Gaps between research and recommendations in rheumatoid arthritis.

OBJECTIVES: To identify recommendations on the diagnosis and management of rheumatoid arthritis (RA) supported by low recommendation grades, to study the causes of this low grading, and to propose solutions. METHODS: A group of six rheumatologists, with extensive experience in the development of systematic reviews, reviewed national and international RA recommendations and practice guidelines. They identified all recommendations with a low level of evidence or recommendation grade (levels equivalent to 4, 5, or grades C or D of the Oxford Levels of Evidence), classified them by areas (diagnosis, follow-up, treatment, others), and analyzed plausible causes of low graduation. A Delphi was used to select 10 recommendations where it was most important to obtain quality evidence to support them. Subsequently, actions were proposed to improve evidence and recommendation grading. RESULTS: Fourteen documents were analyzed, in which 192 recommendations with low evidence/grade of recommendation were identified, most of which were on treatment. The two most frequent causes of this low level are the absence of studies and the discrepancy between the wording of the recommendation and the evidence used. Finally, the proposed solution to the critical recommendations is a list of unanswered research questions and possible designs to answer them. CONCLUSIONS: We propose to design and promote research that truly supports or rectifies clinical practice and, thus, bridges the gap between existing evidence and critical recommendations.

Implementation of an assessment checklist for patients with spondyloarthritis in daily practice.

OBJECTIVES: To analyse the feasibility and changes in the collection of clinical measures after the implementation in daily practice of a checklist designed for an optimal evaluation and monitoring of patients with spondyloarthritis (SpA). METHODS: An observational prospective study was performed. The feasibility of the assessment checklist (paper/on-line format) for patients with SpA was tested (time to complete the checklist, simplicity, amenity clarity, usefulness). Through a medical files review, changes in the number of the checklist variables collected were analysed previous to the implementation of the checklist and 6 months later. A descriptive and bivariate analysis was performed. RESULTS: A total 6 hospitals and 11 rheumatologists participated. The median time to checklist completion was 15 (12-20) minutes, and the mean scores for the rest of variables of the feasibility test were in general positives. A total of 83 and 68 medical files pre-implementation and post-implementation were reviewed respectively. We observed a significant increase in the collection of many of the checklist variables after the implementation. The record of BASDAI increased from 46.2% to 73.1% (p=0.001), physical activity from 48.2% to 88.2% (p<0.0001), physician global (VAS) from 28.0% to 73.5% (p<0.0001), patient global (VAS) from 48.8% to 85.3% (p<0.0001), morning stiffness from 62.8% to 84.8% (p=0.003), ASDAS from 12.2% to 32.8% (p=0.002), BASFI from 43.7% to 65.7% (p=0.008), or DAS28 from 24.7% to 46.3% (p=0.006). These changes were observed irrespectively of SpA classification. CONCLUSIONS: The implementation of an assessment checklist in daily practice is feasible and improves the assessment of SpA patients.

Multidisciplinary dermatology-rheumatology management for patients with moderate-to-severe psoriasis and psoriatic arthritis: a systematic review.

The aim of the study was to analyze the efficacy and satisfaction of multidisciplinary dermatology-rheumatology management for patients with moderate-to-severe psoriasis and psoriatic arthritis (PsA). We conducted a systematic literature search in MEDLINE, EMBASE, and Cochrane Library up to September 2015. Selection criteria include (1) adult patients with moderate-to-severe psoriasis and PsA, (2) assessed in a multidisciplinary consultation, (3) comparison with routine separate consultations, and (4) outcome measures to evaluate efficacy and/or satisfaction. Meta-analyses, systematic reviews, clinical trials, cohort studies, and case series were included. The quality of the studies included was graded according to the Oxford Level of Evidence scale. Of 195 articles, three studies complied with the inclusion criteria: two case series and one descriptive study in which 506 patients were evaluated. Patients were referred to the multidisciplinary consultation from dermatology and rheumatology consultations in all but one study, in which primary care was also involved. The reason for the referral was to confirm the diagnosis and/or treatment. Patients were evaluated on a weekly and monthly basis in two and one study, respectively. The evidence obtained is scarce but suggests the efficacy of multidisciplinary consultations in terms of improved skin and joint symptoms after changing treatment (82-56 %), showing higher scores for this type of consultation compared to the usual [4.91 vs. 2.85 (0-5)] and a high level of satisfaction among patients (94 % "very satisfied"). However, waiting times were higher. With the limited evidence found, multidisciplinary management seems to be more effective and more satisfactory for patients with moderate-to-severe psoriasis and PsA than conventional consultations, though this could not be conclusively demonstrated. The results of this review support the benefit of implementing this type of consultation.

Effect of temperature stress on the early vegetative development of Brassica oleracea L.

BACKGROUND: Due to its biennual life cycle Brassica oleracea is especially exposed to seasonal changes in temperature that could limit its growth and fitness. Thermal stress could limit plant growth, leaf development and photosynthesis. We evaluated the performance of two local populations of B. oleracea: one population of cabbage (B. oleracea capitata group) and one population of kale (B. oleracea acephala group) under limiting low and high temperatures. RESULTS: There were differences between crops and how they responded to high and low temperature stress. Low temperatures especially affect photosynthesis and fresh weight. Stomatal conductance and the leaf water content were dramatically reduced and plants produce smaller and thicker leaves. Under high temperatures there was a reduction of the weight that could be associated to a general impairment of the photosynthetic activity. CONCLUSIONS: Although high temperatures significantly reduced the dry weight of seedlings, in general terms, low temperature had a higher impact in B. oleracea physiology than high temperature. Interestingly, our results suggest that the capitata population is less sensitive to changes in air temperature than the acephala population.

Consensus statement on a framework for the management of comorbidity and extra-articular manifestations in rheumatoid arthritis.

The objective of the study was to develop evidence-based and practical recommendations for the detection and management of comorbidity in patients with rheumatoid arthritis (RA) in daily practice. We used a modified RAND/UCLA methodology and systematic review (SR). The process map and specific recommendations, based on the SR, were established in discussion groups. A two round Delphi survey permitted (1) to prioritize the recommendations, (2) to refine them, and (3) to evaluate their agreement by a large group of users. The recommendations cover: (1) which comorbidities should be investigated in clinical practice at the first and following visits (including treatments, risk factors and patient's features that might interfere with RA management); (2) how and when should comorbidities and risk factors be investigated; (3) how to manage specific comorbidities, related or non-related to RA, including major adverse events of RA treatment, and to promote health (general and musculoskeletal health); and (4) specific recommendations to assure an integral care approach for RA patients with any comorbidity, such as health care models for chronic inflammatory patients, early arthritis units, relationships with primary care, specialized nursing care, and self-management. These recommendations are intended to guide rheumatologists, patients, and other stakeholders, on the early diagnosis and management of comorbidity in RA, in order to improve disease outcomes.

Long-Term Benefit of Perlingual Polybacterial Vaccines in Patients with Systemic Autoimmune Diseases and Active Immunosuppression.

INTRODUCTION: We have previously shown that trained-immunity-based vaccines, namely TIbV, significantly reduce the rate of recurrent infections, both of the respiratory tract (RRTI) and urinary tract infections (RUTI) in SAD patients on disease-modifying drugs (DMARDs). OBJECTIVE: We evaluated the frequency of RRTI and RUTI from 2018 to 2021 in those SAD patients that received TIbV until 2018. Secondarily, we evaluated the incidence and clinical course of COVID-19 in this cohort. METHODS: A retrospective observational study was conducted in a cohort of SAD patients under active immunosuppression immunized with TIbV (MV130 for RRTI and MV140 for RUTI, respectively). RESULTS: Forty-one SAD patients on active immunosuppression that were given TIbV up to 2018 were studied for RRTI and RUTI during the 2018-2021 period. Approximately half of the patients had no infections during 2018-2021 (51.2% no RUTI and 43.5% no RRTI at all). When we compared the 3-year period with the 1-year pre-TIbV, RRTI (1.61 ± 2.26 vs. 2.76 ± 2.57; p = 0.002) and RUTI (1.56 ± 2.12 vs. 2.69 ± 3.07; p = 0.010) episodes were still significantly lower. Six SAD patients (four RA; one SLE; one MCTD) with RNA-based vaccines were infected with SARS-CoV-2, with mild disease. CONCLUSIONS: Even though the beneficial protective effects against infections of TIbV progressively decreased, they remained low for up to 3 years, with significantly reduced infections compared to the year prior to vaccination, further supporting a long-term benefit of TIbV in this setting. Moreover, an absence of infections was observed in almost half of patients.

Development and feasibility of 4 checklists for the evaluation of comorbidity in patients with rheumatoid arthritis, axial spondyloarthritis and psoriatic arthritis: GECOAI Project.

OBJECTIVE: To develop and assess the feasibility in daily practice of four comorbidity checklists, for common use in rheumatoid arthritis (RA), axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA). METHODS: A multidisciplinary panel of experts on comorbidity was established. Data from the GECOAR, GECOAX and GECOAP projects were analysed and a narrative literature review in Medline on RA, axSpA and PsA comorbidity was performed in order to select the most relevant and common comorbidities across the three diseases. With these results and those obtained from a focus group of patients, in a nominal group meeting, the experts generated preliminary checklists. These were afterwards modified by an external evaluation by two associations, a patients' association and an association of health professionals related to rheumatology. As a result, the final checklists were generated. A cross-sectional study was conducted to test the feasibility of three of the checklists in daily practice, in which eight health professionals evaluated the checklists in five patients with RA, five with axSpA and five with SpA. RESULTS: Four comorbidity checklists were designed, three for health professionals (one to assess current comorbidity, one on prevention/health promotion and one with the referral criteria to other health professionals), and another for patients. The feasibility study showed them to be simple, clear, and useful for use in routine clinical practice. CONCLUSIONS: The use of specific and common checklists for patients with RA, axSpA and PsA is feasible and might contribute favorably to their prognosis as well as in daily practice.

Sublingual Bacterial Vaccination Reduces Recurrent Infections in Patients With Autoimmune Diseases Under Immunosuppressant Treatment.

Introduction: Conventional or biologic disease-modifying anti-rheumatic drugs (DMARDs) are the mainstay of treatment for systemic autoimmune disease (SAD). Infectious complications are a major concern in their use. Objective: To evaluate the clinical benefit of sublingual mucosal polybacterial vaccines (MV130 and MV140), used to prevent recurrent respiratory and urinary tract infections, in patients with SAD and secondary recurrent infections following conventional or biologic DMARDs. Methods: An observational study in SAD patients with recurrent respiratory tract infections (RRTI) and/or recurrent urinary tract infections (RUTI) was carried out. All patients underwent mucosal (sublingual) vaccination with MV130 for RRTI or with MV140 for RUTI daily for 3 months. Clinical evaluation was assessed during 12 months of follow-up after the first dose, i.e., 3 months under treatment and 9 months once discontinued, and compared with the previous year. Results: Forty-one out of 55 patients completed 1-year follow-up. All patients were on either conventional or biologic DMARDs. A significant decrease in the frequency of RUTI (p<0.001), lower respiratory tract infections (LRTI) (p=0.009) and upper respiratory tract infections (URTI) (p=0.006) at 12-mo with respect to the previous year was observed. Antibiotic prescriptions and unscheduled medical visits decreased significantly (p<0.020) in all groups. Hospitalization rate also declined in patients with RRTI (p=0.019). The clinical benefit demonstrated was concomitant to a significant increase in both anti-S. pneumoniae IgA and IgG antibodies following MV130 vaccination. Conclusions: Sublingual polybacterial vaccines prevent recurrent infections in patients with SAD under treatment with immunosuppressant therapies, supporting a broad non-specific anti-infectious effect in these patients.

Comparative results of the implementation in daily practice of an evaluation checklist for patients with axial spondyloarthritis and psoriatic arthritis.

OBJECTIVE: To analyse and compare changes in the collection of clinical variables after the implementation in daily practice of an evaluation checklist for patients with axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA). METHODS: An observational study was performed based on medical records review. The number and type of variables of the evaluation checklist in the medical records were collected. The first review was made before the implementation of the checklist, and the second one 6 months after the implementation (in different patients). A descriptive and bivariate analysis was carried out. RESULTS: Six hospitals and 11 rheumatologists participated. A total of 83 and 68 medical records were reviewed before and after the implementation of the checklist. After the implementation, in the axSpA patients, a significant increase was recorded in alcohol consumption, diarrhoea or IBD and urethritis, diabetes mellitus, hyperlipidaemia, depression, obesity or gout/hyperuricaemia, weight, height, blood pressure, patient and physician global assessments of disease activity, BASDAI and DAS28. And, in the PsA patients, alcohol consumption, hypertension, diabetes mellitus, hyperlipidaemia, disease, gout/hyperuricaemia, thoracic expansion, cervical rotation, weight, height, blood pressure, patient and physician global assessments of disease, ASDAS, BASDAI, and BASFI were recorded. In general, there was a trend towards greater recording in axSpA compared with PsA. CONCLUSIONS: The implementation of a specific checklist in daily practice improves the evaluation of patients with axSpA and PsA. More efforts are necessary to continue improving the evaluation of patients with axSpA, but especially of those with PsA.

Development and feasibility of 4 checklists for the evaluation of comorbidity in patients with rheumatoid arthritis, axial spondyloarthritis and psoriatic arthritis: GECOAI Project. / Desarrollo y viabilidad de cuatro checklists para la evaluación de la comorbilidad en pacientes con artritis reumatoide, espondiloartritis axial y artritis psoriásica: Proyecto GECOAI.

OBJECTIVE: To develop and assess the feasibility in daily practice of four comorbidity checklists, for common use in rheumatoid arthritis (RA), axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA). METHODS: A multidisciplinary panel of experts on comorbidity was established. Data from the GECOAR, GECOAX and GECOAP projects were analysed and a narrative literature review in Medline on RA, axSpA and PsA comorbidity was performed in order to select the most relevant and common comorbidities across the three diseases. With these results and those obtained from a focus group of patients, in a nominal group meeting, the experts generated preliminary checklists. These were afterwards modified by an external evaluation by two associations, a patients' association and an association of health professionals related to rheumatology. As a result, the final checklists were generated. A cross-sectional study was conducted to test the feasibility of three of the checklists in daily practice, in which eight health professionals evaluated the checklists in five patients with RA, five with axSpA and five with SpA. RESULTS: Four comorbidity checklists were designed, three for health professionals (one to assess current comorbidity, one on prevention/health promotion and one with the referral criteria to other health professionals), and another for patients. The feasibility study showed them to be simple, clear, and useful for use in routine clinical practice. CONCLUSIONS: The use of specific and common checklists for patients with RA, axSpA and PsA is feasible and might contribute favorably to their prognosis as well as in daily practice.

Orthopedic Surgery in Rheumatoid Arthritis: Results from the Spanish National Registry of Hospitalized Patients over 17 Years.

OBJECTIVE: To analyze the trend of orthopedic surgery (OS) rates on patients with rheumatoid arthritis (RA). METHODS: Retrospective observational study based on information provided by the Spanish National System of Hospital Data Surveillance. All hospitalizations of patients with RA for orthopedic surgery [total hip arthroplasty (THA), total knee arthroplasty (TKA), arthrodesis, and upper limb arthroplasty (ULA)] during 1999-2015 were analyzed. The age-adjusted rate was calculated. Generalized linear models were used for trend analysis. RESULTS: There were 21,088 OS in patients over 20 years of age (77.9% women). OS rate adjusted by age was 754.63/100,000 RA patients/year (women 707.4, men 861.1). Neither an increasing nor a decreasing trend was noted for the total OS. However, trend and age interacted, so in the age ranges 20-40 years and 40-60 years, an annual reduction of 2.69% and 2.97%, respectively, was noted. In the age ranges over 80 years and 60-80 years, we noted an annual increase of 5.40% and 1.09%, respectively. The average age at time of OS increased 5.5 years during the period analyzed. For specific surgeries, a global annual reduction was noted in rates for arthrodesis. In THA, there was an annual reduction in patients under 80 years. In TKA and ULA, there was an annual reduction in patients under 60 years. CONCLUSION: Although the overall OS rate has not changed, there is a decrease in the rate of arthrodesis at all ages, THA in patients under 80 years of age, as well as TKA and ULA in patients under 60 years of age.

Trends in hip fracture in patients with rheumatoid arthritis: results from the Spanish National Inpatient Registry over a 17-year period (1999-2015). TREND-AR study.

PURPOSE: To analyse trends in hip fracture (HF) rates in patients with rheumatoid arthritis (RA) over an extended time period (17 years). METHODS: This observational retrospective survey was performed by reviewing data from the National Surveillance System for Hospital Data, which includes more than 98% of Spanish hospitals. All hospitalisations of patients with RA and HF that were reported from 1999 to 2015 were analysed. Codes were selected using the Ninth International Classification of Diseases, Clinical Modification: ICD-9-CM: RA 714.0 to 714.9 and HF 820.0 to 820.3. The crude and age-adjusted incidence rate of HF was calculated by age and sex strata over the last 17 years. General lineal models were used to analyse trends. RESULTS: Between 1999 and 2015, 6656 HFs occurred in patients with RA of all ages (84.25% women, mean age 77.5 and 15.75% men, mean age 76.37). The age-adjusted osteoporotic HF rate was 221.85/100 000 RA persons/ year (women 227.97; men 179.06). The HF incidence rate increased yearly by 3.1% (95% CI 2.1 to 4.0) during the 1999-2015 period (p<0.001) and was more pronounced in men (3.5% (95% CI 2.1 to 4.9)) than in women (3.1% (95% CI 2.3 to 4.1)). The female to male ratio decreased from 1.54 in 1999 to 1.14 in 2015. The average length of hospital stays (ALHS) decreased (p<0.001) from 16.76 days (SD 15.3) in 1999 to 10.78 days (SD 7.72) in 2015. Age at the time of hospitalisation increased (p<0.001) from 75.3 years (SD 9.33) in 1999 to 79.92 years (SD 9.47) in 2015. There was a total of 326 (4.9%) deaths during admission, 247 (4.4%) in women and 79 (7.5%) in men (p<0.001). CONCLUSION: In Spain, despite the advances that have taken place in controlling disease activity and in treating osteoporosis, the incidence rate of HF increased in both male and female patients with RA.

Systematic review of the value of ultrasound and magnetic resonance musculoskeletal imaging in the evaluation of response to treatment of gout.

BACKGROUND: Imaging may be useful for monitoring response to therapy. Within the OMERACT proposal for the core set domains for outcome measures in chronic gout, serum urate levels, recurrence of gouty flares, tophus regression, and joint damage imaging have been included, among other proposed issues. OBJECTIVES: To perform a systematic literature review of the usefulness of magnetic resonance imaging (MRI) and ultrasound (US) on assessment of treatment response in patients with gout. METHODS: MEDLINE, EMBASE, Cochrane Library (up to February 2012), and abstracts presented at the 2010 and 2011 meetings of the American College of Rheumatology and European League Against Rheumatism, were searched for treatment studies of any duration and therapeutic options, examining the ability of MRI/US to assess treatment response in gouty patients. Meta-analyses, systematic reviews, randomized clinical trials, cohort and case-control studies and validation studies were included. Quality was appraised using validated scales. RESULTS: There were only 3 US published studies in the literature that analysed US utility on assessment of response to treatment in patients with gout. All of them were prospective case studies with a small number of patients and they were reviewed in detailed. A total of 36 patients with gout were examined with US. All of them had a baseline serum urate >6mg/dL. US features of gout (double contour sign, hyperechoic spots in synovial fluid, hyperechoic cloudy areas, tophus diameter and volume) achieved significant reduction in patients who reached the objective of uricemia ≤6mg/dL in all the studies; however, patients in whom levels did not drop below 6mg/dL had no change of US features of gout. Other parameters evaluated in one study included ESR, CRP, number of tender joints (TRN), number of swollen joints, and pain score (SP). All of them decreased with uricemia reduction, but only TRN and SP were statistically significant. No data was found on the value of MRI on treatment response assessment in patients with gout. CONCLUSIONS: The improvement in ultrasound features shows concurrent validity with uric acid reduction. According to the published evidence, US can be a useful tool for monitoring treatment of gouty patients, although more research is needed. The value of MRI on treatment response assessment in patients with gout remains to be determined.

Symptomatic and asymptomatic interphalageal osteoarthritis: An ultrasonographic study.

OBJECTIVE: To date few studies have examined whether ultrasonography can depict morphologic differences in painful and painless osteoarthritis (OA). This study describes and compares the clinical, radiographic and ultrasonographic findings of patients with both painful and painless proximal interphalgeal (PIP) and/or distal interphalgeal (DIP) OA. METHODS: Patients with PIP and/or DIP OA (ACR criteria) were prospectively recruited. The clinical rheumatologist chose up to 3 painful joints and up to 3 painless symmetric joints in each patient to define 2 cohorts of OA: symptomatic (SG) and asymptomatic (ASG). A conventional postero-anterior hand x ray was performed and read by one rheumatologist following the OARSI atlas, blinded to clinical and sonographic data. Ultrasound (US) was performed by an experienced rheumatologist, blinded to both clinical and radiographic data in joints previously selected by the clinical rheumatologist. US-pathology was assessed as present or absent as defined in previous reports: osteophytes, joint space narrowing, synovitis, intra-articular power doppler signal, intra-articular bony erosion, and visualization of cartilage. Radiographic and ultrasonographic intrareader reliability test was performed. RESULTS: A total of 50 joints in the SG and ASG were included from 20 right handed women aged 61.85 (46-73) years with PIP and DIP OA diagnosed 6.8 (1-17) years ago. 70% SG joints and ASG were right and left sided respectively. The SG showed significantly more osteophytes, synovitis and non-visualization of joint cartilage. Intrareader radiographic and ultrasonographic agreement was excellent. CONCLUSION: This study demonstrates that painful PIP and/or DIP OA have more ultrasonographic structural changes and synovitis.

Motivations and objections to implement a spondyloarthritis integrated care pathway. A qualitative study with primary care physicians.

BACKGROUND AND OBJECTIVES: Previous to the development of a clinical pathway (CP) for early spondyloarthritis (SpA), a qualitative study was performed to know the attitude of primary care physicians (PCP) with respect to CP implementation. METHODS: 5 discussion groups (2 in Madrid, 2 in Barcelona and 1 in Sevilla) and 3 interviews in Bilbao, were performed. PCP with different profiles were included. Groups and interviews were carried out by experts on qualitative methodology. RESULTS: PCP know little about CP. Motivations of professionals to work on a SpA CP were: to improve patients care, availability of a specialist consultant, possibility of learning and doing research, remuneration, and professional recognition. Objections to CP implementation were: extra work, excessive bureaucracy, absence of a specialist consultant, computer difficulties, and no remuneration. SpA knowledge by PCP was defective. PCP associated the term «spondylitis¼ with osteoarthritis, low-back pain, ankylosing spondylitis and psoriatic arthritis. They only referred patients to the rheumatologist to confirm the diagnosis, when patients complained and when treatment was ineffective. CONCLUSIONS: For an optimal CP implementation, the following is deemed necessary: 1) a practical, simple program that eases the interaction with the rheumatologist without an increase on the PCP work load; 2) to provide continuous feedback by the specialist and 3) to provide knowledge on SpA to PCP.

Impact of clonal variability in Vitis vinifera Cabernet franc on grape composition, wine quality, leaf blade stilbene content, and downy mildew resistance.

In this study, 10 clones of Vitis vinifera Cabernet franc (not yet commercial) have been phenotyped on precocity, grape composition, and assessment of wine quality made by microvinification in 2008-2010. Additionally, two original criteria have been considered: concentration of 3-isobutyl-2-methoxypyrazine (IBMP) in grapes and wines (the green bell pepper flavor) and resistance of grapevines to downy mildew ( Plasmopara viticola ) by stilbene quantification upon infection. Precocity of veraison varied up to four days at veraison. Berry size and yield were highly variable among clones. However, these variables were not correlated. Tanins and anthocyanins varied among clones in grapes and wines. Variations in grape and wine IBMP were not significant. Some clones showed lower susceptibility for downy mildew on leaves. Lower susceptibility was linked to a higher production of stilbenic phytoalexins involved in downy mildew resistance mechanisms.

Susceptibility to downy mildew in grape clusters: New microscopical and biochemical insights.

Grape clusters of different Vitis genotypes, including Vitis vinifera cvs Chasselas and Merlot, and two interspecific grape varieties, Solaris (cvs. Merzling* x (Saperavi severneyi x Muscat ottonel)) and 2091 (cvs. Gamaret x Bronner), are susceptible or resistant to downy mildew. These cultivars were inoculated with Plasmopara viticola at three developmental stages (BBCH stages 53, 69 and 75). Samples were examined by scanning electron microscopy and the synthesis of stilbenes was measured. Microscopical examinations of pedicels, rachis and calyptras showed important differences in stomatal structures within seasonal development. At BBCH 53, successful infections were observed on all tested cultivars and functional stomata were present, while no infections were observed after this stage. At BBCH 69 and 75, cracks were observed around the stomata and guard cells were unstructured or completely collapsed, leading to closed-like stomata. At BBCH 53, significant stilbene accumulation was quantified in 2091 and Solaris; pterostilbene and δ-viniferin were produced in large amounts. In the susceptible varieties, only piceid and resveratrol were induced. At the other two stages, the concentration of all measured stilbenes was undetectable. The critical roles of seasonal development and stilbenes in the resistance of grape clusters towards downy mildew are discussed.

Protease inhibitors decrease the resistance of Vitaceae to Plasmopara viticola.

Plasmopara viticola must successfully infect susceptible grapevine cultivars to complete its biological cycle. In resistant grapevine varieties, P. viticola is blocked by the activation of defense mechanisms; these defense mechanisms produce hypersensitive reactions, which are related to programmed cell death. In animals, programmed cell death is dependent on caspase activities. In plants, different caspase-like proteases assume the same functions. To examine the roles of caspase-like proteases in P. viticola-grapevine interactions, three varieties of grapevine with different levels of P. viticola resistance were chosen. These grapevine varieties were treated with either PMSF, a serine protease inhibitor, or E-64, a cysteine protease inhibitor. The development of the pathogen was followed microscopically, and the plant defense reactions were estimated through stilbene quantification. Both protease inhibitor treatments increased the infection rate in the resistant and immune varieties, diminished the production of toxic stilbenes and changed the level of the plants' susceptibility to the pathogen. In particular, after either protease treatment, the cultivar that was originally immune became resistant (hyphae and haustoria were observed), the resistant cultivar reached the level of a susceptible cultivar (sporulation was observed) and the susceptible cultivar became more sensitive (P. viticola colonized the entirety of the leaf mesophyll).

[Characteristics of early arthritis units that may be associated with better referral efficiency: survey of SERAP units]. / Características de una unidad de artritis precoz que mejoran la eficiencia de la derivación: encuesta a las unidades SERAP.

OBJECTIVE: To identify characteristics of early arthritis units, that may be associated with better referral eficiency. METHODS: A national survey of the 36 early arthritis units (EAU) in Spanish Rheumatology Units in 2004 (SERAP project). Survey collected information about general practitioners (GP) educational program to improve knowledge and practical skills of early arthritis, networking and feed-back system and referral efficiency. EAU were classified in two groups according to 25 and 50% of inappropriate referral process, respectively. RESULTS: Thirty four of the 36 (94%) EAU, answered the survey. GP were trained in only 1 medical meeting in the primary care clinic, with one or more rheumatologists responsible of GP education. Fourteen of the 34 EAU (42.4%) regularly interacted with GP and only 20 (39.4%) contacted the GP who were responsible for the wrong referral process. Median lag time for referral to the Rheumatology out-patient clinic, was 73 days (15-365 days). The percentage of wrongly referred patients was between 0 and 80% (38% ± 21). Only 10 EAU (27.8%) referred patients appropriately according to the most strict criteria (25% of inappropriate referral) and 27 EAU (75%), according to 50% of inappropriate referral criteria. CONCLUSIONS: Only two aspects of the EAU implementation strategy were associated with better referral efficiency: 1) interaction with the GP responsible of the inappropriate referral process and 2) a lower median lag time for referral to the Rheumatology out-patient clinic.

The effectiveness of stilbenes in resistant Vitaceae: ultrastructural and biochemical events during Plasmopara viticola infection process.

Leaves of different Vitis vinifera L. cultivars, susceptible or resistant to downy mildew, Chasselas, Solaris, IRAC 2091 (cvs. Gamaret x Bronner) and Muscadinia rotundifolia were inoculated with Plasmopara viticola. Samples were then examined by scanning and transmission electron microscopy, by light microscopy and for their ability to synthesise stilbenes. These phytoalexins were strictly analysed at infection sites. In the susceptible Chasselas, P. viticola colonises, at 72h post-infection (hpi), all of the spongy mesophyll with functional haustoria and produces mainly the non toxic piceide. No necrotic zone was observed on Chasselas leaves. The ultrastructural response to downy mildew infection is different in each of the other three resistant grape cultivars. In Solaris, where leaf necrosis are rapidly induced, the infection is restricted to the upper part of the loose spongy mesophyll, and associated with a rapid cell wall disruption and the dispersion of cytoplasmic content along with the production of viniferins. In IRAC 2091, leaf necrosis are quite similar to those observed on Solaris but the infected plant cell, as well as the haustoria, show high electron dense cellular particles without any recognisable organelles, probably related to the effect of the toxic compound pterostilbene, which is synthesised in this grape cultivar. In M. rotundifolia leaf necrosis are much more scarce and smaller than in other cultivars, but pathogen and plant cells are both strongly affected, with concomitant expulsion of cytoplasmic materials through the stomata after P. viticola penetration. In this cultivar, the concentration of all identified stilbenes exceeds 1×10³ µmol mg(-1) FW. The critical role of stilbenes in the resistance of Vitis spp. is discussed.