalase activities and increased H2O2and MDA levels. Unexpectedly, tempol administration exacerbated anti-GBM-GN as evidenced by intensification of proteinuria, the presence of severe crescentic GN with leukocyte influx, and accelerated mortality in the treated group. Tempol treatment raised SOD activity and H2O2level in urine, upregulated p65-NF-κB and osteopontin in the kidney, but had no effect on renal catalase activity. Thus tempol aggravates anti-GBM-GN by increasing production of H2O2which is a potent NF-κB activator and as such can intensify inflammation and renal injury. This supposition is supported by increases seen in p65-NF-κB, osteopontin, and leukocyte influx in the kidneys of the tempol-treated group.

To identify potential biomarkers in immune-mediated nephritis, urine from mice subjected to an augmented passive model of anti-glomerular basement membrane (GBM)-induced experimental nephritis was resolved using two-dimensional gels. The urinary proteome in these diseased mice was comprised of at least 71 different proteins. Using orthogonal assays, several of these molecules, including serum amyloid P (SAP), PG D synthase, superoxide dismutase, rennin, and total protease were validated to be elevated in the urine and kidneys of mice during anti-GBM disease, as well as in mice with spontaneously arising lupus nephritis. Among these, urinary protease was the only marker that appeared to be exclusively renal in origin, whereas the others were partly serum-derived. Longitudinal studies in murine lupus demonstrated that total urinary protease had better predictive value for histologically active nephritis (r = 0.78) compared with proteinuria (r = −0.04), azotemia (r = 0.28), or the other markers examined, whereas urine SAP emerged as the single most predictive marker of histological glomerulonephritis. Collectively, these studies uncover total urinary protease, PG D synthase, SAP, and superoxide dismutase as novel biomarkers of anti-GBM disease and lupus nephritis, with stronger correlation to renal disease compared with currently employed biomarkers. These findings could have important diagnostic and prognostic ramifications in the management of these renal diatheses.

Chronically increased sympathetic nerve activity is present during chronic kidney disease (CKD); however, its role in contributing to hypertension or the progression of CKD remains poorly understood. The aim of the present study was to determine if neonatal sympathectomy attenuates hypertension in 5/6 nephrectomized rats and affects renal structure and function in a blood pressure independent manner. We performed 5/6 nephrectomy (referred to as CKD) in both sympathetically-intact and sympathectomized (injected neonatally with guanethidine, referred to as CKD+Sympath) male Sprague Dawley rats. Sham operated sympathetically-intact and sympathectomized rats (referred to as Sham and Sham+Sympath, respectively) were used as the control groups. Radiotelemetry was used to monitor blood pressure throughout the six week duration of the study, after which renal function and histology were assessed. The overall average systolic arterial pressure and final urinary protein excretion was significantly lower in the CKD+Sympath rats (168±7 mmHg, 33±5 mg/24 hr) compared to the CKD rats (184±6 mmHg, 66±7 mg/24 hr), respectively. However, the level of proteinuria in the CKD+Sympath group was reduced to a greater extent than what would be expected solely on the basis of lower blood pressure. All other indices of renal function and histology were comparable between both CKD groups. All measurements were comparable between Sham and Sham+Sympath groups. We conclude the following: (1) sympathectomy attenuated hypertension by approximately one-third in 5/6 nephrectomized rats, and (2) sympathetic nerves to the kidney during 5/6 nephrectomy may contribute to proteinuria in a blood pressure independent manner. Keywords: sympathetic nervous system, pressure, glomerulosclerosis, renal failure INTRODUCTION Chronic kidney disease (CKD) is frequently accompanied by increased sympathetic nerve activity, which may contribute to the pathogenesis and progression of renal parenchymal hypertension via neurogenically-mediated vasoconstriction, and directly to renal damage, via renal ischaemia and trophic effects of noradrenaline (1). The premise that the sympathetic nervous system should be an important drug target in patients with CKD has stimulated interest in the greater use of centrally-acting sympatholytic agents and third generation α- and/or β-blockers (1–3). However, the body of scientific evidence to support this enthusiasm is limited. The evidence that sympatholytic agents can slow the progression of CKD is largely based on relatively small, uncontrolled clinical studies in patients with essential hypertension (4–6), not CKD, and there are no large clinical trials in CKD patients that address this issue. Although plasma catecholamine levels predict mortality in chronic hemodialysis patients (7), such studies are observational and cannot prove causality. Finally, direct evidence of increased sympathetic nerve activity during CKD in humans comes from measurements of muscle sympathetic nerve activity (8–10). Such measurements may not contribute to hypertension or reflect efferent sympathetic nerve activity to the kidney, the organ of interest. When considering limitations that exist with rat studies in the 5/6 nephrectomy model of renal parenchymal hypertension, it is important to distinguish a key methodological detail. That is, 5/6 nephrectomy can be performed either using the renal excision method (uninephrectomy + removal of upper and lower pole of the contralateral kidney) or the renal infarction method (uninephrectomy + ligation of multiple branches of the renal artery of the contralateral kidney). In the renal excision model, resection of renal afferent neural pathways (via dorsal rhizotomy) ameliorated the hypertension and prevented the decline in renal function (11, 12). This suggests that renal afferent activation is a critical mechanism that leads to increases in efferent sympathetic nerve activity that are thought to occur in this model (13). However, the tail-cuff measure of blood pressure that was used is indirect and sensitive to the arousal state of the animal, making it difficult to quantify a sympathetic contribution to the hypertension. Furthermore, renal sympathetic nerve activity has been shown to contribute to the progression of CKD in a blood pressure independent manner, because non-hypotensive doses of sympatholytic agents reduce renal structural/functional damage in renal excision 5/6 nephrectomized rats (14, 15). Importantly, the renal excision model does not exhibit hypertension when blood pressure is measured with radiotelemetry (16). This is a key difference between the renal excision model and clinical CKD, wherein hypertension and pressure-induced renal damage are typical. Thus, the magnitude of the efferent sympathetic neural contribution to renal parenchymal hypertension is unknown, as is whether renal sympathetic nerves independently affect renal structure and function in the setting of profound hypertension. Accordingly, we used neonatal sympathectomy, which renders efferent sympathetic nerves nonfunctional, to, 1) determine its effect on hypertension in the renal infarction 5/6 nephrectomy model while using radiotelemetry to measure blood pressure, and 2) to determine if sympathetic nerves directly contribute to decline in renal structure/function independent of their effect on blood pressure. We studied adult rats that were either intact or had been neonatally-sympathectomized, while monitoring blood pressure for six weeks following 5/6 nephrectomy. We show that sympathectomy attenuates hypertension during 5/6 nephrectomy by approximately one-third, and provide evidence that renal sympathetic nerves may effect proteinuria in a blood pressure independent manner.

Increased Type I IFNs or IFN-I have been associated with human systemic lupus erythematosus. Interestingly augmenting or negating IFN-I activity in murine lupus not only modulates systemic autoimmunity, but also impacts lupus nephritis, suggesting that IFN-I may be acting at the level of the end-organ. We find resident renal cells to be a dominant source of IFN-I in an experimental model of autoantibody-induced nephritis. In this model, augmenting IFN-I amplified antibody-triggered nephritis, whereas ablating IFN-I activity ameliorated disease. One mechanism through which increased IFN-I drives immune-mediated nephritis might be operative through increased recruitment of inflammatory monocytes and neutrophils, though this hypothesis needs further validation. Collectively, these studies indicate that an important contribution of IFN-I toward the disease pathology seen in systemic autoimmunity may be exercised at the level of the end-organ.

An association between intravascular large B-cell lymphoma (IVLBCL) and the mixed lineage leukemia (MLL) gene has never been demonstrated. Here, we report an IVLBCL in a 47-year-old Asian man. Morphologically, the atypical lymphoid infiltrate was entirely confined in the lumina of capillaries, small vessels, and sinusoidal space. Within the kidney, the neoplastic lymphoid cells exhibited both the glomerular and peritubular capillary distribution pattern. Conventional cytogenetic analysis from the bone marrow aspirates displayed a complex karyotype, with a notable triple tandem repeat at band segment q22–q25 of chromosome 11. Fluorescence in situ hybridization with an MLL probe set, performed on both interphase cells and metaphase spreads, confirmed the presence of 3 copies of the MLL gene on the derivative chromosome 11. From this finding and 3 other IVLBCL cases reported in the literature, we conclude that MLL may play an important role in the lymphomagenesis of IVLBCL at least in a subset of cases.

The Y-linked autoimmune accelerating (Yaa) locus drives the transition to fatal lupus nephritis when combined with B6.Sle1 in our C57BL/6J (B6)-congenic model of systemic autoimmunity. We and others recently demonstrated that the translocation of a cluster of X-linked genes onto the Y chromosome is the genetic lesion underlying Yaa (Subramanian, S. et al., Proc. Natl. Acad. Sci. USA 2006. 103: 9970–9975; Pisitkun, P. et al., Science 2006. 312: 1669–1672). In male mice carrying Yaa, the transcription of several genes within the translocated segment is increased roughly twofold. Although the translocated X chromosome segment in Yaa may contain as many as 16 genes, the major candidate gene for causation of the Yaa-associated autoimmune phenotypes has been TLR7. To confirm the role of TLR7 in Yaa-mediated autoimmune phenotypes, we introgressed a targeted disruption of TLR7 (TLR7–) onto B6.Sle1Yaa to produce B6.Sle1YaaTLR7– and examined evidence of disease at 6 and 9 months of age. Our results demonstrate that the up-regulation of TLR7 in the B6.Sle1Yaa strain is responsible for splenomegaly, glomerular nephritis and the majority of the cellular abnormalities of B, T and myeloid cells. The up-regulation of TLR7 was also responsible for driving the infiltration and activation of leukocytes in the kidney, in which activated T cells were a primary component. However, the resolution of TLR7 up-regulation did not eliminate the enhanced humoral autoimmunity observed in B6.SleYaa, suggesting that additional elements in the translocation may contribute to the disease phenotype. See accompanying commentary http://dx.doi.org/10.1002/eji.200838478

Genetic analyses of the lupus-prone NZM2410 mouse have identified multiple susceptibility loci on chromosome 7, termed Sle3 and Sle5. Both of these loci were contained within a large congenic interval, originally termed as Sle3 that strongly impacts a variety of myeloid and T-cell phenotypes and mediates fatal lupus nephritis when combined with Sle1. We have now produced two subcongenic strains, B6.Sle3 and B6.Sle5, carrying the Sle3 and Sle5 intervals separately and characterized their phenotypes as monocongenic strains and individually in combination with Sle1. Neither B6.Sle3 nor B6.Sle5 monocongenic strain develop severe autoimmunity; however, both of these intervals cause the development of severe glomerulonephritis when combined with Sle1. Thus, B6.Sle1Sle3 and B6.Sle1Sle5 exhibit splenomegaly, expansion of activated B and CD4+ T-cell populations and high levels of IgG and IgM autoantibodies targeting multiple nuclear antigens, intact glomeruli and various other autoantigens. In addition, B6.Sle1Sle3 mice also produced higher levels of IgA antinuclear autoantibodies, which were implicated in the development of IgA nephropathy. Our results indicate that Sle3 and Sle5 can independently complement with Sle1, through shared and unique mechanisms, to mediate the development of severe autoimmunity.

An NZM2410-derived lupus susceptibility locus on murine chromosome 4, Sle2z, has previously been noted to engender generalized B cell hyperactivity. To study how Sle2z impacts B cell tolerance, two Ig H chain site-directed transgenes, 3H9 and 56R, with specificity for DNA were backcrossed onto the C57BL/6 background with or without Sle2z. Interestingly, the presence of the NZM2410 “z” allele of Sle2 on the C57BL/6 background profoundly breached B cell tolerance to DNA, apparently by thwarting receptor editing. Whereas mAbs isolated from the spleens of B6.56R control mice demonstrated significant usage of the endogenous (i.e., nontargeted) H chain locus and evidence of vigorous L chain editing; Abs isolated from B6.Sle2z.56R spleens were largely composed of the transgenic H chain paired with a spectrum of L chains, predominantly recombined to Jk1 or Jk2. In addition, Sle2z-bearing B cells adopted divergent phenotypes depending on their Ag specificity. Whereas Sle2z-bearing anti-DNA transgenic B cells were skewed toward marginal zone B cells and preplasmablasts, B cells from the same mice that did not express the transgene were skewed toward the B1a phenotype. This work illustrates that genetic loci that confer lupus susceptibility may influence B cell differentiation depending on their Ag specificity and potentially contribute to antinuclear autoantibody formation by infringing upon B cell receptor editing. Taken together with a recent report on Sle1z, these studies suggest that dysregulated receptor-editing of nuclear Ag-reactive B cells may be a major mechanism through which antinuclear Abs arise in lupus.