Severely destructive unilateral wrist arthritis as a rare variant of rheumatoid arthritis: analysis of clinical and imaging features.

OBJECTIVES: Rheumatoid arthritis (RA) is a common autoimmune disease typically affecting joints symmetrically. A small number of patients develop unilateral and severely destructive wrist arthritis (DWA). The objective of our study was to characterise patients with this type of affection. METHODS: This was a retrospective cohort study of RA patients with positive RF/anti-CCP antibodies. Clinical characteristics, including, age, gender, disease duration, dexterity, occupational history, smoking status, and the number of prescribed DMARDs were recorded. Conventional radiographs were evaluated using the modified Sharp/van der Heijde scoring (mSS) method. RESULTS: We analysed our laboratory database of 1247 patients and identified 559 patients with a clinical diagnosis of RA. For 395 of the patients, radiographs of the hands were available for evaluation. 25 patients had extensive unilateral DWA, corresponding to a prevalence of 6.3% (25 of 395 patients). 11 patients were excluded due to incomplete data. Of the remaining 14 patients, 13 were female with a median age of 61 (33-83) years, and median disease duration of 18 (1-33) years. 8 of 11 (72.7%) patients were smokers; in three, smoking status was not known. 80% with known dexterity developed unilateral DWA in the dominant hand. Total mSS was significantly higher on the affected side (39, interquartile range 35.25-46.25) versus non-affected (13, IQR 3-23). MSS were not different if the carpal bones were excluded from scoring. Side of involvement (left vs. right), or dominant versus non-dominant hand, did not result in a different mSS. CONCLUSIONS: Unilateral DWA is a rare variant of RA which predominantly affects women who smoke.

Antisynthetase Syndrome-Associated Interstitial Lung Disease: Monitoring of Immunosuppressive Treatment Effects by Chest Computed Tomography.

Background: Antisynthetase syndrome (ASyS) is a rare autoimmune disease characterized by inflammatory myopathy, arthritis, fever, and interstitial lung disease (ILD). Pulmonary involvement in ASyS significantly increases morbidity and mortality and, therefore, requires prompt and effective immunosuppressive treatment. Owing to the rarity of ASyS, limited data exists on progression and prognosis of ILD under immunosuppression. Objectives: The objective of the study was to evaluate the radiological progression and outcome measures of ILD with immunosuppressive therapy in patients with ASyS. Methods: Twelve patients with ASyS-associated ILD (ASyS-ILD) were included. Demographic and clinical data, including organ involvement, pulmonary function tests (PFT), laboratory parameters, imaging studies, and treatment regimens were retrospectively analyzed from routinely collected data. The extent of ground glass opacities, fibrotic changes and honeycombing was analyzed and scored using high-resolution chest computed tomography (HRCT) scans. HRCT findings were compared between baseline and follow-up examinations. In addition, patients were stratified depending on whether they had received rituximab (RTX) or not. Results: Pulmonary function tests revealed stable lung function and follow-up HRCT scans showed an improvement of radiological alterations in the majority of ASyS patients under immunosuppressive therapy. We did not detect significant differences between the RTX- and non-RTX-treated groups, but the RTX-treated patients more frequently had myositis and relapsing disease. Conclusions: Radiographic alterations in ASyS-associated ILD respond to immunosuppressive treatment. RTX is a feasible treatment option with similar clinical and radiographic outcomes in patients with relapsing disease and clinically apparent myositis.

The "rapid atrial swirl sign" for assessing central venous catheters: Performance by medical residents after limited training.

RATIONALE: Central venous catheter (CVC) placement is a standard procedure in critical care. Ultrasound guidance during placement is recommended by current guidelines, but there is no consensus on the best method for evaluating the correct CVC tip position. Recently, the "rapid atrial swirl sign" (RASS) has been investigated in a limited number of studies. OBJECTIVES: We performed a prospective diagnostic accuracy study of focused echocardiography for the evaluation of CVC tip position in our medical ICU and IMC units. METHODS: We performed a prospective diagnostic accuracy study in 100 patients admitted to the Intensive Care Unit and Intermediate Care Unit at our center. The first 10 subjects were assessed by one staff physician investigator (reference cohort), the remaining 90 patients by different residents (test cohort). All patients received a post-procedural chest radiograph (CXR) as gold standard. CVC placement was assessed with focused echocardiography performed by residents after a short training session. A rapid opacification of the right atrium (RASS) after injection of 10 mL of normal saline was regarded as "positive", flush after more than two seconds was defined as "delayed", no flush was a "negative" test result. MEASUREMENTS AND MAIN RESULTS: Overall sensitivity of the RASS was 100% (95% CI 73.54-100%), specificity was 94.32% (CI 87.24-98.13%). Positive and negative predictive values were 70.59% (CI 44.04-89.09%) and 100% (CI 95.65-100%), respectively. Median time for echocardiographic testing was 5 minutes (1-28) in the whole cohort, CXRs were available after 49.5 minutes (13-254). Interrater agreement of the RASS was 0.77 (Cohen's kappa), Measurement of CVC tip position was not different between two observers. Test characteristics were similar among differently experienced residents. CONCLUSIONS: Presence of the RASS by focused echocardiography showed excellent sensitivity and specificity and was equally performed by residents after minimal training. In patients with a positive RASS, routine CXR can be safely omitted, reducing time, costs and radiation exposure. A negative RASS should lead to a search for misplaced catheters. CLINICAL TRIAL REGISTRATION: The study was registered with www.clinicaltrials.gov (NCT02661607).

Dental and periodontal health, and microbiological and salivary conditions in patients with or without diabetes undergoing haemodialysis.

OBJECTIVE: The aim of this cross-sectional study was to evaluate the dental and periodontal health, as well as the microbiological and salivary conditions, of patients with and without diabetes mellitus (DM) who are receiving haemodialysis. METHODS: One-hundred and fifty-nine haemodialysis patients were included and divided into groups according to the pre-existing diabetes status: DM or no DM. The oral examination included dental findings and assessment of the periodontal situation. The periodontal condition was classified as healthy/mild, moderate or severe periodontitis. Subgingival biofilm samples were analysed using the polymerase chain reaction. The salivary diagnostics included measurement of unstimulated and stimulated salivary flow, pH and buffer capacity. Statistical analyses used Fisher's test, the t-test and the Mann-Whitney U-test (α = 5%). RESULTS: The dental findings showed no significant difference between patients with and without DM (P = 0.44). The prevalence of periodontitis was high (96% in patients with DM and 97% in patients who did not have DM) and there was no significant difference between the groups (P = 0.71). There was a higher prevalence of Porphyromonas gingivalis, Parvimonas micros, Eubacterium nucleatum and Capnocytophaga spp. in patients without DM (P < 0.05). The salivary pH was significantly higher in patients without DM (P < 0.01). CONCLUSION: While differences in the prevalence of periodontal pathogenic bacteria and in the salivary pH were detected between the groups, the dental and periodontal status was comparable between patients with and without DM. Accordingly, DM appears to have no decisive influence on the oral health in patients treated with haemodialysis who have well-controlled diabetes.

Oral behavior, dental, periodontal and microbiological findings in patients undergoing hemodialysis and after kidney transplantation.

BACKGROUND: Aim of this single center cross-sectional study was to investigate oral behavior, dental, periodontal and microbiological findings in patients undergoing hemodialysis (HD) and after kidney transplantation (KT). METHODS: Patients undergoing HD for end-stage renal failure and after KT were investigated. Oral health behavior was recorded using a standardized questionnaire, e.g. dental behavior, tooth brushing, oral hygiene aids. Oral investigation included screening of oral mucosa, dental findings (DMF-T) and periodontal situation (Papilla bleeding index [PBI] periodontal probing depth [PPD] and clinical attachment loss [CAL]). Additionally, microbiological analysis of subgingival biofilm samples (PCR) was performed. STATISTICAL ANALYSIS: Student's t-test or Mann-Whitney-U-test, Fisher's exact test (α = 5 %). RESULTS: A total of 70 patients (HD: n = 35, KT: n = 35) with a mean age of 56.4 ± 11.1 (HD) and 55.8 ± 10.9 (KT) years were included. Lack in use of additional oral hygiene (dental floss, inter-dental brush) was found. KT group presented significantly more gingivial overgrowth (p = 0.01). DMF-T was 19.47 ± 5.84 (HD) and 17.61 ± 5.81 (KT; p = 0.21). Majority of patients had clinically moderate and severe periodontitis; showing a need for periodontal treatment of 57 % (HD) and 71 % (KT; p = 0.30). Significantly higher prevalence of Parvimonas micra and Capnocytophaga species in the HD group were found (p < 0.01). CONCLUSION: Periodontal treatment need and lack in oral behavior for both groups indicate the necessity of an improved early treatment and prevention of dental and periodontal disease, e.g. in form of special care programs. Regarding microbiological findings, no major differences between KT and HD patients were found.

Vimentin fragments are potential markers of rheumatoid synovial fibroblasts.

OBJECTIVES: To study the protein expression differences between primary fibroblasts explanted from synovial membranes of patients with rheumatoid arthritis (RA) and osteoarthritis (OA). METHODS: Fibroblast cultures were obtained from 10 patients with RA and 5 patients with OA. After two-dimensional gel electrophoresis, proteins were excised and identified using peptide mass fingerprint. Expression of selected proteins was subsequently examined by immunoblot. Furthermore, we examined the cellular lysates for the presence of citrullinated proteins. RESULTS: The study was designed to compare expression changes of the common proteins detected in all studied fibroblast cultures (i.e. detected in all patients samples). We totally identified 191 shared proteins between RA and OA fibroblasts. A significant difference was defined as at least 2-fold upregulation or 0.6-fold downregulation of protein expression. The most obvious alteration observed in RA was the appearance of several vimentin fragments not present in OA. We did not detect citrullinated proteins in lysates from RA fibroblasts. This corroborates the current assumption that fibroblasts are not able to citrullinate proteins by themselves and that invading macrophages play a central role in this process. CONCLUSIONS: We demonstrated that fibroblasts from patients with RA, despite being grown under identical conditions, preserve a particular feature and generate vimentin fragments not present in fibroblasts from OA. Elevated levels of different vimentin fragments have been recently reported in several rheumatic conditions. Further studies are needed to elucidate the pathogenic mechanisms induced by vimentin fragments in RA.

Peroxisomes and Kidney Injury.

SIGNIFICANCE: Peroxisomes are organelles present in most eukaryotic cells. The organs with the highest density of peroxisomes are the liver and kidneys. Peroxisomes possess more than fifty enzymes and fulfill a multitude of biological tasks. They actively participate in apoptosis, innate immunity, and inflammation. In recent years, a considerable amount of evidence has been collected to support the involvement of peroxisomes in the pathogenesis of kidney injury. RECENT ADVANCES: The nature of the two most important peroxisomal tasks, beta-oxidation of fatty acids and hydrogen peroxide turnover, functionally relates peroxisomes to mitochondria. Further support for their communication and cooperation is furnished by the evidence that both organelles share the components of their division machinery. Until recently, the majority of studies on the molecular mechanisms of kidney injury focused primarily on mitochondria and neglected peroxisomes. CRITICAL ISSUES: The aim of this concise review is to introduce the reader to the field of peroxisome biology and to provide an overview of the evidence about the contribution of peroxisomes to the development and progression of kidney injury. The topics of renal ischemia-reperfusion injury, endotoxin-induced kidney injury, diabetic nephropathy, and tubulointerstitial fibrosis, as well as the potential therapeutic implications of peroxisome activation, are addressed in this review. FUTURE DIRECTIONS: Despite recent progress, further studies are needed to elucidate the molecular mechanisms induced by dysfunctional peroxisomes and the role of the dysregulated mitochondria-peroxisome axis in the pathogenesis of renal injury. Antioxid. Redox Signal. 25, 217-231.

The Role of CHI3L1 (Chitinase-3-Like-1) in the Pathogenesis of Infections in Burns in a Mouse Model.

In severe burn injury the unique setting of a depleted, dysfunctional immune system along with a loss of barrier function commonly results in opportunistic infections that eventually proof fatal. Unfortunately, the dynamic sequence of bacterial contamination, colonization and eventually septic invasion with bacteria such as Pseudomonas species is still poorly understood although a limiting factor in clinical decision making. Increasing evidence supports the notion that inhibition of bacterial translocation into the wound site may be an effective alternative to prevent infection. In this context we investigated the role of the mammalian Chitinase-3-Like-1 (CHI3L1) non-enyzmatic protein predominately expressed on epithelial as well as innate immune cells as a potential bacterial-translocation-mediating factor. We show a strong trend that a modulation of chitinase expression is likely to be effective in reducing mortality rates in a mouse model of burn injury with superinfection with the opportunistic PA14 Pseudomonas strain, thus demonstrating possible clinical leverage.

The Secretome of Hydrogel-Coembedded Endothelial Progenitor Cells and Mesenchymal Stem Cells Instructs Macrophage Polarization in Endotoxemia.

UNLABELLED: : We previously reported the delivery of endothelial progenitor cells (EPCs) embedded in hyaluronic acid-based (HA)-hydrogels protects renal function during acute kidney injury (AKI) and promotes angiogenesis. We attempted to further ameliorate renal dysfunction by coembedding EPCs with renal mesenchymal stem cells (MSCs), while examining their paracrine influence on cytokine/chemokine release and proinflammatory macrophages. A live/dead assay determined whether EPC-MSC coculturing improved viability during lipopolysaccharide (LPS) treatment, and HA-hydrogel-embedded delivery of cells to LPS-induced AKI mice was assessed for effects on mean arterial pressure (MAP), renal blood flow (RBF), circulating cytokines/chemokines, serum creatinine, proteinuria, and angiogenesis (femoral ligation). Cytokine/chemokine release from embedded stem cells was examined, including effects on macrophage polarization and release of proinflammatory molecules. EPC-MSC coculturing improved stem cell viability during LPS exposure, an effect augmented by MSC hypoxic preconditioning. The delivery of coembedded EPCs with hypoxic preconditioned MSCs to AKI mice demonstrated additive improvement (compared with EPC delivery alone) in medullary RBF and proteinuria, with comparable effects on serum creatinine, MAP, and angiogenesis. Exposure of proinflammatory M1 macrophages to EPC-MSC conditioned medium changed their polarization to anti-inflammatory M2. Incubation of coembedded EPCs-MSCs with macrophages altered their release of cytokines/chemokines, including enhanced release of anti-inflammatory interleukin (IL)-4 and IL-10. EPC-MSC delivery to endotoxemic mice elevated the levels of circulating M2 macrophages and reduced the circulating cytokines/chemokines. In conclusion, coembedding EPCs-MSCs improved their resistance to stress, impelled macrophage polarization from M1 to M2 while altering their cytokine/chemokines release, reduced circulating cytokines/chemokines, and improved renal and vascular function when MSCs were hypoxically preconditioned. SIGNIFICANCE: This report provides insight into a new therapeutic approach for treatment of sepsis and provides a new and improved strategy using hydrogels for the delivery of stem cells to treat sepsis and, potentially, other injuries and/or diseases. The delivery of two different stem cell lines (endothelial progenitor cells and mesenchymal stem cells; delivered alone and together) embedded in a protective bioengineered scaffolding (hydrogel) offers many therapeutic benefits for the treatment of sepsis. This study shows how hydrogel-delivered stem cells elicit their effects and how hydrogel embedding enhances the therapeutic efficacy of delivered stem cells. Hydrogel-delivered stem cells influence the components of the overactive immune system during sepsis and work to counterbalance the release of many proinflammatory and prodamage substances from immune cells, thereby improving the associated vascular and kidney damage.

Modulation of cellular stress response via the erythropoietin/CD131 heteroreceptor complex in mouse mesenchymal-derived cells.

Tissue-protective properties of erythropoietin (EPO) have let to the discovery of an alternative EPO signaling via an EPO-R/CD131 receptor complex which can now be specifically targeted through pharmaceutically designed short sequence peptides such as ARA290. However, little is still known about specific functions of alternative EPO signaling in defined cell populations. In this study, we investigated effects of signaling through EPO-R/CD131 complex on cellular stress responses and pro-inflammatory activation in different mesenchymal-derived phenotypes. We show that anti-apoptotic, anti-inflammatory effects of ARA290 and EPO coincide with the externalization of CD131 receptor component as an immediate response to cellular stress. In addition, alternative EPO signaling strongly modulated transcriptional, translational, or metabolic responses after stressor removal. Specifically, we saw that ARA290 was able to overcome a TNFα-mediated inhibition of transcription factor activation related to cell stress responses, most notably of serum response factor (SRF), heat shock transcription factor protein 1 (HSF1), and activator protein 1 (AP1). We conclude that alternative EPO signaling acts as a modulator of pro-inflammatory signaling pathways and likely plays a role in restoring tissue homeostasis. Key message: Erythropoietin (EPO) triggers an alternative pathway via heteroreceptor EPO/CD131. ARA290 peptide specifically binds EPO/CD131 but not the canonical EPO/EPO receptor. Oxidative stress and inflammation promote cell surface expression of CD131. ARA290 prevents tumor necrosis factor-mediated inhibition of stress-related genes. Alternative EPO signaling modulates inflammation and promotes tissue homeostasis.

Curtailing endothelial TGF-ß signaling is sufficient to reduce endothelial-mesenchymal transition and fibrosis in CKD.

Excessive TGF-ß signaling in epithelial cells, pericytes, or fibroblasts has been implicated in CKD. This list has recently been joined by endothelial cells (ECs) undergoing mesenchymal transition. Although several studies focused on the effects of ablating epithelial or fibroblast TGF-ß signaling on development of fibrosis, there is a lack of information on ablating TGF-ß signaling in the endothelium because this ablation causes embryonic lethality. We generated endothelium-specific heterozygous TGF-ß receptor knockout (TßRII(endo+/-)) mice to explore whether curtailed TGF-ß signaling significantly modifies nephrosclerosis. These mice developed normally, but showed enhanced angiogenic potential compared with TßRII(endo+/+) mice under basal conditions. After induction of folic acid nephropathy or unilateral ureteral obstruction, TßRII(endo+/-) mice exhibited less tubulointerstitial fibrosis, enhanced preservation of renal microvasculature, improvement in renal blood flow, and less tissue hypoxia than TßRII(endo+/+) counterparts. In addition, partial deletion of TßRII in the endothelium reduced endothelial-to-mesenchymal transition (EndoMT). TGF-ß-induced canonical Smad2 signaling was reduced in TßRII(+/-) ECs; however, activin receptor-like kinase 1 (ALK1)-mediated Smad1/5 phosphorylation in TßRII(+/-) ECs remained unaffected. Furthermore, the S-endoglin/L-endoglin mRNA expression ratio was significantly lower in TßRII(+/-) ECs compared with TßRII(+/+) ECs. These observations support the hypothesis that EndoMT contributes to renal fibrosis and curtailing endothelial TGF-ß signals favors Smad1/5 proangiogenic programs and dictates increased angiogenic responses. Our data implicate endothelial TGF-ß signaling and EndoMT in regulating angiogenic and fibrotic responses to injury.

High-mobility group box 1 is a novel deacetylation target of Sirtuin1.

High-mobility group box 1 (HMGB1) undergoes acetylation, nuclear-to-cytoplasmic translocation, and release from stressed kidneys, unleashing a signaling cascade of events leading to systemic inflammation. Here, we tested whether the deacetylase activity of Sirtuin1 (SIRT1) participates in regulating nuclear retention of HMGB1 to ultimately modulate damage signaling initiated by HMGB1 secretion during stress. When immunoprecipitated acetylated HMGB1 was incubated with SIRT1, HMGB1 acetylation decreased by 57%. Proteomic analysis showed that SIRT1 deacetylates HMGB1 at four lysine residues (55, 88, 90, and 177) within the proinflammatory and nuclear localization signal domains of HMGB1. Genetic ablation or pharmacological inhibition of SIRT1 in endothelial cells increased HMGB1 acetylation and translocation. In vivo, deletion of SIRT1 reduced nuclear HMGB1 while increasing its acetylation and release into circulation during basal and ischemic conditions, causing increased renal damage. Conversely, resveratrol pretreatment led to decreased HMGB1 acetylation, its nuclear retention, decreased systemic release, and reduced tubular damage. Thus, a vicious cycle is set into motion in which the inflammation-induced repression of SIRT1 disables deacetylation of HMGB1, facilitates its nuclear-to-cytoplasmic translocation, and systemic release, thereby maintaining inflammation.

Sirtuin 1 ablation in endothelial cells is associated with impaired angiogenesis and diastolic dysfunction.

Discordant myocardial growth and angiogenesis can explain left ventricular (LV) hypertrophy progressing toward heart failure with aging. Sirtuin 1 expression declines with age; therefore we explored the role played by angiogenesis and Sirtuin 1 in the development of cardiomyopathy. We compared the cardiac function of 10- to 15-wk-old (wo), 30-40 wo, and 61-70 wo endothelial Sirtuin 1-deleted (Sirt1(endo-/-)) mice and their corresponding knockout controls (Sirt1(Flox/Flox)). After 30-40 wk, Sirt1(endo-/-) animals exhibited diastolic dysfunction (DD), decreased mRNA expression of Serca2a in the LV, and decreased capillary density compared with control animals despite a similar VEGFa mRNA expression. However, LV fibrosis and hypoxia-inducible factor (HIF)1α expression were not different. The creation of a transverse aortic constriction (TAC) provoked more severe DD and LV fibrosis in Sirt1(endo-/-) compared with control TAC animals. Although the VEGFa mRNA expression was not different and the protein expression of HIF1α was higher in the Sirt1(endo-/-) TAC animals, capillary density remained reduced. In cultured endothelial cells administration of Sirtuin 1 inhibitor decreased mRNA expression of VEGF receptors FLT 1 and FLK 1. Ex vivo capillary sprouting from aortic explants showed impaired angiogenic response to VEGF in the Sirt1(endo-/-) mice. In conclusion, the data demonstrate 1) a defect in angiogenesis preceding development of DD; 2) dispensability of endothelial Sirtuin 1 under unstressed conditions and during normal aging; and 3) impaired angiogenic adaptation and aggravated DD in Sirt1(endo-/-) mice challenged with LV overload.