Unraveling the parahormetic mechanism underlying the health-protecting effects of grapeseed procyanidins.

Proanthocyanidins (PACs), the predominant constituents within Grape Seed Extract (GSE), are intricate compounds composed of interconnected flavan-3-ol units. Renowned for their health-affirming properties, PACs offer a shield against a spectrum of inflammation associated diseases, such as diabetes, obesity, degenerations and possibly cancer. While monomeric and dimeric PACs undergo some absorption within the gastrointestinal tract, their larger oligomeric and polymeric counterparts are not bioavailable. However, higher molecular weight PACs engage with the colonic microbiota, fostering the production of bioavailable metabolites that undergo metabolic processes, culminating in the emergence of bioactive agents capable of modulating physiological processes. Within this investigation, a GSE enriched with polymeric PACs was employed to explore in detail their impact. Through comprehensive analysis, the present study unequivocally verified the gastrointestinal-mediated transformation of medium to high molecular weight polymeric PACs, thereby establishing the bioaccessibility of a principal catabolite termed 5-(3',4'-dihydroxyphenyl)-γ-valerolactone (VL). Notably, our findings, encompassing cell biology, chemistry and proteomics, converge to the proposal of the notion of the capacity of VL to activate, upon oxidation to the corresponding quinone, the nuclear factor E2-related factor 2 (Nrf2) pathway-an intricate process that incites cellular defenses and mitigates stress-induced responses, such as a challenge brought by TNFα. This mechanistic paradigm seamlessly aligns with the concept of para-hormesis, ultimately orchestrating the resilience to stress and the preservation of cellular redox equilibrium and homeostasis as benchmarks of health.

Biomedical doctoral students' research practices when facing dilemmas: two vignette-based randomized control trials.

Our aim was to describe the research practices of doctoral students facing a dilemma to research integrity and to assess the impact of inappropriate research environments, i.e. exposure to (a) a post-doctoral researcher who committed a Detrimental Research Practice (DRP) in a similar situation and (b) a supervisor who did not oppose the DRP. We conducted two 2-arm, parallel-group randomized controlled trials. We created 10 vignettes describing a realistic dilemma with two alternative courses of action (good practice versus DRP). 630 PhD students were randomized through an online system to a vignette (a) with (n = 151) or without (n = 164) exposure to a post-doctoral researcher; (b) with (n = 155) or without (n = 160) exposure to a supervisor. The primary outcome was a score from - 5 to + 5, where positive scores indicated the choice of DRP and negative scores indicated good practice. Overall, 37% of unexposed participants chose to commit DRP with important variation across vignettes (minimum 10%; maximum 66%). The mean difference [95%CI] was 0.17 [- 0.65 to 0.99;], p = 0.65 when exposed to the post-doctoral researcher, and 0.79 [- 0.38; 1.94], p = 0.16, when exposed to the supervisor. In conclusion, we did not find evidence of an impact of postdoctoral researchers and supervisors on student research practices.Trial registration: NCT04263805, NCT04263506 (registration date 11 February 2020).

Acute preexercise supplementation of combined carnosine and anserine enhances initial maximal power of Wingate tests in humans.

Classic in vitro experiments (Severin's phenomenon) demonstrated that acute carnosine supplementation may potentiate muscle contractility. However, upon oral ingestion, carnosine is readily degraded in human plasma by the highly active serum carnosinase-1 (CN1). We developed a novel strategy to circumvent CN1 by preexercise ingestion of combined carnosine (CARN) and anserine (ANS), the methylated analog with similar biochemical properties but more resistant to CN1. First, in vitro hydrolysis was tested by adding carnosine and anserine to human plasma, alone or in combination. Second, five subjects were supplemented with 25 mg/kg anserine or 25 mg/kg of each anserine and carnosine to test in vivo bioavailability. Third, two double-blind, placebo-controlled, crossover studies investigated the effect of preexercise ANS + CARN (20 mg/kg body wt of each) supplementation on performance during a single all-out Wingate test following 6-min high-intensity cycling (study A) or three repeated Wingate tests (study B). In vitro experiments demonstrated slower degradation of anserine versus carnosine, which was further slowed by simultaneously adding carnosine. In vivo bioavailability of plasma anserine was more prominent [2.5-fold increased area under the curve (AUC)] when ANS + CARN versus ANS was ingested. Study A showed significantly higher (+6% ± 11%; P = 0.04) power in the first 5 s of the Wingate test following ANS + CARN (12.8 ± 2.4 W/kg) versus placebo (12.1 ± 2.2 W/kg). Study B demonstrated increased peak power (+3%) throughout three consecutive Wingate tests (ANS + CARN 10.5 ± 0.6 W/kg vs. placebo 10.2 ± 9.9 W/kg). These experiments reveal a novel acute nutritional method to effectively raise plasma anserine and carnosine by high-dose combined supplementation. This approach led to improved initial cycling power, revealing a new nutritional strategy to increase exercise performance.NEW & NOTEWORTHY Current results reveal that carnosine and anserine competitively bind to the highly active carnosinase enzyme in human plasma. Acute combined carnosine and anserine supplementation is therefore described as novel strategy to raise plasma anserine and carnosine. We report that indices of maximal exercise/muscle power during the initial stage of a Wingate test were significantly improved by preexercise 20-25mg/kg body wt anserine and carnosine supplementation, pointing toward a novel acute nutritional strategy to improve high-intensity exercise performance.

Quebec's Multi-Party Observatory on Zoonoses and Adaptation to Climate Change.

Climate change has been linked with the establishment and geographical expansion of zoonotic diseases, an example of which is the well-documented increase in human cases of Lyme disease in Quebec, Canada. As temperatures continue to increase in Quebec, it is anticipated that several zoonotic diseases will be affected. In response to the growing zoonotic issues facing public health authorities, Quebec's Multi-Party Observatory on Zoonoses and Adaptation to Climate Change (Observatoire multipartite québécois sur les zoonoses et l'adaptation aux changements climatiques) (the Observatory) was founded in 2015 as part of the Quebec government's Climate Change Action Plan (Plan d'action 2013-2020 sur les changements climatiques). The Observatory was designed to bring together agencies involved in formulating public policy and experts from the disciplines of human health, animal health and environmental sciences, in a manner similar to the innovative "One World, One Health" approach. The Observatory provides a platform for knowledge sharing and consensus building among representatives of public policy decision makers and scientists. Its main objectives are to anticipate and prioritize potential issues associated with zoonotic diseases in Quebec, in order to support applicable risk management and climate change adaptation. This article describes what the Observatory is, what it does and outlines its plans for the future.

Management of oral bisphosphonates treatment by rheumatologists and determinants of therapeutic changes: a case-vignette-based study.

Using case vignette methodology, this study shows that only 4% of patients are maintained on oral bisphosphonates over 5 years, and prescribers switch or stop the treatment in 20-30% of cases at each visit. There are few determinants of these changes. More information on appropriate follow-up could help in patients' management. INTRODUCTION: Persistence to oral bisphosphonates, the most commonly prescribed anti-osteoporotic treatments, is low. The aim of this study was to evaluate the role of rheumatologists on the treatment patterns, and to assess the determinants of treatment changes. METHODS: We used the methodology of case vignettes with the participation of 142 rheumatologists. Three baseline clinical vignettes were presented: (1) the physician was asked to indicate the most appropriate period to schedule the next visit over 5 years, (2) the physician was tested about parameters for follow-up (including traps), and (3) various results (both clinical, biological, densitometric, and radiological) were given by random and analyzed as determinants of treatment changes. RESULTS: The study allowed assessment of 426 virtual clinical cases. Clinical examinations, patient's height, inquiries about falls, and adherence to treatment were deemed necessary in > 90% of cases. Bone mineral density was measured in 22, 40, and 71% of cases at 2, 3, and 5 years, respectively. Dental follow-up was recommended in less than 25% of cases. Only 4.2% of patients were maintained on the same treatment at 5 years, and a change of treatment (stop or switch) occurs in 20-30% of cases at each visit. Significant determinants were adherence to treatment, serum C-terminal crosslinking telopeptide of type 1 collagen (CTX) value, change in patient's height, and the occurrence of an incident vertebral fracture. CONCLUSION: Our study shows that maintenance of oral bisphosphonate in postmenopausal women managed by rheumatologists is low; there are few determinants of these changes and more information on appropriate follow-up could help in patients' management.

Pharmacokinetic profile of bilberry anthocyanins in rats and the role of glucose transporters: LC-MS/MS and computational studies.

The aim of the present investigation was to better understand the pharmacokinetic profile of bilberry (Vaccinium Myrtillus) anthocyanins and the role of glucose transporters (sGLT1 and GLUT2) on their absorption. In particular, the absorption of 15 different anthocyanins contained in a standardized bilberry extract (Mirtoselect®) was measured in rats by a validated LC-ESI-MS/MS approach. The plasma concentration peak (Cmax) of 11.1ng/mL was reached after 30min and fasting condition significantly increased the bioavailability of anthocyanins by more than 7 fold in respect to fed rats. Glucose co-administration did not interfere with the overall anthocyanin uptake. Bioavailability of each anthocyanin was then estimated by comparing the relative content in plasma vs extract. The 15 anthocyanins behaved differently in term of bioavailability and both the aglycone and the sugar moiety were found to affect the absorption. For instance, arabinoside moiety was detrimental while cyanidin enhanced bioavailability. Computational studies permitted to rationalize such results, highlighting the role of glucose transporters (sGLT1 and GLUT2) in anthocyanins absorption. In particular a significant correlation was found for the 15 anthocyanins between sGLT1 and GLUT2 recognition and absorption.

Predictive risk factors of serious infections in patients with rheumatoid arthritis treated with abatacept in common practice: results from the Orencia and Rheumatoid Arthritis (ORA) registry.

OBJECTIVES: Little data are available regarding the rate and predicting factors of serious infections in patients with rheumatoid arthritis (RA) treated with abatacept (ABA) in daily practice. We therefore addressed this issue using real-life data from the Orencia and Rheumatoid Arthritis (ORA) registry. METHODS: ORA is an independent 5-year prospective registry promoted by the French Society of Rheumatology that includes patients with RA treated with ABA. At baseline, 3 months, 6 months and every 6 months or at disease relapse, during 5 years, standardised information is prospectively collected by trained clinical nurses. A serious infection was defined as an infection occurring during treatment with ABA or during the 3 months following withdrawal of ABA without any initiation of a new biologic and requiring hospitalisation and/or intravenous antibiotics and/or resulting in death. RESULTS: Baseline characteristics and comorbidities: among the 976 patients included with a follow-up of at least 3 months (total follow-up of 1903 patient-years), 78 serious infections occurred in 69 patients (4.1/100 patient-years). Predicting factors of serious infections: on univariate analysis, an older age, history of previous serious or recurrent infections, diabetes and a lower number of previous anti-tumour necrosis factor were associated with a higher risk of serious infections. On multivariate analysis, only age (HR per 10-year increase 1.44, 95% CI 1.17 to 1.76, p=0.001) and history of previous serious or recurrent infections (HR 1.94, 95% CI 1.18 to 3.20, p=0.009) were significantly associated with a higher risk of serious infections. CONCLUSIONS: In common practice, patients treated with ABA had more comorbidities than in clinical trials and serious infections were slightly more frequently observed. In the ORA registry, predictive risk factors of serious infections include age and history of serious infections.

[Regulation of bone metabolism in osteoporosis : novel drugs for osteoporosis in development]. / Regulation des Knochenstoffwechsels bei Osteoporose : Neuartige Osteoporosemedikamente in der Entwicklung.

Bone is continuously regenerated and remodeled as an adaptation to mechanical load. Bone mass and fracture resistance are maintained by a balanced equilibrium between bone formation and bone resorption. Regeneration and response to mechanical load are, however, impaired in osteoporosis and during aging. Bone resorption is enhanced by chronic inflammation while bone formation is altered by rising levels of inhibitors in the aging organism. Core molecular principles of the regulation of bone metabolism in health and disease have been characterized and developed as therapeutic targets. The receptor activator of nuclear factor kappaB ligand (RANKL) and osteoclast-derived protease cathepsin K are important regulators and effectors of osteoclast differentiation and bone resorption. Bone formation is stimulated by bone morphogenetic proteins (BMP) and via the parathyroid hormone receptor and the Wnt signaling pathway. The principles of osteoclast inhibition using bisphosphonates have now been known for almost three decades. Based on more recent knowledge RANKL and cathepsin K have been developed as new therapeutic targets to inhibit bone resorption. While denosumab, a RANKL antibody, has already been introduced into routine treatment strategies, the cathepsin K antagonist odanacatib is currently in the licensing process. Bone formation can also be stimulated by local administration of BMPs, by systemic treatment with the parathyroid hormone fragment teriparatide and by using antibodies targeting the Wnt inhibitor sclerostin. The latter are presently being tested in phase III clinical studies. In the near future a panel of traditional and novel treatment strategies will be available that will enable us to meet the individual clinical needs during aging and for the treatment of osteoporosis.

Adalimumab in patients with hand osteoarthritis refractory to analgesics and NSAIDs: a randomised, multicentre, double-blind, placebo-controlled trial.

AIM: To test the efficiency of tumour necrosis factor blockers (adalimumab) in patients with painful refractory (non-responders to analgesics and non-steroidal anti-inflammatory drugs (NSAIDs)) hand osteoarthritis (OA). METHODS: We performed a randomised, double-blind, placebo-controlled, parallel group, multicentre study. Patients were randomised to: 1/1 adalimumab 40 mg for two subcutaneous injections at a 15-day interval or placebo and monitored for 6 months. The primary outcome was the percentage of patients with an improvement of more than 50% in global pain (Visual Analogue Scale) between week 0 (W0) and week 6 (W6). Secondary outcomes included the number of painful joints, swollen joints, morning stiffness duration, patient and practitioner global assessments, functional indexes for hand OA, and consumption of analgesics. Analysis on the mean primary outcome measure was done on patients who received at least one injection. RESULTS: 99 patients were recruited and 85 patients were randomised. Among them, 37 patients in the placebo group and 41 in the adalimumab group received at least one injection and were evaluated at W6 (n=78) on the main efficacy outcome. Mean age was 62 years, 85% were women, and mean level of pain was 62 mm at W0. At W6, 35.1% in the adalimumab group versus 27.3% in the placebo group had a pain reduction ≥50% (RR 1.12 (95% CI 0.82 to 1.54; p=0.48). There were no statistical differences for all secondary end points. The rate of adverse events was similar in the two groups. CONCLUSIONS: Adalimumab was not superior to placebo to alleviate pain in patients with hand OA not responding to analgesics and NSAIDs. TRIALS REGISTRATION NUMBER: NCT00597623.

A multicentric study regarding the use of hormone therapy during female mid-age (REDLINC VI).

BACKGROUND: Menopausal hormone therapy (HT) has shown benefits for women; however, associated drawbacks (i.e. risks, costs, fears) have currently determined its low use. OBJECTIVE: To determine the prevalence of current HT use among mid-aged women and describe the characteristics of those who have never used, have abandoned or are currently using HT. In addition, reasons for not using HT were analyzed. METHOD: This was a cross-sectional study that analyzed a total of 6731 otherwise healthy women (45-59 years old) of 15 cities in 11 Latin American countries. Participants were requested to fill out the Menopause Rating Scale (MRS) and a questionnaire containing sociodemographic data and items regarding the menopause and HT use. RESULTS: The prevalence of current HT use was 12.5%. Oral HT (43.7%) was the most frequently used type of HT, followed by transdermal types (17.7%). The main factors related to the current use of HT included: positive perceptions regarding HT (odds ratio (OR) 11.53, 95% confidence interval (CI) 9.41-14.13), being postmenopausal (OR 3.47, 95% CI 2.75-4.36) and having a better socioeconomic level. A total of 48.8% of surveyed women had used HT in the past, but abandoned it due to symptom improvement or being unconcerned; fear of cancer or any other secondary effects were also reported but in less than 10%. Among women who had never used HT, 28% reported the lack of medical prescription as the main reason, followed by the absence of symptoms (27.8%). Among those reporting lack of prescription as the main reason for not using HT, 30.6% currently had severe menopausal symptoms (total MRS score > 16); 19.5% of women were using alternative 'natural' therapies, with 35.1% of them displaying severe menopausal symptoms as compared to a 22.5% observed among current HT users. CONCLUSION: The use of HT has not regained the rates observed a decade ago. Positive perceptions regarding HT were related to a higher use. Lack of medical prescription was the main reason for not using HT among non-users, many of whom were currently displaying severe menopausal symptoms.

Type II diabetes mellitus and menopause: a multinational study.

BACKGROUND: Type II diabetes mellitus causes metabolic changes that may lead to early menopause and worsen climacteric symptoms. OBJECTIVES: To determine the risk factors for type II diabetes mellitus and assess the impact of this disease on the age of menopause and on climacteric symptoms. METHODS: A total of 6079 women aged between 40 and 59 years from 11 Latin American countries were requested to answer the Menopause Rating Scale and Goldberg Anxiety-Depression Scale. RESULTS: The prevalence of diabetes was 6.7%. Diabetes mellitus was associated with arterial hypertension (odds ratio (OR) 4.49; 95% confidence interval (CI) 3.47-5.31), the use of psychotropic drugs (OR 1.54; 95% CI 1.22-1.94), hormonal therapy (OR 1.46; 95% CI 1.11-1.92), ≥ 50 years of age (OR 1.48; 95% CI 1.17-1.86), overweight or obese (OR 1.47; 95% CI 1.15-1.89), and waist circumference ≥ 88 cm (OR 1.32; 95% CI 1.06-1.65). Factors associated with lower risk of diabetes were the use of hormonal contraceptives (OR 0.55; 95% CI 0.35-0.87), alcohol (OR 0.73; 95% CI 0.54-0.98) and living in cities > 2500 meters above sea level (OR 0.70; 95% CI 0.53-0.91) or with high temperatures (OR 0.67; 95% CI 0.51-0.88). In turn, diabetes tripled the risk of menopause in women under 45 years of age. Diabetes did not increase the risk of deterioration of quality of life due to climacteric symptoms. CONCLUSION: Menopause does not increase the risk of type II diabetes mellitus. Diabetes is associated with early menopause in women under 45 years of age.

Positivity for anti-cyclic citrullinated peptide is associated with a better response to abatacept: data from the 'Orencia and Rheumatoid Arthritis' registry.

OBJECTIVES: Very limited data are available regarding the efficacy of abatacept (ABA) in real life. The aims of this study were to determine the efficacy of ABA in rheumatoid arthritis and predicting factors of efficacy in common practice. METHODS: The Orencia and Rheumatoid Arthritis" (ORA) prospective registry, promoted by the French Society of Rheumatology, has included 1003 patients with RA. RESULTS: 773 patients had already fulfilled the 6-month follow-up visit. Only 21.3% of patients would have fulfilled inclusion criteria used in pivotal controlled trials. The European League Against Rheumatism (EULAR) response, was observed in 330 (59.1%) of the 558 assessed patients (good response: 20.4%, moderate response: 38.7%) and was similar in patients who did and in patients who did not fulfill inclusion criteria of controlled trials. Among EULAR responders, initial 28-joint disease activity score (5.4 (4.7-6.5) in responders vs 4.9 (4.0-6.0) in non responders, p< 0.0001), the proportion of rheumatoid factor (75.6% vs 66.7%, p= 0.03) and the proportion of anti-cyclic citrullinated peptide antibody (anti-CCP)-positivity (75.9% vs 62.2%, p= 0.001) were significantly higher. In multivariate analysis adjusted on initial 28-joint disease activity score and CRP, anti-CCP positivity was associated with EULAR response (OR=1.9;95% CI=1.2 to 2.9, p=0.007), but not rheumatoid factor (OR=1.0;95% CI=0.6 to 1.6, p=0.9). Anti-CCP positivity was also significantly associated with a higher ABA retention rate at 6 months. CONCLUSIONS: Real life efficacy of ABA in the ORA registry was similar as that reported in clinical trials. Anti-CCP positivity was associated with a better response to ABA, independently from disease activity.

Menopausal symptoms appear before the menopause and persist 5 years beyond: a detailed analysis of a multinational study.

OBJECTIVE: Few Latin American studies have described menopausal symptoms in detail by means of a standardized assessment tool. The objective of this study was to assess the prevalence and severity of menopausal symptoms and their impact over quality of life among mid-aged Latin American women. METHOD: In this cross-sectional study, 8373 otherwise healthy women aged 40-59 years from 12 Latin American countries were asked to fill out the Menopause Rating Scale (MRS) and a questionnaire containing personal sociodemographic data. Menopause status (pre-, peri- and postmenopausal) was defined according to the criteria of the Stages of Reproductive Aging Workshop. RESULTS: Of all the studied women, 90.9% had at least one menopausal symptom (complaint) that they rated. Muscle and joint discomfort, physical and mental exhaustion and depressive mood were highly prevalent and rated as severe-very severe (scores of 3 and 4), at a higher rate than vasomotor symptoms (15.6%, 13.8% and 13.7% vs. 9.6%, respectively). Of premenopausal women (40-44 years), 77.0% reported at least one rated complaint, with 12.9% displaying MRS scores defined as severe (> 16). The latter rate increased to 26.4% in perimenopausal, 31.6% in early postmenopausal and 29.9% among late postmenopausal women. As measured with the MRS, the presence of hot flushes increased the risk of impairment of overall quality of life in both premenopausal (odds ratio 12.67; 95% confidence interval 9.53-16.83) and peri/postmenopausal women (odds ratio 9.37; 95% confidence interval 7.85-11.19). CONCLUSION: In this large, mid-aged, female Latin American series, muscle/joint discomfort and psychological symptoms were the most prevalent and severely rated menopausal symptoms. The symptoms appear early in the premenopause, significantly impair quality of life and persist 5 years beyond the menopause.

Risk factors for severe infections in patients with rheumatoid arthritis treated with rituximab in the autoimmunity and rituximab registry.

OBJECTIVE: The risk of severe infection is a crucial factor in the assessment of the short-term risk:benefit ratio of biologic drugs in rheumatoid arthritis (RA). There is no increase in severe infections in RA patients treated with rituximab (RTX) in controlled trials, but this has not yet been assessed in daily practice. We undertook this study to investigate the occurrence of and risk factors for severe infections in off-trial patients using data from the AutoImmunity and Rituximab (AIR) registry. METHODS: The AIR registry was set up by the French Society of Rheumatology. The charts of patients with severe infections were reviewed. RESULTS: Of the enrolled patients, 1,303 had at least 1 followup visit at 3 months or later, with a mean ± SD followup period of 1.2 ± 0.8 years (1,629 patient-years). Eighty-two severe infections occurred in 78 patients (5.0 severe infections per 100 patient-years), half of them in the 3 months following the last RTX infusion. Multivariate analysis showed that chronic lung disease and/or cardiac insufficiency (odds ratio 3.0 [95% confidence interval 1.3-7.3], P = 0.01), extraarticular involvement (odds ratio 2.9 [95% confidence interval 1.3-6.7], P = 0.009), and low IgG level (<6 gm/liter) before initiation of RTX treatment (odds ratio 4.9 [95% confidence interval 1.6-15.2], P = 0.005) were significantly associated with increased risk of a severe infection. CONCLUSION: The rate of severe infections in current practice is similar to that reported in clinical trials. The risk factors for severe infections include chronic lung and/or cardiac disease, extraarticular involvement, and low IgG before RTX treatment. This suggests that serum IgG should be checked and the risk:benefit ratio of RTX discussed for patients found to have low levels of IgG.

Molecular sieve properties of mesoporous silica with intraporous nanocarbon.

Biporous carbon-silica materials (CSM) with molecular sieve properties and high sorption capacity were developed by synthesizing nano-sized carbon crystallites in the mesopores of Al-MCM-41.

Clinical and ultrasonographic predictors of joint replacement for knee osteoarthritis: results from a large, 3-year, prospective EULAR study.

OBJECTIVES: To determine clinical and ultrasonographic predictors of joint replacement surgery across Europe in primary osteoarthritis (OA) of the knee. METHODS: This was a 3-year prospective study of a painful OA knee cohort (from a EULAR-sponsored, multicentre study). All subjects had clinical evaluation, radiographs and ultrasonography (US) at study entry. The rate of knee replacement surgery over the 3-year follow-up period was determined using Kaplan-Meier survival data analyses. Predictive factors for joint replacement were identified by univariate log-rank test then multivariate analysis using a Cox proportional-hazards regression model. Potential baseline predictors included demographic, clinical, radiographic and US features. RESULTS: Of the 600 original patients, 531 (88.5%), mean age 67+/-10 years, mean disease duration 6.1+/-6.9 years, had follow-up data and were analysed. During follow-up (median 3 years; range 0-4 years), knee replacement was done or required for 94 patients (estimated event rate of 17.7%). In the multivariate analysis, predictors of joint replacement were as follows: Kellgren and Lawrence radiographic grade (grade > or =III vs or =4 mm vs <4 mm) (HR = 2.63 (95% CI 1.70 to 4.06), p<0.0001); knee pain intensity on a 0-100 mm visual analogue scale (> or =60 vs <60) (HR = 1.81 (95% CI 1.15 to 2.83), p=0.01) and disease duration (> or =5 years vs <5 years) (HR=1.63 (95% CI 1.08 to 2.47), p=0.02). Clinically detected effusion and US synovitis were not associated with joint replacement in the univariate analysis. CONCLUSION: Longitudinal evaluation of this OA cohort demonstrated significant progression to joint replacement. In addition to severity of radiographic damage and pain, US-detected effusion was a predictor of subsequent joint replacement.

Measure of function in rheumatoid arthritis: individualised or classical scales?

BACKGROUND: The Health Assessment Questionnaire Disability Index (HAQ-DI) is the most widely used measure of function in rheumatoid arthritis (RA). OBJECTIVE: To evaluate individualised forms of the HAQ-DI and thus enhance the incorporation of patients' views in outcome assessment. PATIENTS AND METHODS: HAQ-DI data were prospectively obtained from 370 outpatients with RA treated with leflunomide over a 6-month period. At baseline and final visits, patients had to rate the importance they attached to each activity addressed by the 20 HAQ-DI items, and to select the five activities they considered the most important. Different individualised scales were evaluated: scales preserving all domains, in which the score for each item is multiplied by or added to its importance; and scales involving, for each patient, only the five most important items. The psychometric properties of these scales were compared with those of the HAQ-DI. RESULTS: For each HAQ-DI item, severity and importance scores were weakly correlated. Scores for all individualised scales were highly correlated with the HAQ-DI score (r(s)>0.75). All scales had a good internal consistency (Cronbach's alpha 0.87-0.88). Compared with the HAQ-DI, individualised scales did not have better sensitivity to change (standardised response mean 0.64-0.69 vs 0.74). CONCLUSION: Individualised scales have similar properties to the HAQ-DI. However, individualised questionnaires measuring importance gave complementary information to the measure of disability. Individualisation is probably not needed for group assessment in all randomised controlled trials but, the use of individualised questionnaires may be clinically relevant for individual patients with RA.

Incidence and risk factors of early thromboembolic events after mechanical heart valve replacement in patients treated with intravenous unfractionated heparin.

OBJECTIVE: To evaluate the incidence and risk factors, including timing and intensity of anticoagulation, of early thromboembolic events (TE) after mechanical heart valve replacement (MHVR) in patients treated by intravenous unfractionated heparin (IVUH). DESIGN: Prospective observational study, conducted between December 2005 and May 2007. SETTING: Haemostasis laboratory, surgical intensive care unit and ward in a university hospital. PATIENTS: Three hundred consecutive patients undergoing MHVR. Mitral or double MHVR was performed in 149 patients, and aortic MHVR in 151 patients. Postoperative anticoagulation was achieved with continuous IVUH according to a standardised protocol. The timing of efficient anticoagulation was recorded for each patient. MAIN OUTCOME MEASURES: The end point was the occurrence of any arterial TE from day 1 to day 30. Transoesophageal echocardiography was systematically performed after mitral MHVR. RESULTS: Early TE occurred in 22 patients (14.8%; 95% CI 9% to 20%) after a mitral or double MHVR and in two patients (1.3%; 95% CI 0% to 3%) after an aortic MHVR (p = 0.005). After adjustment for diabetes mellitus (adjusted OR (aOR) = 3.3; 95% CI 1.0 to 10.9, p = 0.049), and for the presence of predisposing factors (heparin-induced thrombocytopenia or bradycardia requiring definitive pacemaker implantation) (aOR = 12.8; 95% CI 3.1 to 53.3, p<0.001), effective anticoagulation on day 3 was a protective factor (aOR = 0.28; 95% CI 0.1 to 0.8, p = 0.018) for early TE after mitral MHVR. CONCLUSIONS: Despite the use of IVUH, the rate of early TE after mitral MHVR remained elevated. These results suggest that early effective anticoagulation is required after mitral MHVR, since inappropriate anticoagulation on day 3 was significantly associated with early TE.

Leukoaraiosis and pulse-wave encephalopathy: observations with phase-contrast MRI in mild cognitive impairment.

PURPOSE: To test the pathogenic hypothesis of a breakdown in the vital buffering of the arterial pulsations behind leukoaraiosis (LA) in mild cognitive impairment (MCI). METHODS: Seventy-one elderly patients with MCI underwent a combined structural and dynamic MR examination (3D T1-weighted and fast-FLAIR T2-weighted sequences, phase contrast sequences). Arterial indices of pulsatility (IP) and composite indicators of the amplitude transfer function between cerebrospinal fluid and cerebral venous flow (Icsf/veins) were used to assess the large artery stiffness and the intracranial compliance respectively. Cerebral total arterial blood flow (tCBF), superficial and deep venous flow rates were also measured. Intracranial dynamic parameters and potential confounders including age, gender and vascular risk factors were compared between two groups respectively with and without significant LA. RESULTS: The only dynamic changes on multivariate analyse were an IP increase, a lowering of deep venous outflow and Icsf/veins in patients with LA. There was a significant interaction between IP and Icsf/veins in the logistic regression: as compared with patients with low IP (suggestive of high large artery compliance) and high Icsf/veins (suggestive of high intracranial compliance), the adjusted odds ratios for the presence of LA were 9 (95% CI 1-64, P=0.02) in cases of both high IP and Icsf/veins, 10 (95% CI 1-64, P=0.02) in cases of both high IP and low Icsf/veins and 19 (95% CI 3-127, P=0.002) in cases of both low IP and Icsf/veins. CONCLUSION: LA may reflect an arteriosclerotic and/or resistive pulse wave encephalopathy in MCI.

Trend towards increased arterial stiffness or intima-media thickness in ankylosing spondylitis patients without clinically evident cardiovascular disease.

OBJECTIVES: Increased incidence of cardiovascular disease (CVD) has been observed in AS. The reasons of this increase are not fully understood (greater prevalence of traditional cardiovascular risks, consequences of treatment (NSAID) or biological inflammation). The objectives of this study are to assess intima-media thickness (IMT) and arterial stiffness (i.e augmentation index AIx), markers of sub-clinical atherosclerosis in AS patients and to examine the effects of TNF-alpha inhibitors on arterial stiffness in active AS patients. METHODS: Sixty AS patients were enrolled with 60 healthy controls. Their BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) and BASFI (Bath Ankylosing Spondylitis Functional Index) scores, ESR and CRP levels were recorded. Subclinical atherosclerosis was assessed by measurement of AIx by pulse wave analysis and IMT by carotid echography. RESULTS: We found significantly increased IMT in the AS group compared with healthy controls. After adjustment for confounding factors, an underlying trend towards increased IMT was still present (P = 0.06). No difference was found in arterial stiffness between the two groups. AS patients, treated or not with anti-TNF-alpha at baseline, had significantly increased IMT and AIx or a trend towards increase. IMT was positively correlated with tobacco use, WHR and blood pressure but not correlated with CRP level. Despite improvement in markers of disease activity, arterial stiffness was unchanged after 14 weeks of treatment with TNF antagonists. CONCLUSION: This study shows a trend towards increased subclinical atherosclerosis in AS patients. TNF-alpha blockade does not seem to improve arterial stiffness in AS patients, but our results lack statistical power.