Characterization of functioning in multiple sclerosis using the ICF

The objective of this study was to explore whether it is possible to describe based on the International Classification of Functioning, Disability and Health (ICF) relevant aspects of functioning and disability affected in multiple sclerosis (MS) as well as environmental factors relevant to persons with MS. The specific aim was to identify most relevant 'Body functions', 'Body structures', 'Activities and participation', as well as 'Environmental factors' in patients with MS using the ICF. Additionally, different MS forms were compared with respect to the identified problems. A multi-centre study was conducted in an empirical cross-sectional design. Data from 205 individuals with MS were collected in rehabilitation centres: disease related data, socio-demographic data, single interviews based on the Extended ICF Checklist and a patient questionnaire including ratings on general health and functioning status, Beck Depression Inventory II (BDI-II) and Comorbidity Questionnaire (SCQ). The 129 ICF categories identified represent a comprehensive classification of functioning in MS from the clinical perspective. Differences between MS forms were observed for several ICF categories, EDSS, general health and functioning status, but not for BDI and SCQ. The study showed that it is possible to describe based on the ICF the spectrum in functioning and disability affected in MS as well as environmental factors relevant to persons with MS.

The Combination of Interferon-Beta and HMG-CoA Reductase Inhibition in Multiple Sclerosis: Enthusiasm Lost too Soon?

Recent studies support the notion that statins, widely prescribed cholesterol-lowering agents, may target key elements in the immunological cascade leading to inflammation and tissue damage in the pathogenesis of multiple sclerosis (MS). Compelling experimental and observational clinical studies highlighted the possibility that statins may also exert immunomodulatory synergy with approved MS drugs, resulting in several randomized clinical trials testing statins in combination with interferon-beta (IFN-?). Some data, however, suggest that this particular combination may not be clinically beneficial, and might actually have a negative effect on the disease course in some patients with MS. In this regard, a small North American trial indicated that atorvastatin administered in combination with IFN-? may increase disease activity in relapsing-remitting MS. Although other trials did not confirm this finding, the enthusiasm for studies with statins dwindled. This review aims to provide a comprehensive overview of the completed clinical trials and reports of the interim analyses evaluating the combination of IFN-? and statins in MS. Moreover, we try to address the evident question whether usage of this combination routinely requires caution, since the number of IFN-?-treated MS patients receiving statins for lowering of cholesterol is expected to grow.

Intensity-modulated radiotherapy for a rendu-osler-weber disease patient with recurrent severe epistaxis: a case report

We present a case of a Rendu-Osler-Weber disease patient with recurrent life threatening epistaxis demanding multiple blood transfusions despite of repetitive endoscopic laser and electrocoagulations, endovascular embolisation, septodermoplasty, and long-term intranasal dressings. As alternative treatment modalities repeatedly failed and the patient became almost permanently dependent on nasal dressing, we performed a highly conformal intensity-modulated radiotherapy of the nasal cavity; a total dose of 50 Gy in 2 Gy single fractions was applied. The therapy was very well tolerated, no acute toxicities occurred. Two weeks after the last radiation dose had been applied, the nasal dressing could be removed without problems. Endoscopical control revealed an almost avascular white mucosa without any trace of bleeding spots; previously existing hemangiomas and crusts had disappeared. After a 1-year-follow up, the patient had no significant recurrent epistaxis.

Rapid induction of remission in large vessel vasculitis by IL-6 blockade. A case series

OBJECTIVE: To evaluate the effect of IL-6 blockade using tocilizumab in inducing remission of arterial large vessel vasculitides (LVV). METHODS: Five consecutive patients with giant-cell arteritis (GCA) and two with Takayasu’s arteritis (TA) were treated by tocilizumab infusions (8 mg/kg). Tocilizumab was given every other week for the first month and once monthly thereafter. Clinical symptoms of disease activity, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level and glucocorticoid (GC) dosage necessary to maintain remission were prospectively assessed. MR angiography was performed to monitor local inflammation. RESULTS: Of the seven patients three were newly diagnosed and four showed GC resistance, i.e. GC could not be lowered to less than 7.5 mg/day. The mean follow-up time was 4.3 months (range 3–7 months). All patients achieved a rapid and complete clinical response and normalisation of the acute phase proteins. Remarkably, prednisone dosage could be reduced within 12 weeks to a mean of 2.5 mg/day (range 0–10 mg/day). No relapse and no drug-related side effects were noted. CONCLUSION: Collectively the data suggest that IL-6 blockade using tocilizumab qualifies as a therapeutic option to induce rapid remission in large vessel vasculitides.

Symptomatic therapy in multiple sclerosis: a review for a multimodal approach in clinical practice

As more investigations into factors affecting the quality of life of patients with multiple sclerosis (MS) are undertaken, it is becoming increasingly apparent that certain comorbidities and associated symptoms commonly found in these patients differ in incidence, pathophysiology and other factors compared with the general population. Many of these MS-related symptoms are frequently ignored in assessments of disease status and are often not considered to be associated with the disease. Research into how such comorbidities and symptoms can be diagnosed and treated within the MS population is lacking. This information gap adds further complexity to disease management and represents an unmet need in MS, particularly as early recognition and treatment of these conditions can improve patient outcomes. In this manuscript, we sought to review the literature on the comorbidities and symptoms of MS and to summarize the evidence for treatments that have been or may be used to alleviate them.

[Multiple tooth resorption in an Italian greyhound]

An Italian greyhound was presented three times during a two-year period for dental prophylaxis due to periodontal disease. Clinical examination revealed lesions on several teeth. Radiographs revealed extensive resorptive root lesions. On histological examination, the presence of odontoclasts and signs of boney remodeling of the roots confirmed the resorptive nature of the lesions. Given the extent of the lesions, and poor prognosis with conservative treatment alone, teeth affected by the most severe resorption were extracted at each visit using a flap technique combined with alveolar vestibular osteotomy. Dental resorptive lesions are rarely detected in the dog but may be more frequent than previously thought. The routine use of dental radiographs can be used to reveal these lesions in the dog.

Sequence capture and next-generation resequencing of multiple tagged nucleic acid samples for mutation screening of urea cycle disorders

Molecular genetic testing is commonly used to confirm clinical diagnoses of inherited urea cycle disorders (UCDs); however, conventional mutation screenings encompassing only the coding regions of genes may not detect disease-causing mutations occurring in regulatory elements and introns. Microarray-based target enrichment and next-generation sequencing now allow more-comprehensive genetic screening. We applied this approach to UCDs and combined it with the use of DNA bar codes for more cost-effective, parallel analyses of multiple samples.

Long-term clinical outcomes of biodegradable polymer biolimus-eluting stents versus durable polymer sirolimus-eluting stents in patients with coronary artery disease (LEADERS): 4 year follow-up of a randomised non-inferiority trial

Background The effectiveness of durable polymer drug-eluting stents comes at the expense of delayed arterial healing and subsequent late adverse events such as stent thrombosis (ST). We report the 4 year follow-up of an assessment of biodegradable polymer-based drug-eluting stents, which aim to improve safety by avoiding the persistent inflammatory stimulus of durable polymers. Methods We did a multicentre, assessor-masked, non-inferiority trial. Between Nov 27, 2006, and May 18, 2007, patients aged 18 years or older with coronary artery disease were randomly allocated with a computer-generated sequence to receive either biodegradable polymer biolimus-eluting stents (BES) or durable polymer sirolimus-eluting stents (SES; 1:1 ratio). The primary endpoint was a composite of cardiac death, myocardial infarction, or clinically-indicated target vessel revascularisation (TVR); patients were followed-up for 4 years. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00389220. Findings 1707 patients with 2472 lesions were randomly allocated to receive either biodegradable polymer BES (857 patients, 1257 lesions) or durable polymer SES (850 patients, 1215 lesions). At 4 years, biodegradable polymer BES were non-inferior to durable polymer SES for the primary endpoint: 160 (18·7%) patients versus 192 (22·6%) patients (rate ratios [RR] 0·81, 95% CI 0·66–1·00, p for non-inferiority <0·0001, p for superiority=0·050). The RR of definite ST was 0·62 (0·35–1·08, p=0·09), which was largely attributable to a lower risk of very late definite ST between years 1 and 4 in the BES group than in the SES group (RR 0·20, 95% CI 0·06–0·67, p=0·004). Conversely, the RR of definite ST during the first year was 0·99 (0·51–1·95; p=0·98) and the test for interaction between RR of definite ST and time was positive (pinteraction=0·017). We recorded an interaction with time for events associated with ST but not for other events. For primary endpoint events associated with ST, the RR was 0·86 (0·41–1·80) during the first year and 0·17 (0·04–0·78) during subsequent years (pinteraction=0·049). Interpretation Biodegradable polymer BES are non-inferior to durable polymer SES and, by reducing the risk of cardiac events associated with very late ST, might improve long-term clinical outcomes for up to 4 years compared with durable polymer SES. Funding Biosensors Europe SA, Switzerland.

How valuable are multiple treatment comparison methods in evidence-based health-care evaluation?

Objectives To compare the use of pair-wise meta-analysis methods to multiple treatment comparison (MTC) methods for evidence-based health-care evaluation to estimate the effectiveness and cost-effectiveness of alternative health-care interventions based on the available evidence. Methods Pair-wise meta-analysis and more complex evidence syntheses, incorporating an MTC component, are applied to three examples: 1) clinical effectiveness of interventions for preventing strokes in people with atrial fibrillation; 2) clinical and cost-effectiveness of using drug-eluting stents in percutaneous coronary intervention in patients with coronary artery disease; and 3) clinical and cost-effectiveness of using neuraminidase inhibitors in the treatment of influenza. We compare the two synthesis approaches with respect to the assumptions made, empirical estimates produced, and conclusions drawn. Results The difference between point estimates of effectiveness produced by the pair-wise and MTC approaches was generally unpredictable—sometimes agreeing closely whereas in other instances differing considerably. In all three examples, the MTC approach allowed the inclusion of randomized controlled trial evidence ignored in the pair-wise meta-analysis approach. This generally increased the precision of the effectiveness estimates from the MTC model. Conclusions The MTC approach to synthesis allows the evidence base on clinical effectiveness to be treated as a coherent whole, include more data, and sometimes relax the assumptions made in the pair-wise approaches. However, MTC models are necessarily more complex than those developed for pair-wise meta-analysis and thus could be seen as less transparent. Therefore, it is important that model details and the assumptions made are carefully reported alongside the results.

Incidence, predictive factors, and prognosis of chondrosarcoma in patients with Ollier disease and Maffucci syndrome: an international multicenter study of 161 patients

Enchondromatosis is characterized by the presence of multiple benign cartilage lesions in bone. While Ollier disease is typified by multiple enchondromas, in Maffucci syndrome these are associated with hemangiomas. Studies evaluating the predictive value of clinical symptoms for development of secondary chondrosarcoma and prognosis are lacking. This multi-institute study evaluates the clinical characteristics of patients, to get better insight on behavior and prognosis of these diseases.

Associations of Reactive Hyperemia Index and Intravascular Ultrasound-Assessed Coronary Plaque Morphology in Patients With Coronary Artery Disease

Although reactive hyperemia index (RHI) predicts future coronary events, associations with intravascular ultrasound (IVUS)-assessed coronary plaque structure have not been reported. This study therefore investigated associations between RHI and IVUS-assessed coronary plaques. In 362 patients RHI was measured by noninvasive peripheral arterial tonometry and coronary plaque components (fibrous, fibrofatty, necrotic core, and dense calcium) were identified by IVUS in 594 vessel segments of the left anterior descending, circumflex, and/or right coronary arteries. RHI values <1.67 were considered abnormal. Analysis of variance was used to detect independent associations between RHI and plaque composition. Patients with an abnormal RHI had greater plaque burden (41% vs 39% in patients with normal RHI, p = 0.047). Compared to patients with normal RHI, plaque of patients with abnormal RHI had more necrotic core (21% vs 17%, p <0.001) and dense calcium (19% vs 15%, p <0.001) and less fibrous (49% vs 54%, p <0.001) and fibrofatty (11% vs 14%, p = 0.002) tissue. After adjustment for age, gender, cardiovascular risk factors, and drug therapy, abnormal RHI remained significantly associated with fibrous (F ratio 14.79, p <0.001), fibrofatty (F ratio 5.66, p = 0.018), necrotic core (F ratio 14.47, p <0.001), and dense calcium (F ratio 10.80, p = 0.001) volumes. In conclusion, coronary artery plaques of patients with abnormal RHI had a larger proportion of necrotic core and dense calcium. The association of an abnormal RHI with a plaque structure that is more prone to rupture may explain why these patients exhibit a greater risk of coronary events.

Relationship between chronic stress and carotid intima-media thickness (IMT) in elderly Alzheimer's disease caregivers

The stress associated with providing care for a spouse diagnosed with Alzheimer's disease can have adverse effects on cardiovascular health. One potential explanation is that chronic caregiving stress may contribute to the development of atherosclerosis. The purpose of this study was to determine whether the duration that one has provided care is associated with the degree of atherosclerotic burden, as measured by carotid artery intima-media thickness (IMT). One hundred and ten Alzheimer caregivers [mean age 74 ± 8 (SD) years, 69% female] underwent in-home assessment of carotid artery IMT via B-mode ultrasonography. Data regarding medical history, blood pressure, and multiple indicators of caregiving stress were also collected. Multiple regression indicated that duration of care was positively associated with IMT measured in the internal/bifurcation segments of the carotid artery (β = 0.202, p = 0.044) independent of risk factors such as age, gender, body mass index, smoking history, sleep quality, hypertension status, and caregiving stressors. Duration of care was positively associated with IMT in the common carotid artery, but the relationship was not significant. These findings provide more evidence of the link between chronic caregiving stress and cardiovascular disease and indicate that enduring the experience of caregiving over a period of years might be associated with atherosclerotic burden.

Proteins encoded in genomic regions associated with immune-mediated disease physically interact and suggest underlying biology

Genome-wide association studies (GWAS) have defined over 150 genomic regions unequivocally containing variation predisposing to immune-mediated disease. Inferring disease biology from these observations, however, hinges on our ability to discover the molecular processes being perturbed by these risk variants. It has previously been observed that different genes harboring causal mutations for the same Mendelian disease often physically interact. We sought to evaluate the degree to which this is true of genes within strongly associated loci in complex disease. Using sets of loci defined in rheumatoid arthritis (RA) and Crohn's disease (CD) GWAS, we build protein-protein interaction (PPI) networks for genes within associated loci and find abundant physical interactions between protein products of associated genes. We apply multiple permutation approaches to show that these networks are more densely connected than chance expectation. To confirm biological relevance, we show that the components of the networks tend to be expressed in similar tissues relevant to the phenotypes in question, suggesting the network indicates common underlying processes perturbed by risk loci. Furthermore, we show that the RA and CD networks have predictive power by demonstrating that proteins in these networks, not encoded in the confirmed list of disease associated loci, are significantly enriched for association to the phenotypes in question in extended GWAS analysis. Finally, we test our method in 3 non-immune traits to assess its applicability to complex traits in general. We find that genes in loci associated to height and lipid levels assemble into significantly connected networks but did not detect excess connectivity among Type 2 Diabetes (T2D) loci beyond chance. Taken together, our results constitute evidence that, for many of the complex diseases studied here, common genetic associations implicate regions encoding proteins that physically interact in a preferential manner, in line with observations in Mendelian disease.

Dorsal rather than ventral visual pathways discriminate freezing status in Parkinson's disease

BACKGROUND: Although visuospatial deficits have been linked with freezing of gait (FOG) in Parkinson's disease (PD), the specific effects of dorsal and ventral visual pathway dysfunction on FOG is not well understood. METHOD: We assessed visuospatial function in FOG using an angle discrimination test (dorsal visual pathway bias) and overlapping figure test (ventral visual pathway bias), and recorded overall response time, mean fixation duration and dwell time. Covariate analysis was conducted controlling for disease duration, motor severity, contrast sensitivity and attention with Bonferroni adjustments for multiple comparisons. RESULTS: Twenty seven people with FOG, 27 people without FOG and 24 controls were assessed. Average fixation duration during angle discrimination distinguished freezing status: [F (1, 43) = 4.77 p < 0.05] (1-way ANCOVA). CONCLUSION: Results indicate a preferential dysfunction of dorsal occipito-parietal pathways in FOG, independent of disease severity, attentional deficit, and contrast sensitivity.

Life cycle complexity, environmental change and the emerging status of salmonid proliferative kidney disease

P>1. Proliferative kidney disease (PKD) is a disease of salmonid fish caused by the endoparasitic myxozoan, Tetracapsuloides bryosalmonae, which uses freshwater bryozoans as primary hosts. Clinical PKD is characterised by a temperature-dependent proliferative and inflammatory response to parasite stages in the kidney.;2. Evidence that PKD is an emerging disease includes outbreaks in new regions, declines in Swiss brown trout populations and the adoption of expensive practices by fish farms to reduce heavy losses. Disease-related mortality in wild fish populations is almost certainly underestimated because of e.g. oversight, scavenging by wild animals, misdiagnosis and fish stocking.;3. PKD prevalences are spatially and temporally variable, range from 0 to 90-100% and are typically highest in juvenile fish.;4. Laboratory and field studies demonstrate that (i) increasing temperatures enhance disease prevalence, severity and distribution and PKD-related mortality; (ii) eutrophication may promote outbreaks. Both bryozoans and T. bryosalmonae stages in bryozoans undergo temperature- and nutrient-driven proliferation.;5. Tetracapsuloides bryosalmonae is likely to achieve persistent infection of highly clonal bryozoan hosts through vertical transmission, low virulence and host condition-dependent cycling between covert and overt infections. Exploitation of fish hosts entails massive proliferation and spore production by stages that escape the immune response. Many aspects of the parasite's life cycle remain obscure. If infectious stages are produced in all hosts then the complex life cycle includes multiple transmission routes.;6. Patterns of disease outbreaks suggest that background, subclinical infections exist under normal environmental conditions. When conditions change, outbreaks may then occur in regions where infection was hitherto unsuspected.;7. Environmental change is likely to cause PKD outbreaks in more northerly regions as warmer temperatures promote disease development, enhance bryozoan biomass and increase spore production, but may also reduce the geographical range of this unique multihost-parasite system. Coevolutionary dynamics resulting from host-parasite interactions that maximise fitness in previous environments may pose problems for sustainability, particularly in view of extensive declines in salmonid populations and degradation of many freshwater habitats.