Microchimeric cells promote production of rheumatoid arthritis-specific autoantibodies.

BACKGROUND: Women are more likely to develop autoimmune diseases than men. Contribution from microchimerism (Mc) has been proposed, as women naturally acquire Mc from more sources than men because of pregnancy. Women with Rheumatoid Arthritis (RA) who lack RA-associated HLA alleles have been found to harbor Mc with RA-associated HLA alleles in higher amounts than healthy women in prior work. However, an immunological impact of Mc remains to be elucidated. OBJECTIVES: To test the hypothesis that Mc with RA-risk associated HLA alleles can result in the production of RA-associated autoantibodies, when host genetic risk is absent. METHODS: DBA/2 mice are unable to produce RA-specific anti-citrullinated autoantibodies (ACPAs) after immunization with the enzyme peptidyl arginine deiminase (PAD) in a previously developed model. DBA/2 females were mated with C57BL/6 males humanized to express HLA-DR4, which is associated with RA-risk and production of ACPAs, to evaluate DR4+ fetal Mc contribution. Next, DBA/2 females born of heterozygous DR4+/- mothers were evaluated for DR4+ Mc of maternal or littermate origin. Finally, DBA/2 females from DR4+/- mothers were crossed with DR4+ males, to evaluate the contribution of any Mc source to ACPA production. RESULTS: After PAD immunization, between 20 % and 43 % of DBA/2 females (otherwise unable to produce ACPAs) had detectable ACPAs (CCP2 kit) after exposure to sources of Mc with RA-associated HLA alleles, compared to 0 % of unmated/unexposed DBA/2 females. Further the microchimeric origin of the autoantibodies was confirmed by detecting a C57BL/6-specific immunoglobulin isotype in the DBA/2 response. CONCLUSION: Our study demonstrates that Mc cells can produce "autoantibodies" and points to a role of Mc in the biology of autoimmune diseases, including RA.

PAD2 immunization induces ACPA in wild-type and HLA-DR4 humanized mice.

Rheumatoid arthritis (RA) is associated with HLA-DRB1 alleles expressing the "shared epitope." RA is usually preceded by the emergence of anti-citrullinated protein autoantibodies (ACPAs). ACPAs recognize citrulline residues on numerous proteins. Conversion of arginine into citrulline is performed by enzymes called peptidyl arginine deiminases (PADs). We have previously demonstrated that C3H mice immunized with PADs can produce ACPAs by a hapten-carrier mechanism. Here, we address the influence of HLA-DR alleles in this model in mice expressing RA-associated HLA-DRB1*04:01 (KO/KI*04:01), HLA-DRB1*04:04 (KO/KI*04:04), or non-RA-associated HLA-DRB1*04:02 (KO/KI*04:02) after murine PAD2 immunization. Immunization with mPAD2 triggers production of ACPAs in wild-type (WT) and HLA-DR4 C57BL/6 mice. Both I-Ab and HLA-DR are involved in the activation of mPAD2-specific T lymphocytes. Among HLA-DR4 mice, mice expressing RA-associated HLA-DRB1*04:01 are the best responders to mPAD2 and the best anti-citrullinated peptide antibody producers.

Sustainable development in general practice.

BACKGROUND: As health care accounts for 4-5% of global carbon emissions, many health organisations have called for implementing sustainable development actions in health care. However, sustainable development measures in general practice are rarely implemented by physicians. The aim of this study was to explore the practices of general practitioners (GPs) in terms of sustainable development to identify which actions are appropriate and achievable. METHODS: A qualitative study was conducted in 12 French GPs using face-to-face or telephone interviews, transcribed verbatim and analysed through a global inductive analysis with constant comparison. Semi-structured interviews were focussed on waste management, relationships between health professionals, sustainable development, and GPs' activity. RESULTS: The mean age of the GPs was 42.8 years and they mainly worked in an urban environment. The interviews highlighted 4 themes. It appeared that a balance needs to be found between the environmental impact and the constraints related to medical care. To be able to think about integrating sustainable development into health care, GPs should make a personal commitment to change their routine. In practice, consumption should be reassessed, prescriptions and prevention reconsidered. These actions could be applied to the GPs' environment as role models for their patients, business leaders, and members of the healthcare system. CONCLUSION: GPs felt concerned by sustainable development and were already involved in its implementation in their practice. Tools are available to help GPs to continue to implement their actions described in this article, but their impact remains to be investigated.

In an era where global health is an increasing concern for the population, it appeared necessary to study the extent to which health professionals were willing to change their behaviours in their professional lives. This study was based on the interview of 12 French general practitioners and investigated their perspective on sustainable development and how they implemented it in their practice. Four main themes were highlighted. Some physicians did not spontaneously see the link between their practice and sustainable development. Our study showed that they were willing to adapt their practice despite organisational constraints and the difficulty in changing their behaviour.

Upscaling xylem phenology: sample size matters.

BACKGROUND AND AIMS: Upscaling carbon allocation requires knowledge of the variability at the scales at which data are collected and applied. Trees exhibit different growth rates and timings of wood formation. However, the factors explaining these differences remain undetermined, making samplings and estimations of the growth dynamics a complicated task, habitually based on technical rather than statistical reasons. This study explored the variability in xylem phenology among 159 balsam firs [Abies balsamea (L.) Mill.]. METHODS: Wood microcores were collected weekly from April to October 2018 in a natural stand in Quebec, Canada, to detect cambial activity and wood formation timings. We tested spatial autocorrelation, tree size and cell production rates as explanatory variables of xylem phenology. We assessed sample size and margin of error for wood phenology assessment at different confidence levels. KEY RESULTS: Xylem formation lasted between 40 and 110 d, producing between 12 and 93 cells. No effect of spatial proximity or size of individuals was detected on the timings of xylem phenology. Trees with larger cell production rates showed a longer growing season, starting xylem differentiation earlier and ending later. A sample size of 23 trees produced estimates of xylem phenology at a confidence level of 95 % with a margin of error of 1 week. CONCLUSIONS: This study highlighted the high variability in the timings of wood formation among trees within an area of 1 km2. The correlation between the number of new xylem cells and the growing season length suggests a close connection between the processes of wood formation and carbon sequestration. However, the causes of the observed differences in xylem phenology remain partially unresolved. We point out the need to carefully consider sample size when assessing xylem phenology to explore the reasons underlying this variability and to allow reliable upscaling of carbon allocation in forests.

Do RA associated HLA-DR molecules bind citrullinated peptides or peptides from PAD4 to help the development of RA specific antibodies to citrullinated proteins?

PURPOSE: Rheumatoid arthritis (RA) is associated with HLA-DRB1 genes encoding a five amino acid basic motive, the shared epitope SE). Each HLA-DRB1 genotype defines a genotype specific risk of developing RA. RA is preceded by the emergence of anti citrullinated protein antibodies (ACPAs). Citrullin is a neutral version of arginin, a basic amino acid, formed after post translational modification by Peptidyl Arginyl Deiminases (PADs). HLA-DRB1 genes associated with RA are also associated with ACPAs. Two models might explain this association. Here we tested both models for prediction of HLA-DRB1 genotypic risks of developing RA. METHODS: We calculated the likelihoods for the 2 HLA-DR molecules encoded by 12 common HLA-DRB1 genotypes to bind at least one randomly chosen peptide from PAD4 or fibrinogen(native or citrullinatd) and compared them with the 12 respective HLA-DRB1genotypic risks of developing RA. RESULTS: HLA-DRB1 Genotypic risks of developing RA correlate with likelihoods of binding PAD4 peptides, not citrullinated Fibrinogen peptides. Thus, the molecular basis for the association of HLA-DR and ACPA positive RA is most likely the capability for RA associated HLA-DR molecules to bind peptides(s) from PAD4.

Peptidyl arginine deiminase immunization induces anticitrullinated protein antibodies in mice with particular MHC types.

Autoantibodies to citrullinated proteins (ACPAs) are present in two-thirds of patients with rheumatoid arthritis (RA). ACPAs are produced in the absence of identified T cell responses for each citrullinated protein. Peptidyl arginine deiminase 4 (PAD4), which binds proteins and citrullinates them, is the target of autoantibodies in early RA. This suggests a model for the emergence of ACPAs in the absence of detectable T cells specific for citrullinated antigens: ACPAs could arise because PADs are recognized by T cells, which help the production of autoantibodies to proteins bound by PADs, according to a "hapten/carrier" model. Here, we tested this model in normal mice. C3H are healthy mice whose IEßk chain is highly homologous to the ß1 chain HLA-DRB1*04:01, the allele most strongly associated with RA in humans. C3H mice immunized with PADs developed antibodies and T cells to PAD and IgG antibodies to citrullinated fibrinogen peptides, in the absence of a T cell response to fibrinogen. To analyze the MHC background effect on hapten/carrier immunization, we immunized DBA/2 mice (whose IEßd chain is similar to that of HLA-DRB1*04:02, an HLA-DR4 subtype not associated with RA). DBA/2 mice failed to develop antibodies to citrullinated fibrinogen peptides. Thus, T cell immunization to PAD proteins may trigger ACPAs through a hapten/carrier mechanism. This may constitute the basis for a new mouse model of ACPA-positive RA.

Comparison of nine heart rate-based models to predict work metabolism of Forest workers.

Predicted work metabolism (WM) from 9 heart rate (HR)-based models were compared to measured WM obtained during work in 39 forest workers. Using measured (i.e. raw) HR in these models can overestimate actual WM since the HR increase associated with body heat accumulation is non-metabolic. Hence, accuracy of WM prediction was assessed on all possible combinations of models using raw HR and corrected HR (thermal component removed) and with five different estimates of maximum work capacity (MWC) for the models that require it as an input. The 50 model combinations produced a wide range of WM estimates. Three models using individual calibration produced the lowest RMSE and narrowest LoA with corrected HR (rRMSE ≤13%; LoA [rBias <5% ± 25%]). One of the models that requires neither determination of the thermal component nor individual calibration performed very well (rRMSE = 18%; LoA [rBias = 1% ± 36%]). Practitioner Summary: These results provide a better understanding of the accuracy of various HR-based work metabolism (WM) estimation models. This information should prove particularly useful to ergonomics professionals wishing to select a method that provides accurate estimation of WM from HR measurements during work in varied thermal environments. Abbreviations: BMI: body mass index; HR: heart rate (beats per min); HR99: HR value exceeded during 99% of the duration of the HR recording period; HRcorr: heart rate without thermal pulses; HRraw: measured heart rate; HRres: heart rate reserve; HRrest: heart rate at rest; LoA: limits of agreement; Mrest: resting metabolism; MWC: maximum work capacity; RMSE: root mean square error; VO2: oxygen consumption; VO2 max: maximum oxygen consumption; WM: work metabolism.

Porphyromonas gingivalis experimentally induces periodontis and an anti-CCP2-associated arthritis in the rat.

OBJECTIVES: Association between periodontal disease (PD) and rheumatoid arthritis (RA) has been extensively described, but direct evidence of causal involvement of PD in RA is missing. We investigated the priming role of oral Porphyromonas gingivalis (P. gingivalis) in PD and subsequent RA and we assessed biomarkers of bone resorption and arthritis development in rats. METHODS: Lewis rats were orally exposed to either P. gingivalis, Prevotella intermedia or control gel for 1 month and then followed for 8 months. The onset and development of PD was assessed by serology, gingivitis severity and micro-CT (µCT). We investigated arthritis development using circulating proinflammatory markers, anticyclic citrullinated peptide (CCP), anticitrullinated protein antibody (ACPA), ankle histology and µCT. RESULTS: PD was only observed in the P. gingivalis treated rats, as early as 1 month postexposure. Joint and systemic inflammation were detected only in the P. gingivalis group after 4 and 8 months. At 8 months, inflammatory cell infiltrate was observed in ankle joints and paralleled cortical erosions and overall cortical bone reduction. Furthermore, anti-CCP2 correlated with local and systemic bone loss. CONCLUSIONS: In our long-term study, PD induced by oral exposure to P. gingivalis triggered seropositive arthritis, with systemic inflammation and bone erosions. This is the first in vivo demonstration of arthritis induced by oral priming with P. gingivalis.

Patients' high acceptability of a future therapeutic HIV vaccine in France: a French paradox?

BACKGROUND: France is the European country with the lowest level of confidence in vaccines. Measurement of patients' acceptability towards a future therapeutic HIV vaccine is critically important. Thus, the aim of this study was to evaluate patients' acceptability of a future therapeutic HIV vaccine in a representative cohort of French patients living with HIV-AIDS (PLWHs). METHODS: This multicentre study used quantitative and qualitative methods to assess PLWHs' opinions and their potential acceptance of a future therapeutic HIV vaccine. Cross-sectional study on 220 HIV-1 infected outpatients, aged 18-75 years. RESULTS: The participants' characteristics were similar to those of the overall French PLWH population. Responses from the questionnaires showed high indices of acceptance: the mean score for acceptability on the Visual Analog Scale VAS was 8.4 of 10, and 92% of patients agreed to be vaccinated if a therapeutic vaccine became available. Acceptability depended on the expected characteristics of the vaccine, notably the duration of its effectiveness: 44% of participants expected it to be effective for life. This acceptance was not associated with socio-demographic, clinical (mode of contamination, duration of disease), quality of life, or illness-perception parameters. Acceptability was also strongly correlated with confidence in the treating physician. CONCLUSION: The PLWHs within our cohort had high indices of acceptance to a future therapeutic HIV vaccine. TRIAL REGISTRATION: This study was retroactively registered on ClinicalTrials.gov with ID: NCT02077101 in February 21, 2014.

Worker heat stress prevention and work metabolism estimation: comparing two assessment methods of the heart rate thermal component.

The heart rate thermal component ( ΔHRT ) can increase with body heat accumulation and lead to work metabolism (WM) overestimation. We used two methods (VOGT and KAMP) to assess ΔHRT of 35 forest workers throughout their work shifts, then compared ΔHRT at work and at rest using limits of agreement (LoA). Next, for a subsample of 20 forest workers, we produced corrected WM estimates from ΔHRT and compared them to measured WM. Although both methods produced significantly different ΔHRT time-related profiles, they yielded comparable average thermal cardiac reactivity (VOGT: 24.8 bpm °C-1; KAMP: 24.5 bpm °C-1), average ΔHRT (LoA: 0.7 ± 11.2 bpm) and average WM estimates (LoA: 0.2 ± 3.4 ml O2 kg-1min-1 for VOGT, and 0.0 ± 5.4 ml O2 kg-1min-1 for KAMP). Both methods are suitable to assess heat stress through ΔHRT and improve WM estimation. Practitioner summary: We compared two methods for assessing the heart rate thermal component ( ΔHRT ), which is needed to produce a corrected HR profile for estimating work metabolism (WM). Both methods yielded similar ΔHRT estimates that allowed accurate estimations of heat stress and WM at the group level, but they were imprecise at the individual level. Abbreviations: AIC: akaike information criterion; bpm: beats per minute; CI: confidence intervals; CV: coefficient of variation in %; CV drift: cardiovascular drift; ΔHRT: the heart rate thermal component in bpm; ΔHRT: the heart rate thermal component in bpm; ΔΔHRT: variation in the heart rate thermal component in bpm; ΔTC: variation in core body temperature in °C; HR: heart rate in bpm; HRmax: maximal heart rate in bpm; Icl: cloting insulation in clo; KAMP: Kampmann et al. (2001) method to determe ΔHRT; LoA: Limits of Agreement; PMV-PPD: the Predicted Mean Vote and Predicted Percentage Dissatisfied; PHS: Predicted Heat Strain model; RCM: random coefficients model; SD: standard deviation; TC: core body temperature in °C; TCR: thermal cardiac reactivity in bpm °C-1; τΔHRT: rate of change in the heart rate thermal component in bpm min-1; τTC: rate of change in core body temperature in °C min-1; tα,n-1: Student's t statistic with level of confidence alpha and n-1 degrees of freedom; TWL: Thermal Work Limit model; V̇O2 : oxygen consumption in ml O2 kg-1 min-1; V̇O2 max: maximal oxygen consumption in ml O2 kg-1 min-1; VOGT: Vogt et al. (1973) method to determine ΔHRT; WBGT: Wet-Bulb Globe Temperature in °C; WM: work metabolism.

A case of congenital lipomatous overgrowth, vascular malformations, epidermal nevi, spinal/skeletal anomalies and/or scoliosis syndrome with lipoatrophy as an important clinical manifestation.

Congenital lipomatous overgrowth, vascular malformations, epidermal nevi, spinal/skeletal anomalies and/or scoliosis syndrome is a PIK3CA-related overgrowth spectrum presenting with congenital, asymmetric, disproportionate overgrowth associated with dysregulated adipose tissue, enlarged bony structures, and mixed primarily truncal vascular malformations. We present this case to raise awareness that very thin body habitus (lipoatrophy) contrasting with areas of overgrowth can be an important clinical feature of this syndrome and, if not recognized, can lead to unnecessary investigations.

Acquired Immune Deficiency Syndrome-Associated Kaposi Sarcoma in a Child Presenting as a Solitary Plantar Hyperkeratotic Plaque.

BACKGROUND AND OBJECTIVE: Acquired immune deficiency syndrome (AIDS)-associated Kaposi sarcoma (KS) among the pediatric population is a rare entity in North America and Europe, and its cutaneous manifestations are not well defined in the literature. The investigators report the case of a boy with an AIDS-associated KS presenting as an infiltrated hyperkeratotic plaque of the plantar arch. METHODS AND RESULTS: An 11-year-old African boy with congenital human immunodeficiency virus (HIV) had a skin biopsy of the plantar lesion that was consistent with a KS. The patient also presented intestinal and pulmonary symptoms; combined chemotherapy regimen and highly active antiretroviral therapy were given in the presence of systemic involvement. CONCLUSION: AIDS-associated KS poses a particular challenge to clinical diagnosis, since it can manifest with a variety of lesions. Dermatologists should have a low threshold for performing a skin biopsy in patients with HIV.

Quality of qualitative studies centred on patients in family practice: a systematic review.

BACKGROUND: Qualitative research is often used in the field of general medicine. Our objective was to evaluate the quality of published qualitative studies conducted using individual interviews or focus groups centred on patients monitored in general practice. METHODS: We have undertaken a review of the literature in the PubMed and Embase databases of articles up to February 2014. The selection criteria were qualitative studies conducted using individual interviews or focus groups, centred on patients monitored in general practice. The articles chosen were analysed and evaluated using a score established from the Relevance, Appropriateness, Transparency and Soundness (RATS) grid. RESULTS: The average score of the 52 studies chosen was 28 out of 42. The criteria least often present were the description of the patients who chose not to participate in the study, the justification of the end of data collection, the discussion of the influence of the researchers and the discussion of the confidentiality of the data. The criteria most frequently described were an explicit research question, justified and in relation to existing knowledge, the agreement of the ethical committee and the presence of quotations. The number of studies and the score increased from year-to-year. The score was independent of the impact factor of the journal. CONCLUSIONS: Even though the qualitative research was published in reviews with a low impact factor, our results suggest that this research responded to the quality criteria of the RATS grid. The evaluation scored using RATS could be useful for authors or reviewers and for literature reviews.

Private or salaried practice: how do young general practitioners make their career choice? A qualitative study.

BACKGROUND: Young French postgraduates in general practice increasingly prefer salaried practice to private practice in spite of the financial incentives offered by the French government or local communities to encourage the latter. This study aimed to explore the determinants of choice between private or salaried practice among young general practitioners. METHODS: A qualitative study was conducted in the South West of France. Semi-structured interviews of young general practitioners were audio-recorded until data saturation. Recordings were transcribed and then analyzed according to Grounded Theory by three researchers working independently. RESULTS: Sixteen general practitioners participated in this study. For salaried and private doctors, the main factors governing their choice were occupational factors: working conditions, need of varied scope of practice, quality of the doctor-patient relationship or career flexibility. Other factors such as postgraduate training, having worked as a locum or self-interest were also determining. Young general practitioners all expected a work-life balance. The fee-for-service scheme or home visits may have discouraged young general practitioners from choosing private practice. CONCLUSIONS: National health policies should increase the attractiveness of ambulatory general practice by promoting the diversification of modes of remuneration and encouraging the organization of group exercises in multidisciplinary medical homes and community health centers.

Prediction of work metabolism from heart rate measurements in forest work: some practical methodological issues.

Individual heart rate (HR) to workload relationships were determined using 93 submaximal step-tests administered to 26 healthy participants attending physical activities in a university training centre (laboratory study) and 41 experienced forest workers (field study). Predicted maximum aerobic capacity (MAC) was compared to measured MAC from a maximal treadmill test (laboratory study) to test the effect of two age-predicted maximum HR Equations (220-age and 207-0.7 × age) and two clothing insulation levels (0.4 and 0.91 clo) during the step-test. Work metabolism (WM) estimated from forest work HR was compared against concurrent work V̇O2 measurements while taking into account the HR thermal component. Results show that MAC and WM can be accurately predicted from work HR measurements and simple regression models developed in this study (1% group mean prediction bias and up to 25% expected prediction bias for a single individual). Clothing insulation had no impact on predicted MAC nor age-predicted maximum HR equations. Practitioner summary: This study sheds light on four practical methodological issues faced by practitioners regarding the use of HR methodology to assess WM in actual work environments. More specifically, the effect of wearing work clothes and the use of two different maximum HR prediction equations on the ability of a submaximal step-test to assess MAC are examined, as well as the accuracy of using an individual's step-test HR to workload relationship to predict WM from HR data collected during actual work in the presence of thermal stress.

Felty's syndrome and hypofibrinogenemia: an unusual target for anti-cyclic citrullinated peptide antibodies?

BACKGROUND: Rheumatoid arthritis (RA) is a risk factor for the development of Felty's syndrome and large granular lymphocyte (LGL) leukemia. Anti-cyclic citrullinated peptide (CCP) antibodies are considered highly specific for RA and are directed against various citrullinated antigens, including citrullinated fibrinogen. Anti-CCP antibodies may interfere with the detection of citrullinated proteins and their function. In this article, we describe the possible inhibition of fibrinogen by anti-CCP antibodies with clinical consequences which have never been reported in the literature to our best knowledge. CASE REPORT: We present the case of a 79-year-old Caucasian woman with a longstanding history of untreated seropositive RA and who had been investigated for severe neutropenia since several months. The association of splenomegaly led to suspicion of Felty's syndrome. Flux cytometry was compatible with T-cell LGL leukemia. In addition, severe hypofibrinogenemia was detected. The later finding has not been consistently associated with the former clinical entities. Further investigations demonstrated that the anti-CCP antibodies of the patient also recognized the P41 peptide of citrullinated fibrinogen. The patient deceased of intracranial hemorrhage. CONCLUSION: It is likely, yet not definite, that high anti-citrullinated fibrinogen titers may contribute to low fibrinogen levels and could have contributed to the fatal hemorrhagic event.

Profile of French general practitioners providing opportunistic primary preventive care--an observational cross-sectional multicentre study.

BACKGROUND: Preventive services provided opportunistically by GPs are insufficient. Reasons are most often gathered through GPs' self-reports, rather than through independent observation. OBJECTIVE: To assess with passive observers, the degree to which French GPs opportunistically perform primary preventive care during routine consultation. METHODS: Observational cross-sectional multicentre ancillary study of the French ECOGEN study. The study period extended from 28 November 2011 to 30 April 2012. The inclusion criteria were patients seen by GPs at surgery and home consultations in non-randomized pre-determined half-day blocks per week. The non-inclusion criteria were patient's refusal and consultations initially focused on primary prevention in response to patient's request (ancillary study's specific criterion). Using passive observers, data were collected based on the second version of International Classification of Primary Care. Preventive consultations were defined if at least one problem/diagnosis was considered by consensus as definitely related to primary prevention. For each one of the 128 participating GPs, aggregation of data was performed from all his/her consultations. Determinants of the proportion of preventive consultations per GP were assessed by multivariate linear regression. RESULTS: Considering 19003 consultations, the median proportion of preventive consultations per GP was 14.9% (range: 0-78.3%). It decreased with increased proportion of patients aged 18 or less (P = 0.006), with increased proportion of home visits (P = 0.008) and with increased proportion of consultations lasting under 10 minutes (P = 0.02). None of the GPs' personal characteristics were significantly associated. CONCLUSION: Primary preventive care activity was related to the characteristics of GPs' patients and practice organizational markers and not to GPs' personal characteristics.