Citrus sinensis) is one of the most important fruits world-wide. Because it is a woody plant with a long growth cycle, genetic studies of sweet orange are lagging behind those of other species.Sweet orange (EDI) in CitrusNet using RNA-seq data from four sweet orange tissues, and also analyzed the EDI distribution and variation in different sub-networks.In this analysis, we employed ortholog identification and domain combination methods to predict the protein-protein interaction (PPI) network for sweet orange. The K-nearest neighbors (KNN) classification method was used to verify and filter the network. The final predicted PPI network, CitrusNet, contained 8,195 proteins with 124,491 interactions. The quality of CitrusNet was evaluated using gene ontology (GO) and Mapman annotations, which confirmed the reliability of the network. In addition, we calculated the expression difference of interacting genes (Gene expression in CitrusNet has significant modular features. Target of rapamycin (TOR) protein served as the central node of the hormone-signaling sub-network. All evidence supported the idea that TOR can integrate various hormone signals and affect plant growth. CitrusNet provides valuable resources for the study of biological functions in sweet orange. Homo sapiens. Va. Va16]. ns (DIP) , Moleculns (DIP) , proteinns (DIP) , Search ns (DIP) , Biologins (DIP) , and thens (DIP) .Arabidopsis thaliana containing about 6,200 interactions among 2,700 proteins  and andArabiza sativa. ResearcCitrus is commercially cultivated in over 130 countries and districts, and citrus fruit holds a dominant position in the global fruit industry (http://faostat.fao.org). Although many germplasms and cultivars exist, comprehensive morphological, anatomical, and molecular evidences has confirmed that all modern cultivars (such as sweet orange) are the derived offspring of two primitive species, pummel (C. grandis) and mandarin (C. reticulata) . Ge. GeCitrumandarin ,30]. Sw. SwCitruIn this analysis, we predicted the sweet orange PPI network using ortholog-based and domain-based interaction methods, based on careful preparation and selection of reliable data resources, and then applied K-nearest neighbors (KNN) method to verify and filter the predicted PPIs and obtain a more confident network. The final PPI network in sweet orange, CitrusNet, contains 8,195 proteins and 124,491 interactions. This is the first report of a genome-wide PPI network in a woody plant. The quality of this PPIs network was carefully assessed. Furthermore, using RNA-seq data from four tissues, we analyzed important functional modules and obtained insights into the tissue-specific features of the sweet orange protein interactome.i.e., most nodes had low degrees of connection, whereas a few hub nodes had very high degrees of connection. In total, 602 proteins in CitrusNet had more than 100 connections. Table y = 4885.8*x-1.407  are also very important for a network, because these nodes act as bottlenecks in the network even in the absence of hubs . Table 2The clustering coefficient  of CitrusNet is 0.301, much higher than that of a random network with the same degree distribution (CC = 0.014). This feature indicated that CitrusNet is very intensive, and several sub-networks containing protein complexes or signaling pathways could be identified. The relationship between CC and degree in CitrusNet is shown in Figure Because no experimental PPIs are available in sweet orange, we employed gene ontology (GO) annotation analysis to evaluate CitrusNet. Because interacting proteins tend to have similar or related functions, a reliable PPI network should contain many more functionally related proteins than a random network. We performed GO analysis to compare the functional relationships among protein nodes in CitrusNet and random networks, and then obtained GO annotation from the GO database . In totaMoreover, we analyzed many gene modules in CitrusNet to determine whether they contained known biological pathways in sweet orange. To this end, we used Mapman annotation, which represents biological functions with no redundancy between different terms . We consEDI). Interacting genes with similar expression levels had EDI values closer to zero. We employed the Markov Clustering (MCL)-modular method . In. In37]. r method  to extraomplexes . In totaEDI distribution in CitrusNet based on its topological properties. First, we divided all genes in the network into two groups , and then divided the high-degree genes into two subgroups . Figure EDI around zero was much higher than the percentage of high-degree genes, because the high-degree genes had many interacting partners with different functions and expression levels, whereas low-degree genes had far fewer interacting partners whose functions and expression levels were more likely to be similar. This phenomenon reflects the ‘economical’ principle of gene interactions, i.e., genes tend to interact with as few partners as possible to serve their biological functions. We also observed the same features for EDI and BC topological parameters. The percentage of high-degree/low-BC genes with EDI around zero was higher than that of high-degree/high-BC genes, suggesting that genes with low BC are likely to have similar expression levels.We also analyzed the EDI distribution in different kinds of sub-networks, we also analyzed EDI variations among genes in the four tissues. We performed an in silico analysis to simulate the effect of removing specific nodes in the network. We defined different thresholds of EDIvariation values from 10 to 100, with a step size of 1. Based on these thresholds, we removed nodes with EDIvariation values higher than the thresholds in CitrusNet, and compared the average shortest path length after randomly removing the same number of nodes in CitrusNet. The shortest path length between two nodes reflects the overall network connectivity. In total, we removed 1658 nodes for EDIvariation = 10, and 117 nodes for EDIvariation = 100. The distributions of average shortest path lengths of these two types of interactome networks are shown in Figure EDIvariation-removed networks were all longer than those of randomly-removed networks, indicating that nodes with high EDIvariation values were very important for network connectivity. Figure EDIvariation values in the range 10–20 were crucial for the stability of the network, and that removing these nodes resulted in the largest shortest path lengths.In addition to studying the EDI values of genes in these modules were smaller than those of genes with different functions. Therefore, EDI value reflects the function relationships between interacting gene pairs. Based on this comprehensive analysis, we concluded that gene expression patterns in CitrusNet have modular features.Finally, we analyzed the modular features of gene expression in CitrusNet. Figure Arabidopsis. Al. AlArabinslation . Proteinabidopsis. FurtherThe links among different hormone signaling proteins were very complex, because several of the interacting proteins  were connected to a considerable degree. Many of the hormone-related proteins interacted with each other, indicating that various hormone-signaling pathways exchange information before affecting TOR (or vice versa). Although many plant hormone-related proteins were connected, TOR is undoubtedly the hub of hormone crosstalk. The central role of TOR implies that it integrates environmental information communicated by hormones, and uses this information to regulate plant growth.In this study, we predicted the genome-wide PPI network of sweet orange, based on ortholog identification and domain-combination methods. Because there is no golden-standard PPI dataset in sweet orange, we employed a highly accurate KNN algorithm to filter the predicted interactions. The resultant PPI network, CitrusNet, contains 8,195 proteins with 124,491 interactions. We then employed GO and Mapman annotation to assess the predicted network. The shortest distance of GO terms in CitrusNet was much smaller than that of random networks, and the MapMan biology network demonstrated that gene modules in CitrusNet reflected known biological pathways in sweet orange. We also predicted 159 protein complexes in sweet orange using orthologs of the yeast protein complexes and employed them to assess CitrusNet; the results revealed that protein complexes had relatively tight connections. Together, these analyses confirm that CitrusNet is highly reliable.EDI index to analyze the relationship between gene expression and protein interactions. The percentage of protein nodes with similar gene-expression levels in CitrusNet-derived sub-networks was much higher than those of random networks, especially in protein-complex and MCL-modular networks. Protein complexes are groups of two or more associated polypeptide chains, which are predicted to have tight network connections and to be encoded by genes that are expressed at similar levels. Analysis of the EDI distribution, based on topological properties, revealed that genes interacted with as few partners as possible . Furthermore, EDI values around zero were negatively correlated with topological parameters such as degree and BC. In addition to analyzing EDI distributions, we also compared EDI variation among four tissues and found that genes with low EDIvariation values were important for the stability of CitrusNet.We also analyzed the modular features of PPI networks based on the connections in CitrusNet. We proposed the Arabidopsis, its function in hormone-signaling pathways has not been previously investigated. Although we identified reliable connections between TOR and hormone-signaling proteins, the underlying regulatory patterns have not yet been elucidated. Many of the predicted plant hormone interactions in CitrusNet are supported by experimental evidence in other species ,,,. We propA and B contained m and n domains, respectively. Then, Protein A and B have 2m-1 and 2n-1 possible domain combinations, and (2m-1) × (2n-1) dc-pairs would be obtained. The score for each dc-pair was defined as follows:Suppose a protein pair A and B) was defined as follows.Using equation , all therated-dc-pairs indicates the dc-pairs of protein pair A and B in the six reference organisms, and all-dc-pairs indicates all the dc-pairs of protein A and B. The final score in equation (A and B) obtained from the domain-combination method. An appropriate threshold was set to obtain a credible result.In equation , rated-dequation  denotes Because no experimental PPI dataset is available for sweet orange, we employed third-party cross-validation methods to filter and assess the predicted PPIs based on ortholog identification and domain-combination. K-nearest neighbor (KNN), a simple and accurate method to validate predicted PPIs, requires positive and negative training datasets . In thisA interacted with m genes, we defined the expression difference of interacting genes (EDI) as follows.RNA-seq reads were generated by the Illumina and SOLiD platforms and aligned to the reference genome using TopHat (v1.2.0) and BioScope (v1.3) with default parameters . Gene-exRPKMA and RPKMi indicate the RNA-seq expression values for gene A and its interacting partner i, and DA and Di indicate the degree of gene A and gene i. If gene A has EDI value close to zero, the expression levels of gene A and its interacting partner are similar.In equation , RPKMA aEDI, we calculated EDIvariation values for each gene in four tissues; callus, leaf, flower, and fruit. The EDIvariation value was defined in equation (After obtaining equation .(5)EDIvaEDIhighest and EDIlowest represent the highest and lowest EDI of a gene in the four tissues, respectively. If a gene was not expressed in one tissue, we defined EDIlowest as zero.PPI: Protein-protein interactionKNN: K-nearest neighborsGO: Gene ontologyEDI: Expression difference of interacting genesTOR: Target of rapamycinAP-MS: Affinity purification mass spectrometryY2H: Yeast two-hybridBC: Betweenness centralityCC: Clustering coefficientDDIs: Domain-domain interactionsThe authors declare that they have no competing interests.DYD and CJW collected the data, performed the analysis and wrote the draft manuscript. CLL and CYJ supervised the project and wrote the manuscript. GJ and CDJ set up the web server and helped to collect the data. LS helped to prepare the figures. XQ and DXX provided sequencing materials and revised the manuscript. All authors carefully read and approved the final manuscript.The predicted 159 protein complexes in sweet orange, using best hits of sequence alignments from yeast complexes.Click here for fileGenes highly expressed genes in at least three of the four tissues; callus, flower, fruit, and leaf.Click here for fileHigh-quality PPIs for six model organisms obtained from various public databases.Click here for file


This principle may also be applied to benign conditions as inflammatory cells take up increased amounts of FDG as well. The aim of our study was to retrospectively review the cytological diagnoses made at EUS-FNA of FDG-avid PET-CT lesions in patients with a history of cancer and to determine whether the cause of FDG-avidity was neoplastic or benign.Patients suffering from malignancies often undergo serial positron emission tomography - computed tomography (PET-CT) scans, using 2-deoxy-2-[We used the endoscopy database to extract clinical information on all patients with malignancies who underwent EUS-FNA to obtain tissue from FDG-avid nodes seen on PET-CT at our institution from 2009 – 2012. All patients who were referred for EUS-FNA after their scans were included. Those who had contraindications to endoscopic procedures were excluded.The most common location of positive lymph nodes was the subcarinal region (46%). A definitive diagnosis was obtained in 87.8% cases, of which 51.2% had a diagnosis of malignancy confirmed on cytology, while 36.5% were benign. Out of these, 29% had granulomatous inflammation. In 12.2% of cases no definitive diagnosis was obtained.Our results show that great caution should be exercised when evaluating FDG-avid PET-CT nodes in patients with known malignant disease, as a significant proportion of these lesions may be benign, particularly in geographic locations with a high background prevalence of granulomatous inflammation. ThisWe found that 3/9 patients who were sampled during treatment had benign conditions on cytology, all of which were granulomatous inflammation. For patients who underwent EUS-FNA during their follow-up period, 9/28 (32.1%) had benign lesions, of which eight were granulomatous inflammation. These are significant false positive rates for lesions that mimic cancer, in the setting of cancer, but are in fact benign lesions. Without EUS-FNA, these patients might well have been assumed to have residual cancer, and been subjected to further, potentially hazardous, treatment.Schaefer et al. and Crocchiolo et al. discussed in their reports that 10-40% of FDG avid nodes on PET-CT, thought to be malignant, actually turn out to be benign ,15. In kOur review demonstrates that extreme caution should be exercised when evaluating FDG-avid lymph nodes on PET-CT in patients with known malignant disease, as a significant proportion of FDG-avid lesions may be benign. In our series, 36.5% had non-malignant conditions, with granulomaotus inflammation being the most common non-malignant lesion seen. Our results are of particular significance to physicians practicing in settings where granulomatous inflammatory diseases are widespread and also of importance for oncologists, and other physicians, practicing elsewhere in the world, who regularly deal with patients from these areas. These results have the potential to significantly impact patient diagnosis, staging and subsequent management. Many patients will be able to discontinue cancer treatment sooner, or to avoid unnecessary re-treatment, as a result of an appropriate diagnostic intervention such as EUS-FNA, when FDG-avid nodes are seen on PET-CT scan. This has significant impact in improving quality of life in these patients and all physicians treating such patients need to be aware of these important findings.Our results show that great caution should be exercised when evaluating FDG-avid lymph nodes on PET-CT in patients with known malignant disease, as a significant proportion of these lesions may be benign. Failure to establish a tissue diagnosis in such a situation can lead to patients being treated inappropriately, with potential for harm to the patient. We recommend that all such lesions need to be sampled and an accurate diagnosis made prior to instituting, or making changes to, therapy. EUS-FNA, with rapid on-site evaluation offers an optimal means of sampling such lesions.18F] fluoro-D-glucose; SUV: Standard uptake value; EUS-FNA: Endoscopic ultrasound-fine needle aspiration; ROSE: Rapid on-site evaluation; RPMI: Roswell park memorial institute medium; GIST: Gastrointestinal stromal tumour; AFB: Acid fast bacilli.PET-CT: Positron emission tomography-computed tomography; DG: 2-deoxy-2-[The authors declare no competing interests.MAY conceived the study, participated in data collection and in writing of the first draft of the manuscript. He was also responsible for review of the manuscript. AIM participated in data collection and in writing of the first draft of the manuscript. She also participated in review of the manuscript. NA and AL participated in writing and review of the manuscript. All authors read and approved the final manuscript.


Anterior odontoid screw fixation (AOSF) has been one of the most popular treatments for odontoid fractures. However, the true efficacy of AOSF remains unclear. In this study, we aimed to provide the pooled rates of non-union, reoperation, infection, and approach related complications after AOSF for odontoid fractures.We searched studies that discussed complications after AOSF for type II or type III odontoid fractures. A proportion meta-analysis was done and potential sources of heterogeneity were explored by meta-regression analysis.Of 972 references initially identified, 63 were eligible for inclusion. 54 studies provided data regarding non-union. The pooled non-union rate was 10% (95% CI: 7%–3%). 48 citations provided re-operation information with a pooled proportion of 5% (95% CI: 3%–7%). Infection was described in 20 studies with an overall rate of 0.2% (95% CI: 0%–1.2%). The main approach related complication is postoperative dysphagia with a pooled rate of 10% (95% CI: 4%–17%). Proportions for the other approach related complications such as postoperative hoarseness , esophageal/retropharyngeal injury , wound hematomas , and spinal cord injury  were very low. Significant heterogeneities were detected when we combined the rates of non-union, re-operation, and dysphagia. Multivariate meta-regression analysis showed that old age was significantly predictive of non-union. Subgroup comparisons showed significant higher non-union rates in age ≥70 than that in age ≤40 and in age 40 to <50. Meta-regression analysis did not reveal any examined variables influencing the re-operation rate. Meta-regression analysis showed age had a significant effect on the dysphagia rate.This study summarized the rates of non-union, reoperation, infection, and approach related complications after AOSF for odontoid factures. Elderly patients were more likely to experience non-union and dysphagia. Odontoid fractures account for 10%–15% of all cervical spine fractures To date, many clinical studies have evaluated the effectiveness of AOSF for odontoid fractures A computerized systematic search was conducted up to August 2013 using MEDLINE database. We screened all fields by the term “odontoid fracture” or “odontoid screw” or “odontoid fixation”. Articles were limited to those published in English. We also searched the reference lists and relevant journals by hand. This meta-analysis was performed in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines (when appropriate) .We included studies which were carried out on humans. The studies that discussed fusion results, and/or re-operations, and/or infections, and/or approach related complications after odontoid screw fixation for type II or type III odontoid fractures were selected. We also required a minimum sample size of five to ensure quality and comparability of data. Biomechanical studies, cadaveric studies, animal studies, case report, duplications, and review articles were excluded. Clinical studies with inadequate information or incomplete data were also excluded. We carefully reviewed the department/institute of each potential eligible study to screen whether there were any papers from the same surgical team. For papers that had overlapping patients determined through the overlapping research time, we only included the paper with the largest sample size for analysis.Two investigators reviewed all identified articles to determine if an individual study was eligible for inclusion. Data from each study was extracted using a standardized form. Disagreements on eligibility and data between reviewers were resolved by consensus with the third reviewer. Studies were categorized into levels of evidence according to those published in the Journal of Bone and Joint Surgery (American) Data extracted consisted of study year, country, level of evidence, patients' mean age, sex proportion, mean follow-up duration, classification of the odontoid fracture, number of patients, number of non-unions, number of re-operations, number of infections, and number of approach related complications. Fusion status should be assessed according to radiological (static or dynamic) and/or computed tomography (CT) examinations. Because the fusion criteria might be different among the included studies, we used a universal definition of fusion for data extraction. Criteria for fusion success included formation of trabecular and cortex bony bridges through the fracture site, absence of sclerotic borders adjacent to the fracture site, and absence of movement of the fracture site confirmed on radiographs and/or CT scan. Radiolucent cleft, clear fracture line, fibrous union, or any movement at the fracture site were considered as non-union. Re-operation represented secondary surgical intervention for any reason after odontoid screw fixation. Infections indicated only those located at the surgical site including both superficial and deep ones. We extracted data on five types of approach related complications including postoperative dysphagia, postoperative hoarseness, esophageal /retropharyngeal injury, wound hematomas, and spinal cord injury. In this meta-analysis, data regarding the study characteristics and the outcomes of interest were extracted based on the average value of each study. For studies with overlapping patients, only the one with the largest sample size was entered into meta-analysis.Meta-analyses were performed to pool the rates of non-union, re-operation, infection, and approach related complications. A Freeman-Tukey Double arcsine transformation was implemented to calculate the overall proportion. A test of heterogeneity was carried out, and cut-off p value of 0.1 was established as a threshold of homogeneity. Pooled estimates and 95% confidence intervals (CIs) were summarized by forest plots. Fixed-effect models were applied unless statistical heterogeneity was significant, in which case random-effect models were used. We further investigated potential sources of heterogeneity by arranging groups of studies according to relevant characteristics  and by meta-regression analysis. Factors were examined both individually and in multiple-variable models. To avoid model instability, only factors that showed significant effects individually were enrolled into a multiple regression model. Publication bias was assessed using Egger test. All analyses were done in the statistical software R 3.0.1.In the initial screening, 972 potential studies were selected according to the search strategy. Hand-searching resulted in 12 additional papers. After reviewing titles and abstracts, 814 papers were found to be unrelated to the current topic. Of the remaining 170 papers, the full texts were read and 104 publications which did not meet eligibility criteria were excluded. Further three papers 54 studies 48 citations Surgical site infection was assessed in 20 studies The main approach related complication was postoperative dysphagia. The pooled rate was 10% (95% CI: 4%–17%) with statistically significant heterogeneity . Meta-reWe conducted this study to provide a better understanding of the frequency of non-union, infection, re-operation, and approach related complications after anterior screw fixation for type II and type III odontoid fractures. Non-union can be one of the most important outcomes, because it may lead to spinal cord injury due to atlantoaxial instability. Pooled analysis from our study showed that the non-union rate after AOSF was 10%. It seemed that the fusion rate of AOSF (90%) was better than that of the conservative treatment (60%–80%) Our study revealed that age had a significant impact on the non-union rate. The non-union rate in patients younger than 50 years was 6%. Therefore, AOSF seems to be a good choice for young patients. Although the non-union rate reached 11% to 25% in patients aged 50 years or older, this rate was still acceptable as the non-union rate of conservative treatment for the elderly patients was very high . Esophageal /retropharyngeal injury, wound hematomas, and spinal cord injury were rare approach related complications. Noteworthy was that age also had a significant effect on postoperative dysphagia rate. Dysphagia is a known complication of anterior cervical spine surgery. A recent systematic review showed that female gender, advanced age, multilevel surgery, longer operating time and severe pre-operative neck pain may increase the risk of postoperative dysphagia after cervical spine surgery There are some limitations existing in this study. First, this meta-analysis only focused on the rates of non-union, re-operation, infection, and approach related complications. We did not pool other outcomes like functional results and patient satisfactory outcome because they were not always reported or were reported in various forms. Even the outcomes we combined were not always available. Second, during the extraction of fusion data, we found the fusion status was assessed using different imaging modalities and non-union was defined according to different standards. Thus, pooling of relevant data might lead to bias even though we had predefined unified criteria for non-union. Third, extensive and significant heterogeneities were detected when we combined the rates of non-union, re-operation, and dysphagia. We had explored the heterogeneity through meta-regression analysis according to several study characteristics, but we only found age had a significant effect on the non-union and dysphagia rate. After subgroup analysis, we still observed heterogeneity in each age group, which meant there were potential other factors influencing the two outcomes. For re-operation, we failed to find potential factors which could explain the heterogeneity. The factors we analyzed represented the average value of each study, which could limit the exploration of the heterogeneity. Moreover, the heterogeneity might also be ascribed to various factors, such as other patient characteristics, fracture subtypes, and surgical techniques used. Lastly, the level of evidence of our analysis is low as none of the enrolled studies were randomized controlled trials. Despite these weaknesses, our study obtains some clinical significance since we pooled estimates based on a relatively large sample. This study provides a quantitative description of the frequencies of non-union, re-operation, infection, and approach related complications after AOSF for odontoid fractures. These data can be helpful in making informed surgical decisions. Further studies may be necessary to pool the functional outcomes of using this technique and to determine the factors affecting the efficacy.Table S1Characteristics of the studies included for analyzing non-union, re-operation, and infection.(DOC)Click here for additional data file.Table S2Characteristics of the studies included for analyzing approach related complications.(DOC)Click here for additional data file.Checklist S1PRISMA Checklist.(DOC)Click here for additional data file.


Background and Aim. The sensitivity and specificity of biomarkers used for predicting peripheral neuropathy in patients with systemic lupus erythematosus (SLE) and nephritis (SLE-LN) remain unsatisfactory. This study aimed to determine the autoantibodies levels in SLE-LN patients with peripheral neuropathy. Methods. Data of 559 SLE-LN patients were collected retrospectively, including titers of autoantibodies, electrodiagnostic studies, and clinical manifestations. Results. The neurologic manifestations of the SLE-LN patients were diverse and nonspecific. The prevalence rate of peripheral polyneuropathy was 2.68%, of which about 73.33% was mixed sensory-motor polyneuropathy. Numbness and functional gastrointestinal problems were the most prevalent symptoms and these were noted in every subtype of peripheral neuropathy. Among all the serology markers, anti-Ro was significantly associated with neuropathy related to SLE (P = 0.009). Conclusion. Peripheral neuropathy among LN patients is rare and may be easily overlooked. This study demonstrated that positive anti-Ro antibody may imply neuropathy in LN patients. Thus, anti-Ro can be considered a biomarker that should be added to the panel of conventional autoantibodies in LN patients. Peripheral neuropathy is a well-documented clinical manifestation of systemic lupus erythematosus (SLE) , 2, withIn clinical practice, there are syndromes that overlap with lupus, including rheumatoid arthritis or vasculitis syndrome. Lupus nephritis (LN), a more definite and specific subgroup of lupus, is a major cause of morbidity and mortality in SLE and can affect up to 60% of SLE patients . The fivTo date, very few researches have focused specifically on LN patients complicated by peripheral neuropathy –18. BecaUsing preexisting standardized evaluation forms, the medical records of patients diagnosed with SLE and evidence of LN at Kaohsiung Chang Gung Memorial Hospital, a 2482-bed acute-care teaching hospital providing primary and tertiary referral care, were reviewed. Among the SLE-LN patients, electrodiagnostic tests were collected and evaluated to define the subtype of peripheral neuropathy after excluding patients according to the exclusion criteria. The demographic data, clinical presentation, and treatment were also collected.The patient database in the study institution was searched for the ICD-9-CM code of SLE (710.0) and confirmed by clinical manifestations for the period of June 1, 2005, to June 1, 2011. Five hundred and eighty-two SLE patients with LN were collected. The 1997 update of the 1982 revised criteria was used for the diagnosis of SLE, while LN was diagnosed according to guidelines [The NCS/EMG examinations were done by the hospital's standard laboratory methods according to the recommended protocol of the American Association of Electrodiagnostic Medicine (AAEM) using a Nicolet Viking Select system . All tests were done under similar temperature conditions in the same room. Skin temperature was maintained at ≥32°C.β2GP I), anti-cardiolipin IgM (aCL-IgM), anti-cardiolipin IgG (aCL-IgG), anti-Ro, anti-La, anti-RNP, anti-Jo-1, anti-Sm, anti-scl-70, anti-centromere (anti-cm), peri-nuclear anti-neutrophil cytoplasmic antibody (p-ANCA), and cytoplasmic anti-neutrophil cytoplasmic antibody (c-ANCA). All of the laboratory data were present with absolute values and all of the tests were done by the Thermo Scientific Phadia system by qualified technicians. Major symptoms that might be related to neuropathy were also collected from the charts.The serum markers of autoantibodies were collected thoroughly from each patient, including anti-beta 2-glycoprotein I antibodies .Data were expressed as mean ± SD or median (interquartile range). Categorical variables were compared using the Chi-square test or Fisher's exact test, as appropriate. The autoantibody levels were compared between the two groups. Univariate analyses were compared using the Mann-Whitney There were 1262 SLE patients treated in the hospital between June 1, 2005, and June 1, 2011, accounting for 3555 admissions. There were 582 SLE patients (46.04%) with kidney involvement and 2215 admissions . Each patient had at least one admission. Among the 582 SLE-LN patients, three patients with diabetes and 20 with end-stage renal disease (ESRD) were excluded. Of the 559 patients finally enrolled in this study, 23 had a clinical diagnosis of peripheral neuropathy confirmed by electrophysiologic examinations. Among these 23 neuropathy patients, four patients with radiculopathy and four patients with median nerve neuropathy at wrist were further excluded. Thus, only 15 patients (2.68%) were diagnosed as definite neuropathy among the total 559 patients .By subgroups of peripheral neuropathy, four had autonomic neuropathy, two had pure sensory neuropathy, and 11 had mixed sensory-motor polyneuropathy. Of the 11 with mixed sensory-motor polyneuropathy, two were also complicated with autonomic neuropathy.U test of all aforementioned variables, only anti-Ro (P = 0.009) was independently associated with peripheral neuropathy among the SLE-LN patients.The levels of autoantibodies were shown in n = 8). No patient presented with abnormal blood pressure and heart rate.The clinical symptoms of the 15 neuropathy patients  were claComorbid neuropathy and LN have been presented before but mostly as case reports before. Bódi et al. described an old lady who presented with progressive sensory-motor polyneuropathy and proteinuria. Her SLE was confirmed by biopsy and serology . Acute iP = 0.0002, data not shown).Differences in the relative prevalence of peripheral neuropathy in SLE vary with case determination, inclusion and exclusion criteria, and length of follow-up. The prevalence rate of peripheral neuropathy in SLE is a little bit lower than that of Sjögren's syndrome, which is characterized by positive anti-Ro autoantibodies. The prevalence rate of Sjögren's syndrome is between 8% and 62% . In the All of the different subtypes of peripheral neuropathy occur in SLE-LN patients. The most predominant is mixed sensory-motor polyneuropathy, which is seen in 11 of the 15 patients here (73.33%). The pathogenesis of median nerve neuropathy is either entrapment neuropathy  or polynThe symptoms of polyneuropathy are nonspecific and diverse in this study cohort. Numbness and functional gastrointestinal problems are the most common presenting symptoms. Functional gastrointestinal problems and numbness can happen in any type of peripheral neuropathy, even in median nerve neuropathy and spinal radiculopathy. The combination of numbness on four extremities and functional gastrointestinal problems in an SLE-LN patient raise the index of suspicion on polyneuropathy in the future.Anti-Ro autoantibody occurs in as high as one-third of SLE patients , 27 and This study has several limitations. First, this is a retrospective analysis and is therefore subject to bias of unmeasured factors. Second, peripheral neuropathy can be slowly progressive or acutely devastating, subtle, or even asymptomatic. In clinical practices, only LN patients with clinical peripheral neuropathy suspect or focal neurological signs receive electrodiagnostic studies. Third, LN patients with peripheral neuropathy and underlying conditions like ESRD, diabetes mellitus, and malignancy have been excluded. The findings may underestimate the “true” frequency of peripheral neuropathy in LN patients. Fourth, although the titers of autoantibodies in are semiquantitative, the level has a linear relationship with severity. However, the relationship between the severity of peripheral neuropathy and levels of anti-Ro antibody cannot be exactly evaluated in this study. Lastly, the choice of immunosuppressant therapeutic strategy for LN patients  may be different for each patient based on the preference of the attending physician. This may cause potential bias in the statistical analysis.In conclusion, the occurrence of peripheral neuropathy among LN patients is rare and may be easily overlooked. This study demonstrates that positive anti-Ro antibody may imply neuropathy in LN patients and it can be considered a biomarker that should be added to the panel of conventional autoantibodies in LN.


The relationship between admission serum calcium levels and in-hospital mortality in patients with acute ST-segment elevation myocardial infarction (STEMI) has not been well definitively explored. The objective was to assess the predictive value of serum calcium levels on in-hospital mortality in STEMI patients.From 2003 to 2010, 1431 consecutive STEMI patients admitted to the First Affiliated Hospital of Nanjing Medical University were enrolled in the present study. Patients were stratified according to quartiles of serum calcium from the blood samples collected in the emergency room after admission. Between the aforementioned groups,the baseline characteristics, in-hospital management, and in-hospital mortality were analyzed. The association of serum calcium level with in-hospital mortality was calculated by a multivariable Cox regression analysis.Among 1431 included patients, 79% were male and the median age was 65 years . Patients in the lower quartiles of serum calcium, as compared to the upper quartiles of serum calcium, were older, had more cardiovascular risk factors, lower rate of emergency revascularization,and higher in-hospital mortality. According to univariate Cox proportional analysis, patients with lower serum calcium level  was associated with higher in-hospital mortality. The result of multivariable Cox proportional hazard regression analyses showed that the Killip's class≥3 , aspartate aminotransferase , neutrophil count , serum calcium level , and emergency revascularization  were significantly and independently associated with in-hospital mortality in STEMI patients.Serum calcium was an independent predictor for in-hospital mortality in patients with STEMI. This widely available serum biochemical index may be incorporated into the current established risk stratification model of STEMI patients. Further studies are required to determine the actual mechanism and whether patients with hypocalcaemia could benefit from calcium supplement. Calcium, one of the most important cations, plays a critical role in cardiac contraction, enzymatic activity, and electrophysiological characteristics. The steady state of calcium flux balance is significantly necessary for myocardium From January 2003 to December 2010, a total of 1431 consecutive STEMI patients admitted to the First Affiliated Hospital of Nanjing Medical University were enrolled in the study. The STEMI was defined as: typical continuous chest pain>30 min with ST-segment elevation>2.0 mm in at least 2 contiguous electrocardiographic leads, and more than a two-fold elevation in the creatine kinase-MB (CK-MB) level The blood samples were collected in the emergency room from each patient after admission. In all cases, peripheral venous blood samples for hematologic and biochemical measurements were drawn. The concentrations of calcium (mmol/L), sodium (mmol/L), potassium (mmol/L), and chloride (mmol/L) were measured with the VITROS 5–1 FS chemistry system . Hypocalcaemia was defined as the concentrations of serum calcium<2.15 mmol/L according to reference range. Common blood counting parameters, in general, including the total white blood cell count, neutrophil count, eosinophil count, monocyte count, lymphocyte count, and addicted Alkaline granulocyte count, were measured by an automatic hematology analyzer (Bayer Diagnostics ADVIA120). Meanwhile, the levels of albumin (g/L), HDL-cholesterol (mmol/L), LDL-cholesterol (mmol/L) and aspartate aminotransferase (U/L) were analyzed by the AU2700 automatic biochemical analyzer.Statistical analysis was performed by SPSS 16.0  and SAS version 9.1 . The Kolmogorov–Smirnov test was used to test continuous variables for normal distribution. Normally distributed data, including neutrophil count, TIMI risk score for STEMI, albumin, serum potassium, onset-arrival time and the length of hospitalization were expressed as mean ± standard deviation and comparisons were analyzed by one-way ANOVA among the quartiles. Skewed data, including age, heart rate, high density lipoprotein (HDL)-cholesterol, Low density lipoprotein (LDL)-cholesterol, Peak creatine kinase (CK), Troponin-T, left ventricular ejection fraction (LVEF), aspartate aminotransferase (AST), serum chlorine, serum sodium, were expressed as the median (inter quartile range) and compared by the Kruskal-Wallis H test. Categorical variables were summarized as percentages and compared among the groups by Chi-squared analysis. The cumulative survival curves for in-hospital mortality with different quartiles of serum calcium were constructed using the Kaplan–Meier method, and curves were compared by the log–rank test. The multivariable Cox proportional hazards regression analyses using forward likelihood ratio tests were performed to explore the independent importance of the variables for in-hospital mortality. The assumptions of proportional hazards were assessed by including time dependent covariates in the models and no indication of a violation was found. The linearity of the continuous variables was checked with Martingale residuals. To avoid over fitting, the following variables known to affect prognosis after STEMI were considered in the multivariable Cox regression analyses model: age, gender, Killip's class, LVEF, AST, neutrophil count, albumin, serum calcium level, emergency revascularization. The multivariable analyses were performed in 2 separate multivariable Cox models, with serum calcium entered as continuous data, or stratified by quartiles. All P-values were 2-tailed and P-value<0.05 was considered statistically significant.In this present study, a total of 1431 patients admitted to our department with STEMI were enrolled, and the information about serum calcium of each patient was available at the time of hospital admission. The admission serum calcium levels were normally distributed  with a mThe in-hospital management and mortality of patients according to serum calcium quartiles are listed in The present study was conducted to evaluate the relationship between the admission serum calcium levels and in-hospital mortality of 1431 consecutive patients with STEMI. The result of this study documented that a decreased baseline serum calcium level measured on admission was associated with higher in-hospital all-cause mortality, even after adjusting for the possible confounding predictors. The highest mortality was observed among patients with serum calcium concentration less than 2.14 mmol/L. These findings highlighted that declined serum calcium concentration is a predictor of short term mortality for STEMI rather than just a marker of an acute medical condition. Although there was a significant higher frequency of some cardiovascular risk factors in patients with low serum calcium level, it did not interfere with the significant prognostic effect of serum calcium on in-hospital mortality among STEMI patients in the multivariable analysis.A considerable number of clinical studies have suggested that hypocealcemia is a common electrolyte disturbance among critically ill patients and it has been shown to be associated with increased mortality Calcium plays a critical role in osteogenic function, signalling function The mechanism which may account for the association between the admission serum calcium levels and in-hospital mortality with STEMI was unknown. However, intracellular calcium overload may play a key role. Intracellular calcium acts as a second messenger A large number of studies reached the conclusion that calcium intake were associated with the incidence of heart disease The advantages of our study are a large patient population and the comprehensive available laboratory data, but there are still some limitations in our present study. First, our study protocol is designed as a retrospective, observational, and single-center study rather than a prospective multi-center cohort study. Second, as some sufferers who died before reaching hospital, and these missing data may lead to an underestimated mortality rate in patients with STEMI. Finally, the mechanism of the associations between hypocalcaemia and in-hospital mortality in STEMI is still unclear. Although serum calcium concentration is significantly associated with in-hospital mortality in STEMI in the present study, the clinical significance of this finding needs further investigation.Serum calcium was an independent predictor for in-hospital mortality in STEMI patients. This widely available serum biochemical index may help identify high-risk STEMI individuals, who might benefit from more aggressive interventions. However, the actual pathophysiologic mechanism and whether patients with hypocalcaemia could benefit from calcium supplement requires further study.


TopHat is a popular spliced junction mapper for RNA sequencing data, and writes files in the BAM format – the binary version of the Sequence Alignment/Map (SAM) format. BAM is the standard exchange format for aligned sequencing reads, thus correct format implementation is paramount for software interoperability and correct analysis. However, TopHat writes its unmapped reads in a way that is not compatible with other software that implements the SAM/BAM format.We have developed TopHat-Recondition, a post-processor for TopHat unmapped reads that restores read information in the proper format. TopHat-Recondition thus enables downstream software to process the plethora of BAM files written by TopHat.https://github.com/cbrueffer/tophat-recondition.TopHat-Recondition can repair unmapped read files written by TopHat and is freely available under a 2-clause BSD license on GitHub: The online version of this article (doi:10.1186/s12859-016-1058-x) contains supplementary material, which is available to authorized users. RNA sequencing (RNA-seq) has become as a cornerstone of genomics research. TopHat and TopHat2 , 2 (joinTopHat writes read data in the BAM format – the binary version of the Sequence Alignment/Map (SAM) format , but unlhttp://broadinstitute.github.io/picard), SAMtools [However, all released versions of TopHat to date (version ≤ 2.1.1) generate unmapped.bam files that are incompatible with common downstream software, e.g., the Picard suite  and requires Python 2.6 or higher. The simplified workflow of the software is shown in Fig. TopHat-Recondition is implemented in Python using the Pysam library (https://samtools.github.io/hts-specs/SAMv1.pdf), divergences from the specification’s recommended practices, and different interpretation of acceptable values for some of the file format’s fields between software.TopHat’s unmapped.bam incompatibility with other tools has three origins: software bugs resulting in violations of the SAM/BAM specification  in their FLAGS field. This leads to downstream software incorrectly assuming the reads to be mapped. Second, for unmapped reads where the FLAGS field declares the paired read to be mapped, this mapped paired read may be missing from the sequence files. This makes the unmapped read’s fields invalid and can lead to software searching for, and failing to find the paired read.The SAM/BAM specification contains a section on recommended practices for implementing the format. For read-pairs with one mapped and one unmapped read, TopHat does not follow the recommendations that RNAME and POS of the unmapped read should have the same field values as the mapped read. Additionally we found that setting RNEXT to the mapped read’s RNEXT value, and PNEXT to 0 improves compatibility.Lastly, there are differing interpretations of which field values are acceptable in certain conditions between software packages. For example, the valid range of values for the BAM mapping quality (MAPQ) is 0-255. For unmapped reads, TopHat always sets the MAPQ value of unmapped reads to 255, and BWA  sets theSome BAM-processing software, e.g., Picard and GATK can be configured to accept reads that do not conform to its expectations by ignoring errors, thus allowing processing to succeed. However, the resulting BAM files remain non-compliant to the specification which can lead to issues in later analysis steps that are difficult to debug.The occurrence of these problems is dependent on both the sequencing depth and the percentage of unmapped reads in the dataset; a higher value in either category can result in a higher rate of errors.TopHat-Recondition either repairs or works around these problems, which allows processing to complete with all SAM/BAM-compliant software without relying on reducing strictness requirements.Usage information and a walk-through example can be found in Additional file TopHat-Recondition enables easy and fast post-processing for TopHat unmapped reads. The tool can be used to process TopHat-written unmapped reads to make them compatible with downstream tools such as samtools, the Picard suite and GATK, which is currently not possible with the stock unmapped reads. This will increase the utility of the immense amount of RNA-seq data that has been analyzed by TopHat.Project name: TopHat-ReconditionProject home page:https://github.com/cbrueffer/tophat-reconditionOperating system(s): Platform independentProgramming language: PythonOther requirements: PysamLicense: 2-clause BSDAny restrictions to use by non-academics: none


Web queries are now widely used for modeling, nowcasting and forecasting influenza-like illness (ILI). However, given that ILI attack rates vary significantly across ages, in terms of both magnitude and timing, little is known about whether the association between ILI morbidity and ILI-related queries is comparable across different age-groups. The present study aimed to investigate features of the association between ILI morbidity and ILI-related query volume from the perspective of age.Since Google Flu Trends is unavailable in Italy, Google Trends was used to identify entry terms that correlated highly with official ILI surveillance data. All-age and age-class-specific modeling was performed by means of linear models with generalized least-square estimation. Hold-out validation was used to quantify prediction accuracy. For purposes of comparison, predictions generated by exponential smoothing were computed.Five search terms showed high correlation coefficients of > .6. In comparison with exponential smoothing, the all-age query-based model correctly predicted the peak time and yielded a higher correlation coefficient with observed ILI morbidity (.978 vs. .929). However, query-based prediction of ILI morbidity was associated with a greater error. Age-class-specific query-based models varied significantly in terms of prediction accuracy. In the 0–4 and 25–44-year age-groups, these did well and outperformed exponential smoothing predictions; in the 15–24 and ≥ 65-year age-classes, however, the query-based models were inaccurate and highly overestimated peak height. In all but one age-class, peak timing predicted by the query-based models coincided with observed timing.The accuracy of web query-based models in predicting ILI morbidity rates could differ among ages. Greater age-specific detail may be useful in flu query-based studies in order to account for age-specific features of the epidemiology of ILI. Seasonal influenza is a relatively predictable annual event which causes approximately half a million deaths worldwide every year . It is wad hoc search terms. Indeed, as of February 2015, GFT is available in only 29 countries. While most of the above-mentioned studies confirmed the utility of flu query-based surveillance by documenting a high correlation and prediction accuracy, others pointed out some major limitations .To date (February 2015), GFT is not available in Italy. Query volume (QV) was therefore assessed by means of GT. On GT, weekly search volume data from October 2011 to February 2015 were extracted ; these were regarded as ILI morbidity data. GT analyzes selected web queries (provided that their search volume is sufficient) and displays the results on a normalized scale ranging from 0 to 100 . Search nd week of 2011 to 41st week of 2014)—and a hold-out validation set (the remaining 19 weeks). Since the dependent variable “ILI morbidity” was highly positively skewed, the square-root transformation was applied in order to obtain a more symmetric distributions. Modeling of QV data may be challenging, owing to the serial correlation of residuals [p, q) autoregressive-moving-average (ARMA) process (where p and q determine the order of the process) were constructed. Model selection was performed in two main steps. Firstly, the best subset of independent variables—i.e. the one that minimized the corrected Akaike Information Criterion (AICc)—was identified among all possible regressions estimated by means of an ordinary least squares (OLS) approach. If two or more competing models showed approximately equal AICc (Δ AICc < 2), the more/most parsimonious one was preferred. Secondly, to find an optimal  order for the ARMA process, residual autocorrelations of the preliminary OLS model were examined by plotting autocorrelation and partial autocorrelation functions [r. The difference in the prediction accuracy of GLS and exponential smoothing models was formally tested by means of the Diebold-Mariano test. Statistical significance was set to two-sided p < .05 All data analyses and modeling were performed by means of the R stats package, version 3.1.2 [Pearson’s correlation coefficient with 95% confidence intervals (CIs) was used to evaluate the correlation between the relative QV and ILI morbidity. The whole dataset was split into a training set—comprising three years  showed high correlation coefficients of > .6 with CIRI-IT morbidity data. These five entry terms were therefore reinserted into GT all together and their relative QV was downloaded.The QV of 18 individual search terms was retrieved . Of thesInfluenza, Fever and Tachipirina and residuals followed the ARMA process. The maximum likelihood estimation of the error-autoregressive parameter was sizable. During the validation stage, prediction based on the selected QV model was associated with greater errors (Δ RMSE 27%) in comparison with Holt-Winters exponential smoothing (th week), although the height of the peak was significantly underestimated . Full model specifications and parameter estimates are reported in Table A in p = .036). In the 0–4-year age-class, the QV-based model outperformed the competing model in predicting the peak magnitude and only slight (< 5%) incidence overestimation was observed  to those generated by the Holt-Winters models. Similarly, in other age-groups , the prediction accuracy of QV-based models did not differ significantly from that of exponential smoothing, although the former tended to overestimate and the latter to underestimate ILI peak activity. Despite an observed tendency of QV-based models to overestimate ILI incidence  than in the previous three seasons, and was at the level recorded in the 2010/2011 post-pandemic period. GFT underestimation of ILI activity was also seen earlier; the original GFT model underestimated ILI at the beginning of the last pandemic [Some important remarks and comparisons with previous research regarding the accuracy of our estimates of all-age ILI morbidity should be made. GFT has been shown to have significantly overestimated CDC data in the consecutive influenza seasons 2011/2012 , 2012/20pandemic , 33. Altpandemic , 56.Influenza, is highly correlated with official surveillance data; this is in line with previous research conducted in different settings [Flu and both ILI morbidity and virological surveillance was much lower, or even negative, in the 2008/09 influenza season. A similarly low strength of correlation between the search term Flu and ILI attack rates was reported in Southern China [Bird flu or Tamiflu, which proved to be highly correlated with both virological and syndromic surveillance data. Again, such inconsistence may be due to the different study periods, since both Asian studies included the pandemic period, which could affect search behavior. Indeed, in our study, the QV of H1N1 was insufficient on a weekly basis, while in both Asian studies this entry term was investigated. Another possible explanation may regard cross-cultural differences and variations in the Internet penetration rate.More generally, as far as we know this is the first study to investigate the application and utility of GT QV for near-real-time ILI surveillance in Italy. Overall, our correlation analysis revealed that ILI-related QV, especially settings –29. Howesettings , 24 fromsettings , the corrn China  and KangInfluenza without quotation marks, for example, will also include related searches, such as I’ve got influenza, Influenza symptoms or Influenza remedies. Third, our models did not take into account media activity, which may lead to an increase in ILI-related searches [th week (last week of November) of 2014. In Italy, a series of alleged post-flu shot deaths were reported in the elderly in this period  and on November 27 two batches of a vaccine were suspended for precautionary purposes [Apart from the well-known shortcomings of web-based surveillance methods, which are described elsewhere , 57, thesearches . For inssearches . Our QV-purposes . On the purposes , the webIn conclusion, it is unlikely that web-based techniques of ILI surveillance will substitute traditional surveillance methods in the near future and the former should be seen as a low-cost near-real-time complementary source to the latter. In Italy, digital ILI detection may have a certain value: among users of the Influweb portal, only 55% and 4% phoned and visited, respectively, their GP during an ILI episode . A betteS1 File(PDF)Click here for additional data file.


To investigate the association between insulin resistance (IR) and urinary incontinence in Korean adult women by analyzing the data from the Korea National Health and Nutrition Examination Survey IV (KNHANES) 2007–2009A nationally representative sample of 5318 non-diabetic Korean women ≥19-years-of-age  was included from KNHANES 2008–2010. IR was measured using the homeostasis model assessment of IR (HOMA-IR). Participants in the highest and lowest quartile of HOMA-IR were defined as insulin-resistant and insulin-sensitive respectively. Women who have current physician-diagnosed urinary incontinence were classified as having urinary incontinence.Incontinence was found in 9.18% of the total population, 8.51% of the premenopausal population, and 10.86% of the postmenopausal population. The prevalence of incontinence increased with age, reaching a peak at 60-69-years-of-age. The prevalence of urinary incontinence increased significantly with higher HOMA-IR quartiles in pre- and post-menopausal women (p for linear association = 0.0458 and 0.0009 respectively). Among post-menopausal women, those in the highest quartile of HOMA-IR were significantly more likely to have urinary incontinence compared to those in the lowest quartile . However premenopausal population exhibited no association between incontinence and HOMA-IR quartilesOur results suggest that the prevalence of incontinence increased across HOMA-IR in non-diabetic adult women, and especially, IR might be a risk factor for incontinence in postmenopausal non-diabetic women. Urinary incontinence is a major health issue for women, which diminishes their quality of life (QoL). In addition, this condition exacts emotional and hygienic impairments and economic expense ,2.Although several risk factors including body mass index (BMI), age, number of birth deliveries, and menopause have been suggested ,4, furthMetabolic disturbances including hyperglycemia, hyperinsulinemia, and insulin resistance (IR) are associated with the risk of lower urinary tract symptoms (LUTS) –9. The pResearch to date has focused on males. Data from females are scant. Moreover, the association between IR and urinary incontinence has not been investigated. We hypothesized that IR is associated with urinary incontinence. The aim of this study was to explore the association between IR and urinary incontinence among Korean adult women, using the homeostasis model assessment (HOMA) to assess IR.This study used the data from the Korea National Health and Nutrition Examination Survey IV (KNHANES) 2007–2009. KNHANES is a cross-sectional, nationally representative sample of the Korean non-institutionalized civilian population. and employs a rolling sampling design that uses a complex, stratified, multistage probability sample design. It constitutes a health interview, health examination, laboratory, and nutrition surveys. The study population for this analysis included adults ≥19-years-of-age who participated in all three parts of the survey. Subjects with diabetes mellitus or who were missing data on urinary incontinence or fasting plasma glucose or serum insulin were excluded. Participants who reported cessation of menstruation for more than 1 year formed the postmenopausal population. Women using hormone therapy, pregnant women, and women with premature menopause (before 40-years-of-age) or surgical menopause were excluded. The final study cohort included 5318 women . This study was approved by the Institutional Review Board of the Catholic University of Korea.th percentile, 50th percentile and 75th percentile was 1.667, 2.076, and 2.657, respectively.All general data including socioeconomic, lifestyle, and clinical variables have been fully described previously . The defIndividuals were classified as having urinary incontinence if they answered yes to the survey question "Do you have physician-diagnosed urinary incontinence?” Study participants were instructed that this question dealt with uncontrolled loss of urine in any situation accompanied by coughing, straining, sneezing, exercising, or feelings of urgency or pressure.SAS version 9.2  was used for statistical analysis, using KNHANES sampling weights to acquire nationally representative estimates. The data in this study are presented as the mean ± SE or proportions (SE) for continuous or categorical variables respectively. The characteristics of subjects were compared according to menopausal status. Variables with skewed distributions were analyzed after logarithmic transformations. The prevalence of urinary incontinence was analyzed by general linear model, according to age and the HOMA-IR quartiles in subgroups: pre-menopausal and post-menopausal population. Multivariable logistic regression analyses were applied to examine the association between insulin resistance and urinary incontinence according to the HOMA-IR quartiles by menopausal status. The adjusted odds ratio (aOR) of urinary incontinence was calculated using the insulin-sensitive group as the reference. Calculations were made, adjusting for age, BMI, smoking, drinking, exercise, education, income, hypertension, and parity. A p-value <0.05 was considered statistically significantIncontinence was found in 9.18% of total population, 8.51% of the premenopausal population, and 10.86% of postmenopausal population. The prevalence of incontinence increased with age, reaching a peak at 60-69-years-of-age (p for linear association < 0.0001). In the st quartile of HOMA-IR  and the highest in the 4TH quartile of HOMA-IR  in both groups  was the lowest in 1h groups . A statih groups .The main findings of this study are as follows: (1) the prevalence of incontinence increased across the HOMA-IR quartiles, regardless of the menopause state. (2) postmenopausal non-diabetic women in the higher quartile of HOMA-IR were more likely to be incontinent compared to counterparts in the lowest quartile independent of age, BMI, smoking, drinking, exercise, education, income, and hypertension. (3) elevation of IR is implicated as a risk factor of incontinence in postmenopausal non-diabetic women.The underlying pathophysiology for these findings can be partly explained by the effect of IR on neurologic function, oxidative stress, and muscle mass and function IR may be important in the damage of neuronal function and pathogenesis of neurologic injury ,17. InsuAnother possible explanation is that IR is closely related to increased oxidative stress due to mitochondrial dysfunction along with decreased mitochondrial size and mitochondrial DNA content ,20. IR cIt is also possible that the loss of muscle mass due to IR might be independently associated with urinary incontinence. Recent compelling evidence concerning IR indicated that loss of skeletal muscle is an independent risk factor for the loss of skeletal muscle mass ,23. The The distinctive feature of our study is that it is the first population-based study to suggest a significant association between IR and urinary incontinence in postmenopausal, non-diabetic Korean adults who participated in KNHANES 2008–2010. Although there is only one study regarding the association between diabetes and urinary incontinence, which study reported that diabetes is not independently associated with female incontinence , ActuallThe other distinctive feature of the study is that analyses involved a nationally representative Korean population. The prevalence of urinary incontinence varies across racial and ethnic groups –31, AlthLimitations of this study should be considered. One is the definition of urinary incontinence, which was from self-reported questionnaires; the definition to be used varied with each study. The NHANES definitions relied on an affirmative answer to the question “During the past 12 months, have you leaked or lost control of even a small amount of urine”, while for KNHANES incontinence was defined as a yes answer to the question to be uses is “Do you have physician-diagnosed urinary incontinence?” A considerable number of women with urinary incontinence would feel too shameful to go see a doctor and talk about their incontinence symptom. For these reason, the total burden of urinary incontinence in the study population could be substantially underestimated. This difference of definitions accounts for the higher prevalence in the US survey. But we enrolled participants with physician-diagnosed urinary incontinence to overcome the limitation from the quality of the answers, which may incur excessive impairment due to memorial and individual matters of the participants. The definition for urinary incontinence could vary according to survey. Urinary incontinence is divided into three major subtypes by the International Continence Society: stress urinary incontinence, urge urinary incontinence, and mixed urinary incontinence. We could not provide a subanalysis according to these subtypes, because subtype information is not available in KNHANES. In addition,The other limitation is that KNHANES used the HOMA-IR index to evaluate IR, although the hyperinsulinemic–euglycemic glucose clamp, which can be prohibitively expensive and complex, is the gold standard for insulin sensitivity. However, HOMA-IR shows a high correlation with the hyperinsulinemic–euglycemic glucose clamp and can be reliably used in large-scale or epidemiological studies in which only a fasting blood sample is available to assess insulin sensitivity . The biaThe prevalence of incontinence increased across the HOMA-IR quartiles in non-diabetic adult women. Especially, Postmenopausal women in the higher quartile of HOMA-IR were more likely to have incontinence compared to counterparts in their lowest quartile independent of other risk factors. There may be a significant difference by menopausal status in the association between IR and urinary incontinence in non-diabetic adult women. So, elevation of IR might be a risk factor for incontinence in postmenopausal non-diabetic adult women.


The results indicated that BMP-2 on BMP-g-nHA/PLGA hybrid nanofiber scaffolds greatly stimulated osteoblastic cells growth, contrary to the nHA/PLGA and pristine PLGA nanofiber scaffold, which are used as control. These results suggest that BMP-g-nHA/PLGA hybrid nanofiber scaffold can be used as a nanodrug carrier for the controlled and targeted delivery of BMP-2, which will open new possibilities for enhancing bone tissue regeneration and will help in the treatment of various bone-related diseases in the future.Biomaterials play a pivotal role in regenerative medicine, which aims to regenerate and replace lost/degenerated tissues or organs. Natural bone is a hierarchical structure, comprised of various cells having specific functions that are regulated by sophisticated mechanisms. However, the regulation of the normal functions in damaged or injured cells is disrupted. In order to address this problem, we attempted to artificially generate a scaffold for mimicking the characteristics of the extracellular matrix at the nanoscale level to trigger osteoblastic cell growth. For this purpose, we have chemically grafted bone morphogenetic protein (BMP-2) onto the surface of L-glutamic acid modified hydroxyapatite incorporated into the PLGA nanofiber matrix. After extensive characterization using various spectroscopic techniques, the BMP-g-nHA/PLGA hybrid nanofiber scaffolds were subjected to various  Th. Th4−3 ctively,  23, 24], 244−3 ctively,  showed anHA/PLGA  showed ascaffold . The red of PLGA .An ESCA survey scan was conducted to confirm the presence of pristine nHA and nHA-g in the PLGA nanofiber. The photoelectron signals of nitrogen (N1s) and sulfur (S2p) were considered as the markers of choice for the confirmation of successful grafting of BMP-2 to nHA-g embedded in the PLGA nanofiber , 23. TheThe changes in the chemical composition of pristine PLGA, nHA/PLGA, and BMP-g-nHA/PLGA scaffolds were calculated from the ESCA survey scan spectra. From The grafting of BMP-2 onto the surface of nHA-g embedded into PLGA nanofiber was further confirmed by protein labeling using FITC fluorescent dye. Mostly cells anchorage is dependent on the cell fate process such as proliferation, migration, and differentiation, whereas apoptosis is dependent on the cell adhesion pattern to the artificial/mimic scaffolds. The BrdU assay was performed to calculate the number of newly synthesized DNA by the osteoblastic cells, which were seeded on the pristine PLGA, nHA/PLGA, and BMP-g-nHA/PLGA hybrid nanofiber scaffolds. The actin microfilament comprising the cytoskeleton of the cells is involved in the cellular processes, cell shape determination, and cell attachment pattern. As the cell adheres to a substrate material, filopodia are formed. They are moved into place by actin acting upon the plasma membrane –27.  FigFor analyzing the osteogenic cells, mineralization is assumed to be of prime importance since it is regarded as a functional endpoint for representing cell differentiation. Alizarin red staining is famously known as a marker for the quantification of calcium and evaluation of differentiation , 22.  FiBone nodule formation is considered to be a marker specific to osteoblastic cell differentiation . In FiguBMP-2 was successfully grafted to the nHA/PLGA to prepare BMP-g-nHA/PLGA hybrid nanofibers scaffold. The hybrid nanofiber scaffold was extensively characterized using spectroscopic methods such as FE-SEM, TEM, FTIR, XPS, and FITC labeling to confirm the fibrous morphologies of the scaffolds, presence of nHA in the scaffolds, and grafting of BMP-2 to nHA/PLGA and examine the effect of the grafted BMP-2 on the cellular function. The hybrid nanofiber scaffolds were subjected to the cell adhesion, proliferation, and differentiation. More MC3T3-E1 osteoblastic cells were proliferated on the BMP-g-nHA/PLGA nanofiber scaffold on the contrary to the nHA/PLGA hybrid nanofiber scaffold. In addition, the results obtained from alizarin red and Von Kossa assay confirmed that cells cultured on the BMP-g-nHA/PLGA scaffold produced calcium more effectively than those cultured on the pristine PLGA and nHA/PLGA hybrid nanofiber scaffold, indicating better differentiation of the osteoblastic cells. The results suggested that the BMP-g-nHA/PLGA hybrid nanofiber scaffold has a potential to be used as tissue engineering scaffold for stimulating osteoblastic cells growth.


Conflicting renal effects of nesiritide have been reported in patients with acute decompensated heart failure. To answer this controversy, we performed a meta-analysis of randomized controlled trials to evaluate the influence of nesiritide on renal function in patients with acute decompensated heart failure.Articles were obtained from PubMed, Medline, Cochrane Library and reference review. Randomized controlled studies that investigated the effects of continuous infusion of nesiritide on renal function in adult patients with acute decompensated heart failure were included and analyzed. Fixed-effect model was used to estimate relative risk (RR) and weight mean difference (WMD). The quality assessment of each study, subgroup, sensitivity, and publication bias analyses were performed.P = 0.023). In subgroup analysis, high-dose nesiritide strongly associated with renal dysfunction , but no statistical differences were observed in standard-dose , low-dose groups  and same results were identified in the subgroup analysis of placebo controlled trials. Peak mean change of serum creatinine from baseline was no significant difference .Fifteen randomized controlled trials were eligible for inclusion. Most of included studies had relatively high quality and no publication bias was found. Overall, compared to control therapies, nesiritide might increase the risk of worsening renal function in patients with acute decompensated heart failure (RR 1.08, 95% CI 1.01–1.15, In our meta-analysis, nesiritide may have a dose-dependent effect on renal function in patients with acute decompensated heart failure. High-dose nesiritide is likely to increase the risk of worsening renal function, but standard-dose and low-dose nesiritide probably have no impact on renal function. These findings could be helpful to optimize the use of nesiritide in clinical practice. Worsening renal function (WRF) is prevalent in patients with acute decompensated heart failure (ADHF), and it may independently predict a worse outcome as well as increase the mortality of ADHF patients –3. HenceNesiritide, a recombinant B-type natriuretic peptide (BNP) with a potent vasodilatory property, has been approved for the treatment of ADHF, on the basis of its ability to reduce pulmonary-capillary wedge pressure and improve dyspnea , 5. AftePertinent articles were systematically searched  in PubMed, Medline and Cochrane Library by two trained investigators. The following search strategy developed according to Yan et al  was utilAn article was eligible for inclusion if it met the following criteria: 1) original articles; 2) RCT design; 3) adult (age ≥ 18 years) participants with ADHF; 4) nesiritide administered through intravenous infusion; 5) reporting the incidence of WRF or mean change of serum creatinine (SCr) from baseline. Articles which did not meet the aforementioned criteria were excluded from analysis. This meta-analysis was performed according to the Preferred Reporting Items for Meta-Analyses (PRISMA) statement checklist.Two authors independently extracted the pertinent data for the meta-analysis, with divergences resolved by discussion. The following information was abstracted from each study: characteristics of each study , characteristics of participants , intervention and control treatments  and clinical outcomes (incidence of WRF and peak mean change of SCr from baseline during the treatment of nesiritide). If several articles reported the same clinical trial, the one with the most complete data was included in analysis. And if a trial was designed with three or more than three groups, the control group was considered as a whole in the overall analysis and single group was considered separately in subgroup analysis.Two authors independently evaluated, with disagreement resolved by discussion, the risk of bias for the included RCTs in accordance with the following criteria developed by the Cochrane risk of bias tool: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting and other sources of bias.P ≤ 0.10 indicating significant heterogeneity) and I2 test. The relationship between nesiritide and incidence of WRF was analyzed using Mantel-haenszel (M-H) fixed-effect model (FFE) to calculate the relative risk (RR) and 95% confidence interval (CI), when there was no significant heterogeneity among the included studies; otherwise, a random-effect model was chosen. With regard to the analysis of peak mean change of SCr from baseline, inverse variance (IV) fixed-effect model was used to calculate the weight mean difference (WMD) and 95% CI without significant heterogeneity among the included studies; otherwise, a random-effect model was chosen. In order to evaluate the influence of different doses of nesiritide on the incidence of WRF, subgroup stratification analyses were also conducted. Sensitivity analysis was performed to evaluate the stability of results by exclusion of each study one by one. And publication bias was assessed with the use of funnel plots and Egger’s test.All the statistical analyses were performed with the use of STATA 12.0 . Heterogeneity was evaluated using chi-square test . The funnel plot demonstrated a little asymmetry , overall meta-analysis indicated that the use of nesiritide was associated with a significant increase in the risk of WRF . However, there was no significant influence of nesiritide on renal function in the standard-dose group including five RCTs or subgroups . Furthermore, in the low-dose group consisted of four RCTs or subgroups, significantly renal benefit was not observed either .To further investigate the relationship between continuous infusion doses of nesiritide and renal dysfunction, subgroup meta-analysis was performed. Five RCTs administered nesiritide in a high-dose manner. The data of analysis showed that high-dose nesiritide strongly increased the risk of renal dysfunction in patients with ADHF , but neither standard-dose  nor low-dose nesiritide  statistically increased the risk of WRF. Furthermore, to identify whether baseline chronic kidney disease (CKD) could influence the occurrence of WRF in patients with ADHF, a subgroup analysis based on the condition of baseline renal function was carried out. Interestingly, in comparison with control therapies, nesiritide significantly increased the risk of WRF in non-CKD patients  controlled trials to partly exclude the potential drug-drug interactions by removing the active controlled studies which used dobutamine, nitroglycerin or sodium nitroprusside as control treatments. As shown in P = 0.121; 2 = 22.3%, P = 0.252). Funnel plot did not show obvious asymmetry , standard-dose of nesiritide neither deteriorated nor improved the renal function of patients with ADHF. The conclusions of most RCTs included in these subset analyses were in accordance with our result , 17, 22.There are conflicting data about the effect of low-dose nesiritide on renal function. All the RCTs analyzed in our meta-analysis have not found that low-dose nesiritide had a potential to improve renal function in patients with ADHF , 18, 21.Data from our subgroup analysis indicated that nesiritide significantly increased the risk of WRF in non-CKD patients, however the adverse effect was not observed in ADHF patients with pre-existing CKD. This finding is a little confusing. But it was noteworthy that all the studies in CKD group administered nesiritide with either standard or low dose , 16, 22.SCr is still the main biomarker for predicting the renal function of patients . In our All the studies included in our meta-analysis were randomized design and had relatively high quality. Hence, our conclusions were relatively reliable, while there were several limitations in our study. Firstly, small sample size and limited number of clinical trials in subgroup analyses might produce bias. Secondly, the definition of WRF in included studies was not completely consistent, which might result in clinical and statistical heterogeneity. Thirdly, duration of intravenous nesiritide infusion was not same in each study, which might influence the clinical outcome. Fourthly, besides placebo (standard care), the control therapies also included dobutamine, nitroglycerin, and sodium nitroprusside. Therefore drug-drug interactions were not to be fully considered and might impact clinical outcome.In conclusion, the present meta-analysis demonstrates that nesiritide may have a dose-dependent effect on renal function in patients with ADHF. High-dose nesiritide may increase the risk of WRF, but neither standard-dose nor low-dose nesiritide is likely to have a significant impact on renal function in patients with ADHF. These findings could be helpful to optimize the use of nesiritide in clinical practice. In the future, more powered RCTs will be needed to confirm these findings. Additionally, whether low-dose nesiritide could improve the renal function in patients with ADHF also requires to be addressed.S1 PRISMA Checklist(DOC)Click here for additional data file.S1 FileFig A. Funnel plot of included studies for risk of WRF analysis. Fig B. Egger’s publication bias plot of included studies for risk of WRF analysis. Fig C. Funnel plot of included studies for peak mean change of SCr from baseline analysis. Fig D. Egger’s publication bias plot of included studies for peak mean change of SCr from baseline analysis.(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.


Systemic lupus erythematosus (SLE) represents a challenging autoimmune disease from a clinical perspective because of its varied forms of presentation. Although broad-spectrum steroids remain the standard treatment for SLE, they have many side effects and only provide temporary relief from the symptoms of the disease. Thus, gaining a deeper understanding of the genetic traits and biological pathways that confer susceptibility to SLE will help in the design of more targeted and effective therapeutics. Both human genome-wide association studies (GWAS) and investigations using a variety of mouse models of SLE have been valuable for the identification of the genes and pathways involved in pathogenesis. In this Review, we link human susceptibility genes for SLE with biological pathways characterized in mouse models of lupus, and discuss how the mechanistic insights gained could advance drug discovery for the disease. Systemic lupus erythematosus  is a multi-organ autoimmune disease characterized by loss of immunological tolerance, the system that normally protects self-components from attack by its own immune system. The major immunological targets (or autoantigens) are nuclear components of the cell, including double-stranded DNA (dsDNA), chromatin-associated proteins, and Ro (SSA), La (SSB) and Sm, the RNA-associated proteins that are most abundant in the nucleus . Excess Arthralgia:joint pain.Arthritis:a painful condition of inflammation and stiffness of the joints.Complement:a group of proteins present in the blood plasma and tissue fluid that helps and complements the antibody response to clear pathogens from the body.Creatinine:a compound that is produced by metabolism of creatine and excreted in the urine.Cutaneous vasculitis:a condition characterized by inflammation of the wall of skin blood vessels associated with tissue necrosis.Glomerulonephritis:a condition of acute inflammation of the kidney glomerulus, which is often induced by an immune response.Hemolytic anemia:a form of anemia characterized by increased lysis of red blood cells and their subsequent removal from the blood circulation.Hemophagocytic syndrome:a rare hematologic disorder characterized by over-production and activation of lymphocytes and macrophages.Hypergammaglobulinemia:a medical condition associated with elevated levels of IgG in the blood sera.Hyper IgM globulinemia:a medical condition associated with elevated levels of IgM in the blood sera.Immune complex:a molecular complex that forms after the binding of an antibody to a soluble antigen.Immunological tolerance:the failure to induce an immune response to an antigen. When defined as natural or ‘self’ tolerance, it refers to the failure to respond to the body’s own antigens.Lymphoid hyperplasia:a rapid increase in the number of lymphocytes in the lymph nodes.Lymphopenia:a condition associated with abnormally low levels of lymphocytes in the blood.Myositis:inflammation and degeneration of muscle tissue.Proteinuria:the presence of abnormal quantities of proteins in the urine, which can indicate damage to the kidneys.Serositis:inflammation of the body serous tissues that line the lungs, heart, abdomen and inner abdominal organs.Th1/Th2 responses:+ T-cell-mediated immunity can be classified into two types of responses, depending on the profile of secreted cytokines. Type 1 or Th1 responses are generally induced by IFNγ and orchestrate cell-mediated immunity (e.g. enhanced phagocytosis). Type 2 or Th2 responses are commonly mediated by cytokines such as IL-4, IL-5 and IL-13, and drive humoral immunity (molecule-mediated immunity).CD4Thrombocytopenia:a deficiency of platelets in the blood.The relatively high concordance rate between monozygotic twins in SLE indicates a genetic component to SLE susceptibility . A heavyAlthough the onset of lupus is usually between the ages of 16 and 40, a particularly severe form of juvenile lupus can occur before the age of 16 . As mentBecause of the overlap between the many possible symptoms of lupus and other disorders, SLE is difficult to diagnose accurately and, therefore, a complicated disease index system is used . Within Anti-nuclear antibodies (ANAs) are highly prevalent and a major diagnostic marker for lupus. Serum autoantibodies appear as a consequence of systemic B-cell activation that is targeted toward self-specificities, the most common targets being nuclear proteins. IgM antibody isotypes are predominant in the serum of healthy individuals but, in SLE, immunoglobulin isotypes switch to the pathogenic IgGs, which activate inflammatory cells when deposited in tissues. Serum autoantibodies can be detected using an indirect immunofluorescence assay: Hep-2 cells are permeabilized and absorbed with patient sera, then detected with a fluorochrome-labeled secondary antibody. The autoantibody specificities are numerous; however, examples of autoantibodies that are observed before the clinical onset of the disease are: anti-dsDNA, anti-Ro, anti-La, anti-phospholipid, anti-Sm and anti-snRNP . The preLupus nephritis (glomerulonephritis), a key clinical feature of SLE, is thought to involve glomerular inflammation induced by immune complexes and complement deposition: first, immune complexes are formed by excess of antibodies that accumulate in the kidney; then, complement detects antibody aggregates and initiates an activation cascade that recruits monocytes and granulocytes to the site, ultimately causing tissue destruction. This type of nephritis is diagnosed by the presence of biomarkers for kidney damage such as proteinuria, creatinine and blood urea nitrogen .Cutaneous vasculitis and skin rashes are common in SLE. Typical manifestations are a Malar rash (acute), discoid rash (chronic), photosensitivity or oral ulcers .Musculoskeletal inflammation in SLE presents as arthralgias (joint pain), arthritis (inflammation of the joints) and myositis (inflammation of the muscles) . This paHematological abnormalities, such as anemia, leukopenia, lymphopenia or thrombocytopenia, can be seen in various stages of lupus. These blood disorders can appear in the context of hemolytic anemia, hemophagocytic syndrome or can even be induced by treatment .Neuropsychiatric lupus can have multiple presentations, such as headaches, cognitive dysfunction or affective disorders . These shttps://www.rheumatology.org/Practice/Clinical/Indexes/Systemic_Lupus_Erythematosus_Disease_Activity_Index_SELENA_Modification/).Generally, no single test can be used for the diagnosis of SLE. Instead, the presence of the symptoms shown above in various combinations would be used as a diagnostic tool. The more symptoms presented by an affected individual, the higher the score in the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) as defined by the American College of Rheumatology  and New Zealand White (NZW), known as NZB/NZW F1, develop a female gender-biased lupus-like syndrome characterized by lymphadenopathy, splenomegaly, elevated anti-nuclear antibody titers and immune-complex-mediated glomerulonephritis . NeitherSle1, a congenic strain on the C57BL/6 background containing chromosome 1 derived from NZM2410, develops autoantibodies against subnucleosomes, and displays spontaneous T-cell activation in the absence of renal disease  mice . Of thes disease . A secon disease . Interes disease .lpr phenotype) occurred during inbreeding; this mutation was later identified as a retrotransposon insertion that disrupts the Fas gene , which has been described in some cases in association with human SLE  strain, which does not develop spontaneous disease but is permissive of disease induced by monogenetic alterations . Thus, dFollowing completion of the human genome sequencing effort, various genome-wide association studies (GWAS) have been conducted on patient populations to pinpoint single-nucleotide polymorphisms (SNPs) associated with autoimmune disease . With thHLA) region on chromosome 6 in humans and ‘histocompatibility 2′ (H-2) region on chromosome 17 in mice contain the highly polymorphic major histocompatibility complex (MHC) genes as well as other immunologically important genes , in which the above-mentioned zE and zA transgenics were made, demonstrates that the b allele is linked very strongly to autoantibody production . This contribution of the bH-2 allele to disease may explain why C57BL/6 is the most common background of lupus-prone knockout and transgenic models.In mice, the contribution of MHC haplotype to disease was first reported in the NZB/NZW F1 model . These se in NZB . MoreoveHLA risk haplotypes seem to be more strongly predictive of autoantibody specificity than disease pathogenesis. For example, individuals with the compound heterozygous risk alleles HLA-DR2/HLA-DR3 are more likely to have autoantibodies against Ro, La and Sm, irrespective of an SLE diagnosis  accelerates the production of anti-dsDNA antibodies, but this has no effect on mortality (HLA haplotypes) that are present both in mice and humans are not necessarily the sole factors in determining end-organ pathogenesis.iagnosis . Furtherhe serum . This ocortality . These dSAP-knockout mice have a severe defect in humoral immunity that was found to be due solely to the lack of SAP expression in T cells (SLAM-deficient T cells fail to help B cells produce IgG antibodies in vitro (SAP-deficient mice were found to be protected from autoimmunity in a TLR7-induced model (Sle1 locus develop spontaneous T-cell activation and autoantibody formation (Sle1 region encodes Ly108 (slamf6), another member of the SLAM family, which is implicated in autoimmunity in mice  family are receptors that regulate lymphocyte activation by coupling the effector SLAM-associated protein (SAP) to downstream signaling.  T cells . Additioin vitro . SAP-defed model . These rormation . The Sle in mice . Differe in mice .Ly9 has also been identified in a cohort of SLE patients , was positively associated with susceptibility to lupus  or cytoplasmic (e.g. RIG-I–MDA5–STING) pathways. One potential outcome of engaging these DNA- and RNA-sensing receptors is IRF-dependent production of IFN-I  of B and T cells have the potential to promote autoimmunity. Mice expressing a human transgene encoding the pro-survival gene position . On the  disease . BCL2 lewith SLE . In addiwith SLE . Transgewith SLE . The diswith SLE .Bcl2 transgene, underscoring the importance of both of these pathways in tolerance (p21−/− mice develop lupus in C57BL/6 but are protected from autoimmunity in BXSB strains (P21 are positively associated with lupus nephritis (GADD45 (Gadd45a-deficient mice develop a lupus-like syndrome with unrestricted T-cell proliferation (Gadd45a−/−p21−/− mice develop more severe accelerated disease, suggesting that the two genes play non-redundant roles in the development of SLE (Alterations in cell cycle checkpoints could lead to unrestricted division of cells with autoreactive potential and thus increase the risk of developing SLE. Deficiency of p21, an inhibitor of cyclin-dependent kinases that is essential for cell cycle arrest, leads to T-and B-cell autoimmunity and kidney disease . The effolerance . The gen strains . In humaephritis . An addi (GADD45 . Gadd45aferation . Althougt of SLE .c-Mer-deficient mice display defective phagocytosis of apoptotic cells and, over time, develop autoantibodies against DNA, chromatin and IgG (DNASE1 mutations and lowered DNASE1 expression in diseased kidneys of both individuals with SLE and lupus-prone mice have been described (Apoptotic cells containing nuclear material are a potential source of antigen that can drive TLR activation and autoreactive antibody production in lupus. For example,  and IgG . Clearanescribed . Ineffecescribed .Given the heterogeneous nature of SLE, it has been difficult to design therapies that alleviate all aspects of the disease. Current treatments with steroids aim at total immunomodulation and trigger a variety of side effects when administered on a long-term basis . The hopRegarding therapies that target autoreactive lymphocyte activation, blocking T-cell help with CTLA4Ig, an immunosuppressive agent, was successful in mice , and thiOverall, the variety of mouse models provides a useful toolbox for the analysis of genetic and environmental factors that affect immune-cell activation and self-reactivity. Perhaps the limitation of current mouse models seems to reside in the lack of models that show a flare-and-wane-type of chronic disease that is most common in human SLE: all mouse models represent severe cases with increased severity of pathology over time. Thus, one of the future goals of mouse models of SLE should be to address the heterogeneity in disease course that characterizes human SLE.