Dynamic orifice area variations in functional mitral regurgitation: In vivoreproduction and mechanistic insights

Aims: The spinocerebellar ataxia type 2 (SCA2), type 3 (SCA3) and type 7 (SCA7) are clinically characterized by progressive and severe ataxic symptoms, dysarthria, dysphagia, oculomotor impairments, pyramidal and extrapyramidal manifestations and sensory deficits. Although recent clinical studies reported additional disease signs suggesting involvement of the brainstem auditory system, this has never been studied in detail in SCA2, SCA3 or SCA7. Methods: We performed a detailed pathoanatomical investigation of unconventionally thick tissue sections through the auditory brainstem nuclei (that is, nucleus of the inferior colliculus, nuclei of the lateral lemniscus, superior olive, cochlear nuclei) and auditory brainstem fibre tracts (that is, lateral lemniscus, trapezoid body, dorsal acoustic stria, cochlear portion of the vestibulocochlear nerve) of clinically diagnosed and genetically confirmed SCA2, SCA3 and SCA7 patients. Results: Examination of unconventionally thick serial brainstem sections stained for lipofuscin pigment and Nissl material revealed a consistent and widespread involvement of the auditory brainstem nuclei in the SCA2, SCA3 and SCA7 patients studied. Serial brainstem tissue sections stained for myelin showed loss of myelinated fibres in two of the auditory brainstem fibre tracts (that is, lateral lemniscus, trapezoid body) in a subset of patients. Conclusions: The involvement of the auditory brainstem system offers plausible explanations for the auditory impairments detected in some of our and other SCA2, SCA3 and SCA7 patients upon bedside examination or neurophysiological investigation. However, further clinical studies are required to resolve the striking discrepancy between the consistent involvement of the brainstem auditory system observed in this study and the comparatively low frequency of reported auditory impairments in SCA2, SCA3 and SCA7 patients

New insights into the impact of neuro-inflammation in rheumatoid arthritis.

Rheumatoid arthritis (RA) is considered to be, in many respects, an archetypal autoimmune disease that causes activation of pro-inflammatory pathways resulting in joint and systemic inflammation. RA remains a major clinical problem with the development of several new therapies targeted at cytokine inhibition in recent years. In RA, biologic therapies targeted at inhibition of tumor necrosis factor alpha (TNFα) have been shown to reduce joint inflammation, limit erosive change, reduce disability and improve quality of life. The cytokine TNFα has a central role in systemic RA inflammation and has also been shown to have pro-inflammatory effects in the brain. Emerging data suggests there is an important bidirectional communication between the brain and immune system in inflammatory conditions like RA. Recent work has shown how TNF inhibitor therapy in people with RA is protective for Alzheimer's disease. Functional MRI studies to measure brain activation in people with RA to stimulus by finger joint compression, have also shown that those who responded to TNF inhibition showed a significantly greater activation volume in thalamic, limbic, and associative areas of the brain than non-responders. Infections are the main risk of therapies with biologic drugs and infections have been shown to be related to disease flares in RA. Recent basic science data has also emerged suggesting that bacterial components including lipopolysaccharide induce pain by directly activating sensory neurons that modulate inflammation, a previously unsuspected role for the nervous system in host-pathogen interactions. In this review, we discuss the current evidence for neuro-inflammation as an important factor that impacts on disease persistence and pain in RA

Multinational evidence-based recommendations on how to investigate and follow-up undifferentiated peripheral inflammatory arthritis: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative

Methods: 697 rheumatologists from 17 countries participated in the 3E (Evidence, Expertise, Exchange) Initiative of 2008–9 consisting of three separate rounds of discussions and modified Delphi votes. In the first round 10 clinical questions were selected. A bibliographic team systematically searched Medline, Embase, the Cochrane Library and ACR/EULAR 2007–2008 meeting abstracts. Relevant articles were reviewed for quality assessment, data extraction and synthesis. In the second round each country elaborated a set of national recommendations. Finally, multinational recommendations were formulated and agreement among the participants and the potential impact on their clinical practice was assessed. Results: A total of 39 756 references were identified, of which 250 were systematically reviewed. Ten multinational key recommendations about the investigation and follow-up of UPIA were formulated. One recommendation addressed differential diagnosis and investigations prior to establishing the operational diagnosis of UPIA, seven recommendations related to the diagnostic and prognostic value of clinical and laboratory assessments in established UPIA (history and physical examination, acute phase reactants, autoantibodies, radiographs, MRI and ultrasound, genetic markers and synovial biopsy), one recommendation highlighted predictors of persistence (chronicity) and the final recommendation addressed monitoring of clinical disease activity in UPIA. Conclusions: Ten recommendations on how to investigate and follow-up UPIA in the clinical setting were developed. They are evidence-based and supported by a large panel of rheumatologists, thus enhancing their validity and practical use

EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs

Treatment of rheumatoid arthritis (RA) may differ among rheumatologists and currently, clear and consensual international recommendations on RA treatment are not available. In this paper recommendations for the treatment of RA with synthetic and biological disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids (GCs) that also account for strategic algorithms and deal with economic aspects, are described. The recommendations are based on evidence from five systematic literature reviews (SLRs) performed for synthetic DMARDs, biological DMARDs, GCs, treatment strategies and economic issues. The SLR-derived evidence was discussed and summarised as an expert opinion in the course of a Delphi-like process. Levels of evidence, strength of recommendations and levels of agreement were derived. Fifteen recommendations were developed covering an area from general aspects such as remission/low disease activity as treatment aim via the preference for methotrexate monotherapy with or without GCs vis-à-vis combination of synthetic DMARDs to the use of biological agents mainly in patients for whom synthetic DMARDs and tumour necrosis factor inhibitors had failed. Cost effectiveness of the treatments was additionally examined. These recommendations are intended to inform rheumatologists, patients and other stakeholders about a European consensus on the management of RA with DMARDs and GCs as well as strategies to reach optimal outcomes of RA, based on evidence and expert opinion

Biological evaluation of a novel nitroimidazooxazole derivative, IIIM-MCD-019 against Mycobacterium tuberculosis and its in vivo efficacy

Dysphagia, which can lead to nutritional deficiencies, weight loss and dehydration, represents a risk factor for aspiration pneumonia. Although clinical studies have reported the occurrence of dysphagia in patients with spinocerebellar ataxia type 2 (SCA2), type 3 (SCA3), type 6 (SCA6) and type 7 (SCA7), there are neither detailed clinical records concerning the kind of ingestive malfunctions which contribute to dysphagia nor systematic pathoanatomical studies of brainstem regions involved in the ingestive process. In the present study we performed a systematic post mortem study on thick serial tissue sections through the ingestion-related brainstem nuclei of 12 dysphagic patients who suffered from clinically diagnosed and genetically confirmed spinocerebellar ataxias assigned to the CAG-repeat or polyglutamine diseases (two SCA2, seven SCA3, one SCA6 and two SCA7 patients) and evaluated their medical records. Upon pathoanatomical examination in all of the SCA2, SCA3, SCA6 and SCA7 patients, a widespread neurodegeneration of the brainstem nuclei involved in the ingestive process was found. The clinical records revealed that all of the SCA patients were diagnosed with progressive dysphagia and showed dysfunctions detrimental to the preparatory phase of the ingestive process, as well as the lingual, pharyngeal and oesophageal phases of swallowing. The vast majority of the SCA patients suffered from aspiration pneumonia, which was the most frequent cause of death in our sample. The findings of the present study suggest (i) that dysphagia in SCA2, SCA3, SCA6 and SCA7 patients may be associated with widespread neurodegeneration of ingestion-related brainstem nuclei; (ii) that dysphagic SCA2, SCA3, SCA6 and SCA7 patients may suffer from dysfunctions detrimental to all phases of the ingestive process; and (iii) that rehabilitative swallow therapy which takes specific functional consequences of the underlying brainstem lesions into account might be helpful in preventing aspiration pneumonia, weight loss and dehydration in SCA2, SCA3, SCA6 and SCA7 patients

Definition of treatment goals for moderate to severe psoriasis: a European consensus

Patients with moderate to severe psoriasis are undertreated. To solve this persistent problem, the consensus programme was performed to define goals for treatment of plaque psoriasis with systemic therapy and to improve patient care. An expert consensus meeting and a collaborative Delphi procedure were carried out. Nineteen dermatologists from different European countries met for a face-to-face discussion and defined items through a four-round Delphi process. Severity of plaque psoriasis was graded into mild and moderate to severe disease. Mild disease was defined as body surface area (BSA) ≤10 and psoriasis area and severity index (PASI) ≤10 and dermatology life quality index (DLQI) ≤10 and moderate to severe psoriasis as (BSA > 10 or PASI > 10) and DLQI > 10. Special clinical situations may change mild psoriasis to moderate to severe including involvement of visible areas or severe nail involvement. For systemic therapy of plaque psoriasis two treatment phases were defined: (1) induction phase as the treatment period until week 16; however, depending on the type of drug and dose regimen used, this phase may be extended until week 24 and (2) maintenance phase for all drugs was defined as the treatment period after the induction phase. For the definition of treatment goals in plaque psoriasis, the change of PASI from baseline until the time of evaluation (ΔPASI) and the absolute DLQI were used. After induction and during maintenance therapy, treatment can be continued if reduction in PASI is ≥75%. The treatment regimen should be modified if improvement of PASI is <50%. In a situation where the therapeutic response improved ≥50% but <75%, as assessed by PASI, therapy should be modified if the DLQI is >5 but can be continued if the DLQI is ≤5. This programme defines the severity of plaque psoriasis for the first time using a formal consensus of 19 European experts. In addition, treatment goals for moderate to severe disease were established. Implementation of treatment goals in the daily management of psoriasis will improve patient care and mitigate the problem of undertreatment. It is planned to evaluate the implementation of these treatment goals in a subsequent programme involving patients and physicians

NfL and pNfH are increased in Friedreich's ataxia

Objective: To assess neurofilaments as neurodegenerative biomarkers in serum of patients with Friedreich’s ataxia. / Methods: Single molecule array measurements of neurofilament light (NfL) and heavy chain (pNfH) in 99 patients with genetically confirmed Friedreich’s ataxia. Correlation of NfL/pNfH serum levels with disease severity, disease duration, age, age at onset, and GAA repeat length. / Results: Median serum levels of NfL were 21.2 pg/ml (range 3.6–49.3) in controls and 26.1 pg/ml (0–78.1) in Friedreich’s ataxia (p = 0.002). pNfH levels were 23.5 pg/ml (13.3–43.3) in controls and 92 pg/ml (3.1–303) in Friedreich’s ataxia (p = 0.0004). NfL levels were significantly increased in younger patients (age 16–31 years, p < 0.001) and patients aged 32–47 years (p = 0.008), but not in patients of age 48 years and older (p = 0.41). In a longitudinal assessment, there was no difference in NfL levels in 14 patients with repeated sampling 2 years after baseline measurement. Levels of NfL correlated inversely with GAA1 repeat length (r = − 0.24, p = 0.02) but not with disease severity (r = − 0.13, p = 0.22), disease duration (r = − 0.06, p = 0.53), or age at onset (r = 0.05, p = 0.62). / Conclusion: Serum levels of NfL and pNfH are elevated in Friedreich’s ataxia, but differences to healthy controls decrease with increasing age. Long-term longitudinal data are required to explore whether this reflects a selection bias from early death of more severely affected individuals or a slowing down of the neurodegenerative process with age. In a pilot study over 2 years of follow-up—a period relevant for biomarkers indicating treatment effects—we found NfL levels to be stable

Assessing Disease Activity in Psoriatic Arthritis: A Literature Review

Psoriatic arthritis (PsA) is a multifaceted disease, with a high impact on patients’ psychological and physical well-being. There is increasing recognition that assessment of both clinical aspects of disease and patient identified concerns, such as fatigue, work disability, and treatment satisfaction need to be addressed. Only then can we fully understand disease burden and make well-informed treatment decisions aimed at improving patients’ lives. In recent years, there has been much progress in the development of unidimensional and composite measures of disease activity, as well as questionnaires capturing the patient’s perspective in psoriatic disease. Despite these advances, there remains disagreement amongst clinicians as to which instruments should be used. As a consequence, they are yet to receive widespread implementation in routine clinical practice. This review aims to summarize currently available clinical and patient-derived assessment tools, which will provide clinicians with a practical and informative resource

Golimumab in refractory uveitis related to spondyloarthritis. Multicenter study of 15 patients

Objective: To assess the efficacy of golimumab (GLM) in refractory uveitis associated to spondyloarthritis (SpA). Methods: Multicenter study of SpA-related uveitis refractory to at least one immunosuppressive drug. The main outcome variables were degree of anterior and posterior chamber inflammation, visual acuity, and macular thickness. Results: Fifteen patients (13 men/2 women; 18 affected eyes; mean age 39±6 years) were evaluated. The underlying SpA subtypes were ankylosing spondylitis (n=8), psoriatic arthritis (n=6) and non-radiographic axial SpA (n=1). The ocular involvement patterns were recurrent anterior uveitis in 8 patients and chronic anterior uveitis in 7. Before GLM they have received methotrexate (n=13), sulfasalazine (n=6), pulses of methylprednisolone (n=4), azathioprine (n=3), leflunomide (n=2) and cyclosporine (n=1). Ten of them had also been treated with TNF-? blockers; etanercept (n=7), adalimumab (n=7), infliximab (n=6), and certolizumab (n=1). GLM was given at the standard dose (50 mg/sc/monthly) as monotherapy (n=7) or in combination with conventional immunosuppressive drugs (n=8), mainly methotrexate. Most patients had rapid and progressive improvement of intraocular inflammation parameters. The median number of cells in the anterior chamber at 2 years (0 [0-0]) was significantly reduced compared to baseline findings (1 [0-3]); p=0.04). The mean best corrected visual acuity value also improved (0.84±0.3 at 2 years versus 0.62±0.3 at baseline; p=0.03). Only minor side effects were observed after a mean follow-up of 23±7 months. Conclusions: Our results indicate that GLM may be a useful therapeutic option in refractory SpA-related uveitis