Repolarization dispersion in patients with systemic sclerosis.

OBJECTIVE: Systemic sclerosis (SSc) is associated with increased cardiac morbidity and mortality. Whether some electrocardiographic markers of arrhythmias predispose to early cardiogenic death in SSc remains controversial. This study evaluated the occurrence of previously reported as well as unstudied markers of repolarization in patients with SSc and assessed their prognostic implications. METHODS: A total of 21 patients with SSc and 31 unaffected controls were included in this prospective study. Electrocardiograms were conducted under strict standards. Repolarization and dispersion parameters and markers of late ventricular potentials were determined using designated computer software. Results of multiple beats were averaged. RESULTS: There were no significant differences between the SSc and control groups in average QT intervals, average corrected QT intervals, average QT interval dispersion (QTd), average QT corrected dispersion (QTcd), and QT dispersion ratio. However, average QT apex dispersion, average JT dispersion, average JT corrected dispersion, and Tpeak-Tend corrected were significantly higher in patients with SSc than in controls. Late ventricular potentials were not found in patients with SSc or in controls. Increased QTd and QTcd were recorded in 1 patient who experienced ventricular arrhythmia before inclusion in the study. None of the remaining patients with SSc or the controls developed arrhythmia during the 9-year follow-up. CONCLUSION: Abnormal repolarization parameters may be observed in patients with SSc. However, their prognostic significance with regard to increased risk for repolarization-associated ventricular arrhythmias and increased cardiac death could not be determined in this study. Our findings endorse additional studies on this matter.

Blockade of CCL24 with a monoclonal antibody ameliorates experimental dermal and pulmonary fibrosis.

OBJECTIVES: We aimed to assess the expression of the CCL24 chemokine in systemic sclerosis (SSc) and to evaluate the possible pathogenic implications of the CCL24/CCR3 axis using both in vitro and in vivo models. We further investigated the efficacy of an anti-CCL24 monoclonal antibody (mAb), CM-101, in inhibiting cell activation as well as dermal and pulmonary inflammation and fibrosis in experimental animal models. METHODS: We used ELISA and fluorescence immunohistochemistry to determine CCL24 levels in serum and CCL24/CCR3 expression in skin biopsies of SSc patients. Skin fibroblasts and endothelial cells treated with CCL24 or SSc serum with or without CM-101 were used to follow cell activation and differentiation. Prevention and treatment in vivo bleomycin (BLM)-induced models were used to evaluate experimental dermal and pulmonary fibrosis progression following treatment with the CM-101 mAb. RESULTS: CCL24 circulating levels were significantly elevated in SSc patients. CCL24/CCR3 expression was strongly increased in SSc skin. Blockade of CCL24 with CM-101 significantly reduced the activation of dermal fibroblasts and their transition to myofibroblasts induced by SSc serum. CM-101 was also able to significantly inhibit endothelial cell activation induced by CCL24. In BLM-induced experimental animal models, CM-101 profoundly inhibited both dermal and pulmonary fibrosis and inflammation. CONCLUSIONS: CCL24 plays an important role in pathological processes of skin and lung inflammation and fibrosis. Inhibition of CCL24 by CM-101 mAb can be potentially beneficial for therapeutic use in SSc patients.

Lysyl oxidase-a possible role in systemic sclerosis-associated pulmonary hypertension: a multicentre study.

OBJECTIVE: Lysyl oxidase (LOX) is an extracellular enzyme that cross-links collagen fibrils. LOX was found to be increased in serum of SSc patients and was suggested to be related to skin fibrosis, yet a vascular source of LOX has been demonstrated in idiopathic pulmonary arterial hypertension (iPAH). We aimed to validate elevated LOX serum levels in SSc and to study its correlation with clinical characteristics and investigate its main source at the tissue level. METHODS: A total of 86 established SSc patients were compared with 86 patients with very early diagnosis of systemic sclerosis (VEDOSS), 110 patients with primary RP (PRP) and 80 healthy controls. LOX serum levels were determined by ELISA. Five lung and 12 skin biopsies from SSc patients were stained for LOX and compared with controls. RESULTS: Serum levels of LOX in SSc were significantly higher than in VEDOSS, PRP and healthy controls (P < 0.001). LOX inversely correlated with the diffusing capacity of the lung for carbon monoxide diffusing capacity (DLCO) in diffuse SSc (r = -0.376, P = 0.02). Patients with moderate to severe estimated systolic PAH had higher LOX levels (P < 0.01). Lung biopsies demonstrated intense LOX staining in SSc patients with PAH that was predominantly located in the endothelium of the remodelled pulmonary vessels. CONCLUSION: Serum LOX levels are increased in established SSc and inversely correlate with the DLCO. LOX is elevated in patients with moderate to severe PAH and is located in the proliferating endothelium in lung arterioles, suggesting a possible role for LOX in SSc-associated PAH.

Rheumatological Assessment Is Important for Interstitial Lung Disease Diagnosis.

OBJECTIVE: Interstitial lung diseases (ILD) form a diverse group of parenchymal lung disorders. Currently, a multidisciplinary team (MDT) including pulmonologists, radiologists, and pathologists is the gold standard for ILD diagnosis. Recently, additional subtypes of connective tissue disease (CTD)-ILD with autoimmune features were defined, making the rheumatological assessment increasingly important. We aimed to assess the effect of adding a rheumatologist to the MDT for routine rheumatology assessment. METHODS: A prospective study that assessed newly diagnosed ILD patients by 2 parallel blinded arms; all patients were evaluated by both MDT (e.g., history, physical examination, blood tests, pulmonary function tests, and biopsies, if needed) and a rheumatologist (e.g., history, physical examination, blood and serological tests). RESULTS: Sixty patients were assessed with the mean age of 67.3 ± 12 years, 55% male, and 28% smokers. The rheumatological assessment reclassified 21% of the idiopathic pulmonary fibrosis as CTD. Moreover, the number of CTD-ILD with autoimmune features was increased by 77%. These included antineutrophil cytoplasmic antibody-associated vasculitis, antisynthetase syndrome, and IgG4-related ILD. Retrospectively, rheumatological evaluation could have saved 7 bronchoscopies and 1 surgical biopsy. CONCLUSION: Adding routine rheumatology assessments could significantly increase diagnostic accuracy and reduce invasive procedures.

Sarcoidosis in Israel: Clinical Outcome Status, Organ Involvement, and Long-Term Follow-Up.

PURPOSE: Sarcoidosis is a chronic granulomatous inflammatory disease of unknown etiology with heterogeneous outcomes. This study reviewed the clinical outcome status (COS) and organ involvement of Israeli sarcoidosis patients during a five-year period. Further, we compared our results to the 'World Association of Sarcoidosis and Other Granulomatous Disease' (WASOG) COS and the 'A Case Control Etiologic Study of Sarcoidosis' (ACCESS) instruments in order to evaluate their relevance to the Israeli population. METHODS: The retrospective study group consisted of 166 sarcoidosis patients for the period of 2010-2015. Data on demographic characteristics, presenting symptoms, co-morbidities, disease duration, lung function tests, treatment program, chest X-ray, and chest high-resolution computed tomography were collected. RESULTS: The median patient age was 62 ± 14, which was significantly higher than the WASOG and ACCESS cohorts (p < 0.0001), and the average disease duration was 9.8 ± 7.5 years. Resembling the ACCESS cohort, most patients were women (67.5%). The majority of patients suffered from constitutional symptoms (86%), as well as from respiratory symptoms (38.5%). Similarly to the ACCESS cohort, 91% of patients presented with lung involvement. However, significant differences in the involvement of other organs were noted, including lymph nodes (3 vs. 15.2%), liver (3.6 vs. 11.5%), CNS (7.2 vs. 4.6%), and joints (3.6 vs. 0.5%). In addition, significant differences were observed in the COS of the Israeli population in comparison to the WASOG data (p < 0.01). CONCLUSIONS: Sarcoidosis in Israel is a unique and challenging disease with its clinical presentations that differ from previously reported studies.

Modular 'click-in-emulsion' bone-targeted nanogels.

A new class of nanogel demonstrates modular biodistribution and affinity for bone. Nanogels, ∼70 nm in diameter and synthesized via an astoichiometric click-chemistry in-emulsion method, controllably display residual, free clickable functional groups. Functionalization with a bisphosphonate ligand results in significant binding to bone on the inner walls of marrow cavities, liver avoidance, and anti-osteoporotic effects.

Poly(methyl methacrylate) grafting onto stainless steel surfaces: application to drug-eluting stents.

Drug-eluting stents (DESs) have been associated with adverse clinical effects. Moreover, recent publications have shown that the coating of DESs suffers from defects. The purpose of this contribution is to examine a three-step process for surface modification as a means of improving the durability of DESs. In the first step, 4-(2-bromoethyl)benzenediazonium tetrafluoroborate was electrografted onto a stainless steel (SS) stent. X-ray photoelectron spectroscopy (XPS) of the modified stent confirmed the formation of the organic layer. In the second step, methyl methacrylate was polymerized onto the grafted surface by atom-transfer radical polymerization. XPS, electrochemical impedance spectroscopy, and contact-angle measurements were used to characterize the polymer brushes. The last step involved spray-coating of the stent with a drug-in-polymer matrix [poly(n-butyl methacrylate)/poly(ethylene-co-vinyl acetate) + paclitaxel]. Scanning electron microscopy confirmed the considerably improved durability of the drug-in-polymer matrix. Bare controls showed greater cracking and delamination of the coating than did the two-step modified stents after incubation under physiological (37 degrees C) and accelerated (60 degrees C) conditions. Finally, paclitaxel controlled release from the modified SS DESs was moderate compared with that of nontreated samples. In conclusion, the proposed method significantly improves the durability of drug-in-polymer matrixes on a SS DESs.

Severe gastrointestinal inflammation in adult dermatomyositis: characterization of a novel clinical association.

OBJECT: Gastrointestinal involvement in adult dermatomyositis (DM) and polymyositis (PM) is usually mild, resulting from myoenteric dismotility. Severe inflammation of the alimentary tract in cases of adult DM and PM is rare. The purpose of this study was to examine the prevalence and clinical characteristics of inflammatory gastrointestinal involvement in patients with DM. METHODS: The charts of all cases with polymyositis or dermatomyositis, registered in our rheumatology clinic between 1984 and 2004, were reviewed retrospectively for documentation of severe gastrointestinal involvement. The clinical course and the histopathologic findings in all the patients were noted, and the prevalence of this disorder was computed. RESULTS: Among 48 patients with DM or PM, 3 patients with DM and severe gastrointestinal tract manifestations were identified (6% of the study population). Edematous hyperemic bowel wall, with multiple erosions and ulcerous lesions were the prominent endoscopic findings, whereas diffuse mucosal inflammation and multiple vascular ectasias without vasculitis dominated the histologic picture. The resulting clinical course was notable for recurrent abdominal pain and bloody diarrhea, ending catastrophically in two patients with fatal gastrointestinal perforations, despite aggressive immunosuppressive therapy. CONCLUSIONS: Severe inflammatory gastrointestinal tract disease should be recognized as a grave, albeit rare, manifestation of adult DM that portends a poor prognosis and carries a high rate of fatal complications. The role of vasculopathy in the pathogenesis of this syndrome remains to be determined.

Methotrexate enhances the anti-inflammatory effect of CF101 via up-regulation of the A3 adenosine receptor expression.

Methotrexate (MTX) exerts an anti-inflammatory effect via its metabolite adenosine, which activates adenosine receptors. The A3 adenosine receptor (A3AR) was found to be highly expressed in inflammatory tissues and peripheral blood mononuclear cells (PBMCs) of rats with adjuvant-induced arthritis (AIA). CF101 (IB-MECA), an A3AR agonist, was previously found to inhibit the clinical and pathological manifestations of AIA. The aim of the present study was to examine the effect of MTX on A3AR expression level and the efficacy of combined treatment with CF101 and MTX in AIA rats. AIA rats were treated with MTX, CF101, or both agents combined. A3AR mRNA, protein expression and exhibition were tested in paw and PBMC extracts from AIA rats utilizing immunohistochemistry staining, RT-PCR and Western blot analysis. A3AR level was tested in PBMC extracts from patients chronically treated with MTX and healthy individuals. The effect of CF101, MTX and combined treatment on A3AR expression level was also tested in PHA-stimulated PBMCs from healthy individuals and from MTX-treated patients with rheumatoid arthritis (RA). Combined treatment with CF101 and MTX resulted in an additive anti-inflammatory effect in AIA rats. MTX induced A2AAR and A3AR over-expression in paw cells from treated animals. Moreover, increased A3AR expression level was detected in PBMCs from MTX-treated RA patients compared with cells from healthy individuals. MTX also increased the protein expression level of PHA-stimulated PBMCs from healthy individuals. The increase in A3AR level was counteracted in vitro by adenosine deaminase and mimicked in vivo by dipyridamole, demonstrating that receptor over-expression was mediated by adenosine. In conclusion, the data presented here indicate that MTX induces increased A3AR expression and exhibition, thereby potentiating the inhibitory effect of CF101 and supporting combined use of these drugs to treat RA.

Immunization of naïve mice with mouse laminin-1 affected pregnancy outcome in a mouse model.

PROBLEM: Laminins have important roles during placental and embryonic development. The aim of our study was to determine if active immunization of mice with laminin-1 could elicit an autoimmune response, and induce features of reproductive failure. METHOD OF STUDY: BALB/c mice were immunized with mouse laminin-1. Autoantibodies to laminin-1 were measured by enzyme-linked immunosorbent assay. Pregnant mice were killed on day 14 of pregnancy and examined for pregnancy outcome. RESULTS: Mice immunized with laminin-1 developed elevated levels of anti-laminin-1 auto-antibodies contrary to the control group. A higher fetal resorption rate was found in the laminin-1 immunized group (23.8%) compared with that of the control group (12.2%), and was even higher in the subgroup of those animals with very high levels of anti-laminin-1 (P < 0.01). Laminin-1 immunized mice also had lower fetal and placental weights. CONCLUSIONS: Active immunization with laminin-1 followed by elevated circulating anti-laminin-1 antibodies results in reproductive failure manifested by a higher fetal resorption rate.

[The diverse etiology of hiccups].

Hiccup is a sudden contraction of the inspiratory muscles, followed by an abrupt closure of the glottis, thus producing a characteristic sound. Hiccups serve no known physiologic function. Mostly, it is a benign symptom which terminates without treatment. Persistent and intractable hiccups may indicate an organic disorder, thereby requiring evaluation based on history, physical examination, and selected laboratory tests. The treatment is based on the organic disorder, if it is found. The combination therapy with cisapride, omeprazole and baclofen is the most effective empiric treatment. We describe a number of case reports of patients with hiccups due to digitalis intoxication, ischemia of the inferior wall of the heart, peptic disease and gastroesophageal reflux disease.