Myeloperoxidase:Molecular Mechanisms of Action and Their Relevance to Human Health and Disease

Myeloperoxidase (MPO) is a heme-containing peroxidase abundantly expressed in neutrophils and to a lesser extent in monocytes. Enzymatically active MPO, together with hydrogen peroxide and chloride, produces the powerful oxidant hypochlorous acid and is a key contributor to the oxygen-dependent microbicidal activity of phagocytes. In addition, excessive generation of MPO-derived oxidants has been linked to tissue damage in many diseases, especially those characterized by acute or chronic inflammation. It has become increasingly clear that MPO exerts effects that are beyond its oxidative properties. These properties of MPO are, in many cases, independent of its catalytic activity and affect various processes involved in cell signaling and cell-cell interactions and are, as such, capable of modulating inflammatory responses. Given these diverse effects, an increased interest has emerged in the role of MPO and its downstream products in a wide range of inflammatory diseases. In this article, our knowledge pertaining to the biologic role of MPO and its downstream effects and mechanisms of action in health and disease is reviewed and discussed. Antioxid. Redox Signal. 11, 2899-2937

The Nasal Microbiome in ANCA-Associated Vasculitis:Picking the Nose for Clues on Disease Pathogenesis

PURPOSE OF REVIEW: The onset and progression of small vessel vasculitis associated with anti-neutrophil cytoplasmic antibodies has been linked to microbial infections. Here, we provide a brief overview of the association of nasal colonization of Staphylococcus aureus with ANCA-associated vasculitis (AAV) and discuss several recent studies mapping the nasal microbiome in AAV patients in particular. RECENT FINDINGS: Nasal microbiome studies revealed dysbiosis as a common trait in active AAV which tends to normalize upon immunosuppressive treatment and quiescent disease. However, due to differences in study design, patient selection, and methodology, the reported microbiome profiles differ considerably precluding conclusions on causal relationships. SUMMARY: The microbiome is an emerging area of research in AAV warranting further investigation. Ideally, such studies should be combined with mechanistic studies to unravel key elements related to host-microbe interactions and their relevance for AAV pathogenesis

Obesity-induced chronic inflammation in C57Bl6J mice, a novel risk factor in the progression of renal AA amyloidosis?

Background: Compelling evidence links obesity induced systemic inflammation to the development of chronic kidney disease (CKD). This systemic inflammation may result from exacerbated adipose inflammation. Besides the known detrimental effects of typical pro-inflammatory factors secreted by the adipose tissue (TNF-α, MCP-1 and IL-6) on the kidney, we hypothesize the enhanced obesity-induced secretion of serum amyloid A (SAA), an acute inflammatory protein, to play a key role in aggravating obesity-induced CKD. Methods: Groups of male C57Bl/6J mice (n = 99 in total) were fed a low (10% lard) or high (45% lard) fat diet for a maximum of 52 weeks. Mice were sacrificed after 24, 40 and 52 weeks. Whole blood samples, kidneys and adipose tissues were collected. The development of adipose and renal tissue inflammation was assessed on gene expression and protein level. Adipocytokine levels were measured in plasma samples. Results: A distinct inflammatory phenotype was observed in the adipose tissue of HFD mice prior to renal inflammation, which was associated with an early systemic elevation of TNF-α, leptin and SAA (1A-C). With aging, sclerotic lesions appeared in the kidney, the extent of which was severely aggravated by HFD feeding. Lesions exhibited typical amyloid characteristics (2A) and pathological severity positively correlated with bodyweight (2B). Interestingly, more SAA protein was detected in lesions of HFD mice. Conclusion: Our data suggest a causal link between obesity induced chronic inflammation and AA amyloidosis in C57Bl/6J mice. Though future studies are necessary to prove this causal link and to determine its relevance for the human situation, obesity may hence be considered a risk factor for the development and progression of renal AA amyloidosis in the course of CKD. (Figure Presented)

The dissimilar time course of temporary threshold shifts and reduction of inhibition in the inferior colliculus following intense sound exposure

AbstractExcessive noise exposure is known to produce an auditory threshold shift, which can be permanent or transient in nature. Recent studies showed that noise-induced temporary threshold shifts are associated with loss of synaptic connections to the inner hair cells and with cochlear nerve degeneration, which is reflected in a decreased amplitude of wave I of the auditory brainstem response (ABR). This suggests that, despite normal auditory thresholds, central auditory processing may be abnormal.We recorded changes in central auditory processing following a sound-induced temporary threshold shift. Anesthetized guinea pigs were exposed for 1 h to a pure tone of 11 kHz (124 dB sound pressure level). Hearing thresholds, amplitudes of ABR waves I and IV, and spontaneous and tone-evoked firing rates in the inferior colliculus (IC) were assessed immediately, one week, two weeks, and four weeks post exposure.Hearing thresholds were elevated immediately following overexposure, but recovered within one week. The amplitude of the ABR wave I was decreased in all sound-exposed animals for all test periods. In contrast, the ABR wave IV amplitude was only decreased immediately after overexposure and recovered within a week. The proportion of IC units that show inhibitory responses to pure tones decreased substantially up to two weeks after overexposure, especially when stimulated with high frequencies. The proportion of excitatory responses to low frequencies was increased. Spontaneous activity was unaffected by the overexposure.Despite rapid normalization of auditory thresholds, our results suggest an increased central gain following sound exposure and an abnormal balance between excitatory and inhibitory responses in the midbrain up to two weeks after overexposure. These findings may be associated with hyperacusis after a sound-induced temporary threshold shift

Checks and Balances in Autoimmune Vasculitis

Age-associated changes in the immune system including alterations in surface protein expression are thought to contribute to an increased susceptibility for autoimmune diseases. The balance between the expression of coinhibitory and costimulatory surface protein molecules, also known as immune checkpoint molecules, is crucial in fine-tuning the immune response and preventing autoimmunity. The activation of specific inhibitory signaling pathways allows cancer cells to evade recognition and destruction by the host immune system. The use of immune checkpoint inhibitors (ICIs) to treat cancer has proven to be effective producing durable antitumor responses in multiple cancer types. However, one of the disadvantages derived from the use of these agents is the appearance of inflammatory manifestations termed immune-related adverse events (irAEs). These irAEs are often relatively mild, but more severe irAEs have been reported as well including several forms of vasculitis. In this article, we argue that age-related changes in expression and function of immune checkpoint molecules lead to an unstable immune system, which is prone to tolerance failure and autoimmune vasculitis development. The topic is introduced by a case report from our hospital describing a melanoma patient treated with ICIs and who subsequently developed biopsy-proven giant cell arteritis. Following this case report, we present an in-depth review on the role of immune checkpoint pathways in the development and progression of autoimmune vasculitis and its relation with an aging immune system

Increased frequency of circulating IL-21 producing Th-cells in patients with granulomatosis with polyangiitis (GPA).

INTRODUCTION: The present study aimed to explore a possible role for IL-21 producing Th-cells in the immunopathogenesis of granulomatosis with polyangiitis (GPA). METHODS: Peripheral blood from 42 GPA patients in remission and 29 age-matched healthy controls (HCs) were stimulated in vitro, and the frequencies of IL-21 producing Th-cells were determined by flow cytometry. Since Th17-cells produce a low level of IL-21, IL-17 was also included in the analysis. Given that IL-21 is a hallmark cytokine for T follicular helper cells (T(FH)), we next evaluated the expression of their key transcription factor BCL-6 by RT-PCR and flow cytometry. To investigate the effect of IL-21 on autoantibody-production, PBMCs from GPA patients were stimulated in vitro with BAFF/IL-21 and total IgG and ANCA levels were measured in supernatants. In addition, the expression of IL-21-receptor on B-cells was analyzed. RESULTS: Percentages of IL-21 producing Th-cells were significantly elevated in GPA-patients compared to HCs, and were restricted to ANCA-positive patients. The expression of BCL-6 was significantly higher in ANCA-positive GPA-patients, as compared with ANCA-negative patients and HCs. IL-21 enhanced the production of IgG and ANCA in vitro in stimulated PBMCs from GPA patients. No difference was found in the expression of the IL-21-receptor on B-cells between ANCA-negative patients, ANCA-positive patients, and HCs. CONCLUSION: The increased frequency of circulating IL-21 producing Th-cells in ANCA-positive GPA patients and the stimulating capacity of IL-21 on ANCA-production suggest a role for these cells in the immunopathogenesis of GPA. Blockade of IL-21 could constitute a new therapeutic strategy for GPA

Holistic corpus-based dialectology

This paper is concerned with sketching future directions for corpus-based dialectology. We advocate a holistic approach to the study of geographically conditioned linguistic variability, and we present a suitable methodology, 'corpusbased dialectometry', in exactly this spirit. Specifically, we argue that in order to live up to the potential of the corpus-based method, practitioners need to (i) abandon their exclusive focus on individual linguistic features in favor of the study of feature aggregates, (ii) draw on computationally advanced multivariate analysis techniques (such as multidimensional scaling, cluster analysis, and principal component analysis), and (iii) aid interpretation of empirical results by marshalling state-of-the-art data visualization techniques. To exemplify this line of analysis, we present a case study which explores joint frequency variability of 57 morphosyntax features in 34 dialects all over Great Britain

RHYTHM-AF: design of an international registry on cardioversion of atrial fibrillation and characteristics of participating centers

BACKGROUND Atrial fibrillation is a serious public health problem posing a considerable burden to not only patients, but the healthcare environment due to high rates of morbidity, mortality, and medical resource utilization. There are limited data on the variation in treatment practice patterns across different countries, healthcare settings and the associated health outcomes. METHODS/DESIGN RHYTHM-AF was a prospective observational multinational study of management of recent onset atrial fibrillation patients considered for cardioversion designed to collect data on international treatment patterns and short term outcomes related to cardioversion. We present data collected in 10 countries between May 2010 and June 2011. Enrollment was ongoing in Italy and Brazil at the time of data analysis. Data were collected at the time of atrial fibrillation episode in all countries (Australia, Brazil, France, Germany, Italy, Netherlands, Poland, Spain, Sweden, United Kingdom), and cumulative follow-up data were collected at day 60 (±10) in all but Spain. Information on center characteristics, enrollment data, patient demographics, detail of atrial fibrillation episode, medical history, diagnostic procedures, acute treatment of atrial fibrillation, discharge information and the follow-up data on major events and rehospitalizations up to day 60 were collected. DISCUSSIN A total of 3940 patients were enrolled from 175 acute care centers. 70.5% of the centers were either academic (44%) or teaching (26%) hospitals with an overall median capacity of 510 beds. The sites were mostly specialized with anticoagulation clinics (65.9%), heart failure (75.1%) and hypertension clinics (60.1%) available. The RHYTHM-AF registry will provide insight into regional variability of antiarrhythmic and antithrombotic treatment of atrial fibrillation, the appropriateness of such treatments with respect to outcomes, and their cost-efficacy. Observations will help inform strategies to improve cardiovascular outcomes in patients with atrial fibrillation. TRIAL REGISTRATION Clinical trials NCT01119716Harry JGM Crijns, Lori D Bash, François Chazelle, Jean-Yves Le Heuzey, Thorsten Lewalter, Gregory YH Lip, Aldo P Maggioni, Alfonso Martín, Piotr Ponikowski, Mårten Rosenqvist, Prashanthan Sanders, Mauricio Scanavacca, Alexandra A Bernhardt, Sreevalsa Unniachan, Hemant M Phatak and Anselm K Git

Предсказание торсионных углов в аминокислотных последовательностях белков на основе байесовской процедуры распознавания на цепях Маркова

Запропоновано процедуру розпізнавання торсіонних кутів, утворених C^α атомами чотирьох сусідніх амінокислотних залишків. Отримана послідовність кутів використовується для побудови просторової структури білка на решітці Z³.Torsion angles defined on C^α atoms of four neighbouring residues are predicted using Bayesian pattern recognition procedure on non-stationary Markov chains. The predicted sequence of torsion angles is used for constructing protein 3-dimensional structure on Z³