Publications by authors named "Jean-François Menard"

50 Publications

The neuropeptide substance P regulates aldosterone secretion in human adrenals.

Nat Commun 2020 05 29;11(1):2673. Epub 2020 May 29.

Normandie Univ, UNIROUEN, INSERM, DC2N, 76000, Rouen, France.

Aldosterone, produced by the adrenals and under the control of plasma angiotensin and potassium levels, regulates hydromineral homeostasis and blood pressure. Here we report that the neuropeptide substance P (SP) released by intraadrenal nerve fibres, stimulates aldosterone secretion via binding to neurokinin type 1 receptors (NK1R) expressed by aldosterone-producing adrenocortical cells. The action of SP is mediated by the extracellular signal-regulated kinase pathway and involves upregulation of steroidogenic enzymes. We also conducted a prospective proof-of-concept, double blind, placebo-controlled clinical trial aimed to investigate the impact of the NK1R antagonist aprepitant on aldosterone secretion in healthy male volunteers (EudraCT: 2008-003367-40, NCT00977223). Participants received during two 7-day treatment periods aprepitant (125 mg on the 1 day and 80 mg during the following days) or placebo in a random order at a 2-week interval. The primary endpoint was plasma aldosterone levels during posture test. Secondary endpoints included basal aldosterone alterations, plasma aldosterone variation during metoclopramide and hypoglycaemia tests, and basal and stimulated alterations of renin, cortisol and ACTH during the three different stimulatory tests. The safety of the treatment was assessed on the basis of serum transaminase measurements on days 4 and 7. All pre-specified endpoints were achieved. Aprepitant decreases aldosterone production by around 30% but does not influence the aldosterone response to upright posture. These results indicate that the autonomic nervous system exerts a direct stimulatory tone on mineralocorticoid synthesis through SP, and thus plays a role in the maintenance of hydromineral homeostasis. This regulatory mechanism may be involved in aldosterone excess syndromes.
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May 2020

Diffusion-weighted MRI is not superior to FDG-PET/CT for the detection of neck recurrence in well-differentiated thyroid carcinoma.

Q J Nucl Med Mol Imaging 2019 Sep 3;63(3):311-320. Epub 2017 May 3.

Department of Nuclear Medicine and Radiology, Henri Becquerel Centre & Quant.I.F - LITIS (Equipe d'Accueil) 4108 - Fédération de Recherche CNRS 3638, Faculty of Medicine, University of Rouen, Rouen, France.

Background: Management of patients with well-differentiated thyroid carcinoma (WDTC) and positive thyroglobulin (Tg)/negative iodine-131 whole body scintigraphy (WBS) remains challenging. Here, we investigate the specific role of diffusion-weighted magnetic resonance imaging of the neck (DW-MRI) as compared to rhTSH stimulated FDG-PET/CT in such patients.

Methods: Patients with WDTC, positive Tg/negative WBS were prospectively enrolled in the study. FDG-PET/CT and neck DW-MRI were performed on the same day after rhTSH stimulation. Neck-US was performed 24 hours after FDG-PET/CT and MRI to guide fine-needle aspiration (FNA). Patients with positive FNA underwent surgery. Patient with negative workup underwent new explorations at 6 and 18 months.

Results: A total of 86 FDG-PET/CT and 83 DW-MRI tests were performed in 40 patients (23 females; 17 males; 52±16 years). For detection of neck recurrences, sensitivity was equivalent for FDG-PET/CT and to DW-MRI at baseline (46% vs. 43%), at 6 months (30% vs. 20%) and at 18 months (11 vs. 10%). The comparison with a non-weighted Kappa test shows significant concordance between FDG-PET/CT and DW-MRI (K=0.741±0.062; P<0.0001). A relationship was observed between Tg and results of FDG-PET/CT, but not for DW-MRI. FDG-PET/CT permitted to detect iodine-refractory distant metastasis in 4 patients.

Conclusions: In Tg-positive/WBS-negative DTC patients, low tumour burden, neck DW-MRI does not provide additional information compared to rhTSH-stimulated FDG-PET/CT. FDG-PET/CT has the best sensitivity, is acceptable for patients, allows whole body exploration and distant metastasis detections, and is correlated with Tg levels.
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September 2019

Nail involvement in systemic sclerosis.

J Am Acad Dermatol 2017 Jun 20;76(6):1115-1123. Epub 2016 Dec 20.

Department of Internal Medicine, Rouen University Hospital, Rouen, France; Institut National de la Santé et de la Recherche Médicale U 905, University of Rouen Institut Fédératif Multidisciplinaire sur les Peptides, Institute for Biochemical Research, Rouen, France.

Background: Nail involvement has rarely been recognized in systemic sclerosis (SSc). Indeed, only a few small series have assessed nail changes in SSc, most of which are case reports.

Objective: The aims of the current case-control study were to: (1) determine the prevalence of fingernail changes in SSc; and (2) evaluate the correlation between fingernail changes and other features of SSc.

Methods: In all, 129 patients with SSc and 80 healthy control subjects underwent routine fingernail examination.

Results: The prevalence of fingernail changes was 80.6% in SSc. Patients with SSc more frequently exhibited: trachyonychia (P = .006), scleronychia (P < .0001), thickened nails (P < .0001), brachyonychia (P = .0004), parrot beaking (P < .0001), pterygium inversum unguis (P < .0001), splinter hemorrhages (P < .0001), and cuticle abnormalities (P < .0001) than healthy control subjects. The presence of fingernail changes was associated with digital ulcers (P < .0001), calcinosis cutis (P = .004), and higher values of mean nailfold videocapillaroscopy score (P = .0009).

Limitations: The cohort originated from a single center.

Conclusion: This study underlines that fingernail changes are correlated with more severe forms of SSc characterized by digital microangiopathy, including digital ulcers and calcinosis cutis. Nail changes should be systematically checked in all patients with SSc, and may be included in the American College of Rheumatology/European League Against Rheumatism classification criteria for SSc.
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June 2017

Antineutrophil Cytoplasmic Antibodies Associated With Infective Endocarditis.

Medicine (Baltimore) 2016 Jan;95(3):e2564

From the Department of Internal Medicine, Institute for Biochemical Research, IFRMP, University of Rouen (VL, AL, NG, HL, IM); Department of Infectious diseases (FC); and Department of Biostatistics (J-F M), CHU Rouen, France.

To determine the prevalence of antineutrophil cytoplasmic antibodies (ANCA) in patients with infective endocarditis (IE) in internal medicine; and to compare clinical and biochemical features and outcome between patients exhibiting IE with and without ANCA.Fifty consecutive patients with IE underwent ANCA testing. The medical records of these patients were reviewed.Of the 50 patients with IE, 12 exhibited ANCA (24%). ANCA-positive patients with IE exhibited: longer duration between the onset of first symptoms and IE diagnosis (P = 0.02); and more frequently: weight loss (P = 0.017) and renal impairment (P = 0.08), lower levels of C-reactive protein (P = 0.0009) and serum albumin (P = 0.0032), involvement of both aortic and mitral valves (P = 0.009), and longer hospital stay (P = 0.016). Under multivariate analysis, significant factors for ANCA-associated IE were: longer hospital stay (P = 0.004), lower level of serum albumin (P = 0.02), and multiple valve involvement (P = 0.04). Mortality rate was 25% in ANCA patients; death was because of IE complications in all these patients.Our study identifies a high prevalence of ANCA in unselected patients with IE in internal medicine (24%). Our findings further underscore that ANCA may be associated with a subacute form of IE leading to multiple valve involvement and more frequent renal impairment. Because death was due to IE complications in all patients, our data suggest that aggressive therapy may be required to improve such patients' outcome.
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January 2016

Early phase clinical and biological markers associated with subclinical atherosclerosis measured at 7 years of evolution in an early inflammatory arthritis cohort.

Clin Exp Rheumatol 2016 Jan-Feb;34(1):58-67. Epub 2015 Dec 20.

Rheumatology Department, CIC/CRB1404, Rouen University Hospital, and Inserm Unit 905, IRIB, Rouen University, Rouen, France.

Objectives: Accelerated atherosclerosis has emerged as a critical issue in rheumatoid arthritis (RA). There is a need to better understand the link between RA and atherosclerosis. Our aim was to identify parameters associated with the development of subclinical atheroma in a very early arthritis (VErA) cohort.

Methods: VErA-cohort patients were prospectively recruited from 1998 to 2002. Arthritis treatment was standardised from onset. The clinical, biological and radiological parameters of all patients were collected from inclusion. Carotid intima-media thickness (cIMT) was measured 7 years after their first symptoms.

Results: Among 105 patients included, 82 developed RA (mean age at onset: 51.7±12.8 years). Mean carotid artery IMT at year 7 was 0.67±0.12 mm. Larger thickness defined by values above the median (0.66) was associated with inclusion age (p<10-6), swollen joint count (p=0.01), DAS44 (p=0.048) and hypertension (p=0.006). In contrast, anti-CCP positivity (>50 UA/ml) was associated with thinner cIMT (p=0.03). Baseline as well as cumulated values of markers reflecting systemic inflammation, lymphocyte activation, endothelial dysfunction and oxidative stress were not correlated with carotid subclinical atherosclerosis. Major independent atheroma risk factors retained by multivariate analyses were hypertension (OR 4.33 [1.59-11.73]; p=0.004) and swollen joint count at inclusion (OR 3.87 [1.54-9.72]; p=0.004), while methotrexate use was a protective marker (OR 0.27 [0.11-0.71]; p=0.007).

Conclusions: This study conducted from the VErA vascular cohort of community-cases of RA confirm that cIMT is under the influence of classical CV risk (hypertension), disease marker (SJC) and methotrexate intake.
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April 2016

Botulinum toxin: an endoscopic approach for treating fecal incontinence.

Endoscopy 2016 May 8;48(5):484-8. Epub 2015 Oct 8.

Department of Digestive Physiology, CHU, Rouen, France.

Background And Study Aims: Fecal incontinence is a common, distressing condition with limited therapeutic options. Botulinum toxin A (BTX-A) injections have been proposed as a treatment for patients with fecal incontinence. This study aimed to determine the short-term clinical outcomes of BTX-A injections in patients with fecal incontinence of varying etiology.

Patients And Methods: Twenty-six patients with fecal incontinence were enrolled, 17 with their native rectum and 9 with a neo-reservoir following a proctectomy for rectal cancer. BTX-A was endoscopically injected into the rectum/reservoir. Scores for severity (CCS) and quality of life (FIQL) were recorded at baseline and at the 3-month follow-up visit.

Results: The CCS was significantly lower after 3 months (median 15, range 4 - 20 vs. 8, range 1 - 19; P = 0.001). The quality of life improved in three of the four FIQL domains. The improvement was maintained in 11 of 12 patients who received more than one injection because of recurrent symptoms. There was no significant predictive factor for the success of BTX-A injections.

Conclusion: This preliminary study demonstrated that rectal/reservoir injections are an effective short-term treatment for fecal incontinence.
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May 2016

Fructose Malabsorption in Systemic Sclerosis.

Medicine (Baltimore) 2015 Sep;94(39):e1601

From the Department of Internal Medicine, CHU Rouen, and INSERM U 905 (IM, HL); Department of Digestive Physiology, CHU Rouen, and INSERM UMR 1073, University of Rouen IFRMP, Institute for Biochemical Research (A-ML, GG); Department of Biostatistics, CHU Rouen (J-FM); and Department of Gastroenterology, CHU Rouen, and INSERM UMR 1073, University of Rouen IFRMP, Institute for Biochemical Research, Rouen, France (PD).

The deleterious effect of fructose, which is increasingly incorporated in many beverages, dairy products, and processed foods, has been described; fructose malabsorption has thus been reported in up to 2.4% of healthy subjects, leading to digestive clinical symptoms (eg, pain, distension, diarrhea). Because digestive involvement is frequent in patients with systemic sclerosis (SSc), we hypothesized that fructose malabsorption could be responsible for intestinal manifestations in these patients. The aims of this prospective study were to: determine the prevalence of fructose malabsorption, in SSc; predict which SSc patients are at risk of developing fructose malabsorption; and assess the outcome of digestive symptoms in SSc patients after initiation of standardized low-fructose diet. Eighty consecutive patients with SSc underwent fructose breath test. All SSc patients also completed a questionnaire on digestive symptoms, and a global symptom score (GSS) was calculated. The prevalence of fructose malabsorption was as high as 40% in SSc patients. We also observed a marked correlation between the presence of fructose malabsorption and: higher values of GSS score of digestive symptoms (P = 0.000004); and absence of delayed gastric emptying (P = 0.007). Furthermore, in SSc patients with fructose malabsorption, the median value of GSS score of digestive symptoms was lower after initiation of standardized low-fructose diet (4 before vs. 1 after; P = 0.0009). Our study underscores that fructose malabsorption often occurs in SSc patients. Our findings are thus relevant for clinical practice, highlighting that fructose breath test is a helpful, noninvasive method by: demonstrating fructose intolerance in patients with SSc; and identifying the group of SSc patients with fructose intolerance who may benefit from low-fructose diet. Interestingly, because the present series also shows that low-fructose diet resulted in a marked decrease of gastrointestinal clinical manifestations in SSc patients with fructose malabsorption, our findings underscore that fructose malabsorption may play a significant role in the onset of gastrointestinal symptoms in these patients. Finally, we suggest that fructose malabsorption may be due to reduced fructose absorption by enterocytes, impaired enteric microbiome, and decreased intestinal permeability.
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September 2015

Switching from an anti-TNF monoclonal antibody to soluble TNF-receptor yields better results than vice versa: An observational retrospective study of 72 rheumatoid arthritis switchers.

Joint Bone Spine 2015 Oct 10;82(5):330-7. Epub 2015 Apr 10.

Rheumatology department, Rouen university hospital, Inserm unit 905, institute for research and innovation in biomedicine, university of Rouen, CIC/CRB 1404, 76031 Rouen cedex, France.

Objectives: To evaluate the benefits for rheumatoid arthritis (RA) patients of switching from one tumor necrosis factor inhibitor (TNFi) to another based on reason for change (primary failure, escape or intolerance) and molecule-switching order.

Methods: Between 2000 and 2008, 356 RA patients prescribed a TNFi (infliximab [IFX], etanercept [ETA] or adalimumab [ADA]) and undergoing standardized evaluation were included in this retrospective study. Detailed demographic, clinical and biological data were collected before first biologic use and ≤6 months later to evaluate response based on EULAR-criteria. Primary failure, escape or intolerance of first TNFi triggered switch to another TNFi, the response of which was evaluated 6 months later. Propensity score then measured any interaction with baseline variables.

Results: Of the 356 RA patients, 38 switched from IFX/ADA to ETA, 26 from ETA to IFX/ADA, and eight from one monoclonal antibody (mAb; IFX/ADA) to another. Clinical parameters for switchers and non-switchers were comparable. Switchers changed therapies because of primary failure (36.1%), escape (33.3%), or intolerance (30.6%), with no difference found in these subgroups. More switchers responded to the second TNFi than the first (P<0.01), respectively, regardless of switch (ETA to IFX/ADA: 50 vs. 23.1% [P<0.05]; IFX/ADA to ETA: 57.9 vs. 15.8% [P<0.001]) or reason for changing. In addition, DAS28 decreased more with the second antagonist (P<0.001) and regardless of molecules switched (P<0.01). Survival of the second TNFi was significantly longer with switch from mAb to the soluble receptor than vice versa (P<0.05).

Discussion: Overall, any switching from one TNFi to another, especially mAb to soluble receptor, was often beneficial for RA patients.
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October 2015

Association of occupational exposure with features of systemic sclerosis.

J Am Acad Dermatol 2015 Mar 10;72(3):456-64. Epub 2015 Jan 10.

Department of Internal Medicine, Centre Hospitalier Universitaire (CHU) Rouen, and Institut National de la Santé et de la Recherche Biomédicale (INSERM) Unit 905, University of Rouen Institut Fédératif Multidisciplinaire sur les Peptides (IFRMP), Institute for Biochemical Research, Rouen, France.

Background: Occupational exposure is reported as playing a substantial causative role in systemic sclerosis (SSc).

Objective: We sought to compare the characteristics of SSc in patients with and without occupational exposure to crystalline silica/solvents.

Methods: In all, 142 patients with SSc were enrolled in this prospective study. An expert committee performed blind evaluation of occupational exposure to crystalline silica/solvents.

Results: Patients exposed to crystalline silica more often exhibited: diffuse cutaneous SSc (P = .02), digital ulcers (P = .05), interstitial lung disease (P = .0004), myocardial dysfunction (P = .006), and cancer (P = .06). Patients exposed to solvents more frequently developed: diffuse cutaneous SSc (P = .001), digital ulcers (P = .01), interstitial lung disease (P = .02), myocardial dysfunction (P = .04), and cancer (P = .003); in addition, these patients were more frequently anti-Scl 70 positive and anticentromere negative. Under multivariate analysis, significant factors for SSc associated with exposure to silica/solvents were: male gender (odds ratio 19.31, 95% confidence interval 15.34-69.86), cancer (odds ratio 5.97, 95% confidence interval 1.55-23.01), and digital ulcers (odds ratio 2.42, 95% confidence interval 1.05-5.56).

Limitations: The cohort originated from a single geographic region.

Conclusion: Occupational exposure to crystalline silica/solvents is correlated with more severe forms of SSc characterized by: diffuse cutaneous involvement, interstitial lung disease, general microangiopathy (digital ulcers and myocardial dysfunction), and association with cancer. Occupational exposure should be systematically checked in all patients with SSc, as exposed patients seem to develop more severe forms of SSc.
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March 2015

Validation of the 2010-ACR/EULAR -classification criteria using newly EULAR-defined erosion for rheumatoid arthritis on the very early arthritis community-based (VErA) cohort.

Joint Bone Spine 2015 Jan 7;82(1):38-41. Epub 2014 Oct 7.

Department of Biostatistics, Rouen University Hospital, Rouen, France.

Objective: To validate the 2010-ACR/EULAR criteria for rheumatoid arthritis (RA), taking into account the recent EULAR definition of "erosive disease", on the 310 patients comprising the very early arthritis cohort (VErA).

Methods: 2010-criteria performances were tested by first strictly applying its three items successively: ≥ 1 clinical synovitis/another disease(s)/score ≥ 6/10), then the typical erosion grid without obtaining a score of ≥ 6 to diagnose RA. We tested successively: no erosion (S1), ≥ 1 erosion(s) (S2), EULAR-defined erosive disease (S3). Two gold standards were used: expert diagnosis at six years and EULAR erosive disease at two years.

Results: At inclusion, median age was 52 years; median RA duration 4.2 months. 2010-ACR/EULAR criteria, including EULAR-defined erosive disease applied at baseline, classified comparable numbers of patients as the 1987 criteria (P=0.27). Using expert diagnosis at six years, more patients were classified as RA with S2 than 1987-ACR criteria (P<0.04). In contrast, sensitivity and specificity indicated that 2010-ACR/EULAR-S3 criteria performed slightly but not significantly better than 1987-ACR criteria. On ROC curves, a score ≥ 6 correctly classified RA. When EULAR-defined erosion at two years was the gold standard, the 1987-ACR, the 2010-S1, -S2 and -S3 criteria performed comparably.

Conclusions: Using the very early community-based, conservatively treated VErA cohort, the strict application of 2010-ACR/EULAR criteria using the new EULAR definition of erosive disease or not performed slightly but not significantly better than the 1987-ACR criteria.
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January 2015

Role of Toll-like receptors 2 and 4 in mediating endothelial dysfunction and arterial remodeling in primary arterial antiphospholipid syndrome.

Arthritis Rheumatol 2014 Nov;66(11):3210-20

Rouen University Hospital, INSERM U1096, University of Rouen, and Centre d'Investigation Clinique, INSERM 1404, Rouen, France.

Objective: To assess the role of Toll-like receptors (TLRs) in antiphospholipid antibody (aPL)-mediated vascular abnormalities in patients with primary arterial antiphospholipid syndrome (APS).

Methods: Forty-eight subjects participated in the study. Arterial function and structure and TLR pathway activation were determined in patients with primary arterial APS and matched controls. The pathogenic effects of aPL isolated from patients were assessed in wild-type (WT) and TLR-knockout mice.

Results: APS patients had endothelial dysfunction, arterial stiffening, and hypertrophy, as evidenced by decreased brachial artery endothelium-dependent flow-mediated dilation (FMD) and increased aortic pulse wave velocity and carotid intima-media thickness (IMT), as compared with controls. Plasma samples from APS patients revealed decreased nitric oxide (NO) availability and a pro-oxidative, proinflammatory, and prothrombotic state illustrated by a decrease in nitrite and an increase in lipid peroxidation, tumor necrosis factor α levels, and tissue factor (TF) levels. Furthermore, TLR pathway activation was found in APS patients with increased TLR-2 and TLR-4 messenger RNA expression and increased protein levels of the activated TLR transduction protein interleukin-1 receptor-associated kinase 1 in peripheral blood mononuclear cells. Moreover, agonist-stimulated cell-surface expression of TLR-2 and TLR-4 in circulating monocytes was higher in APS patients than in controls. These changes were positively associated with IMT and negatively associated with FMD. Finally, aPL injection decreased mesenteric endothelium-dependent relaxation and increased TF expression in WT mice but not in TLR-2- or TLR-4-knockout mice.

Conclusion: This translational study supports the notion that TLR-2 and TLR-4 play a role in mediating vascular abnormalities in patients with primary arterial APS. TLRs thus constitute a promising pharmacologic target for preventing cardiovascular complications in APS.
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November 2014

Predictive factors for successful sacral nerve stimulation in the treatment of fecal incontinence: lessons from a comprehensive treatment assessment.

Dis Colon Rectum 2014 Jun;57(6):772-80

1Institut National de la Santé et de la Recherche Médicale U1073, Service de Physiologie Digestive, Centre Hospitalier Universitaire de Rouen, Institut National de la Santé et de la Recherche Médicale Centre d'Investigation Clinique 0204, Rouen, France 2Institut National de la Santé et de la Recherche Médicale U1073, Service de Chirurgie Digestive, Centre Hospitalier Universitaire de Rouen, Rouen, France 3Unité de Biostatistiques, Centre Hospitalier Universitaire de Rouen, Rouen, France.

Background: Sacral nerve stimulation has a place in the treatment algorithm for fecal incontinence, but the predictive factors of its midterm and long-term success are unknown.

Objective: The purpose of this study was to investigate the effect of a 3-year sacral nerve stimulation treatment of fecal continence and to identify specific predictive factors from the pretreatment and per-treatment assessments for the midterm success of sacral nerve stimulation.

Design: A cohort analysis of consecutive patients treated with sacral nerve stimulation for fecal incontinence over a period of 3 years was performed.

Settings: This study was conducted at an academic colorectal unit in a tertiary care center.

Patients: Sixty patients were available for the assessment of 3-year outcomes.

Main Outcome Measures: Clinical outcome (including Cleveland Clinic score) and anorectal physiological data were collected prospectively before and after treatment.

Results: At the 3-year follow-up, 33 of the 60 implanted patients had an improved outcome as defined by a ≥30% improvement in the Cleveland Clinic score from baseline (37.1% on intention to treat and 55.0% per protocol), whereas 22 had an unsuccessful outcome as defined by a <30% improvement in the Cleveland Clinic score from baseline (24.7% on intention to treat and 36.7% per protocol), of whom 7 had their device explanted or switched off permanently before the 3-year assessment, and 3 were lost at follow-up. At 3 years, we failed to identify any factors that could predict the 3-year clinical outcome of sacral nerve stimulation based on preimplantation and postimplantation assessments.

Limitations: This study involved a relatively small number of patients. There was a lack of consistency in the tool used to evaluate the efficacy of the test and permanent stimulations.

Conclusions: Based on per-protocol assessments, 55% of the patients had improved outcomes at the 3-year follow-up. No predictor was identified by the pretreatment and posttreatment assessments (see Video, Supplemental Digital Content 1,
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June 2014

FDG PET during radiochemotherapy is predictive of outcome at 1 year in non-small-cell lung cancer patients: a prospective multicentre study (RTEP2).

Eur J Nucl Med Mol Imaging 2014 Jun 22;41(6):1057-65. Epub 2014 Feb 22.

Department of Nuclear Medicine, Henri Becquerel Cancer Center, Henri Becquerel Center & QuantIF - Litis [EA (Equipe d'Accueil) 4108] & Rouen University Hospital, Rouen, France,

Purpose: To assess prospectively the prognostic value of FDG PET/CT during curative-intent radiotherapy (RT) with or without concomitant chemotherapy in patients with non-small-cell lung cancer (NSCLC).

Methods: Patients with histological proof of invasive localized NSCLC and evaluable tumour, and who were candidates for curative-intent radiochemotherapy (RCT) or RT were preincluded after providing written informed consent. Definitive inclusion was conditional upon significant FDG uptake before RT (PET₁). All included patients had a FDG PET/CT scan during RT (PET₂, mean dose 43 Gy) and were evaluated by FDG PET/CT at 3 months and 1 year after RT. The main endpoint was death (from whatever cause) or tumour progression at 1 year.

Results: Of 77 patients preincluded, 52 were evaluable. Among the evaluable patients, 77% received RT with induction chemotherapy and 73% RT with concomitant chemotherapy. At 1 year, 40 patients (77 %) had died or had tumour progression. No statistically significant association was found between stage (IIIB vs. other), histology (squamous cell carcinoma vs. other), induction or concomitant chemotherapy, and death/tumour progression at 1 year. The SUVmax in the PET2 scan was the single variable predictive of death or tumour progression at 1 year (odds ratio 1.97, 95% CI 1.25 - 3.09, p = 0.003) in multivariate analysis. The area under the receiver operating characteristic curve was 0.85 (95% CI 0.73 - 0.94, p < 10(-4)). A SUVmax value of 5.3 in the PET₂ scan yielded a sensitivity of 70% and a specificity of 92% for predicting tumour progression or death at 1 year.

Conclusion: This prospective multicentre study demonstrated the prognostic value in terms of disease-free survival of SUVmax assessed during the 5th week of curative-intent RT or RCT in NSCLC patients (NCT01261598; RTEP2 study).
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June 2014

Functional outcome and prognostic factors in anti-Jo1 patients with antisynthetase syndrome.

Arthritis Res Ther 2013 Oct 8;15(5):R149. Epub 2013 Oct 8.

Introduction: The aims of this present study were firstly to assess the outcome, including functional course, in anti-Jo1 positive patients with antisynthetase syndrome (ASS), and secondly to determine predictive parameters of poor outcome in these patients.

Methods: The medical records of 86 consecutive anti-Jo1 patients with ASS were reviewed in 4 academic centers.

Results: 13 patients (15.1%) achieved remission of ASS, whereas 55 (63.9%) improved and 18 (20.9%) deteriorated in their clinical status. Both steroid and cytotoxic drugs could be discontinued in only 4.7% of patients. ASS was associated with decreased quality of life at long-term follow-up: only 69.2% of patients considered to be in remission experienced a return to previous normal activities; and 24.7% of other patients with non-remitting ASS still had a marked reduction of activities (as shown by the disability scale of the Health Assessment Questionnaire). Decreased quality of life was further due to calcinosis cutis (8.1%) and adverse effects of steroid therapy (36%). Factors associated with ASS deterioration were older age, pulmonary and esophageal involvement, calcinosis cutis and cancer. Higher anti-Jo1 levels were further associated with disease severity in ASS patients.

Conclusions: The present study shows high morbidity related to ASS. Furthermore, we suggest that patients with predictive factors of ASS deterioration may require more aggressive therapy. Our findings also suggest that in anti-Jo1 patients with severe esophageal manifestations, combined high dose steroids and intravenous immunoglobulins might be proposed as the first line therapy. Finally, as cancer occurred in 14% of anti-Jo1 patients, our findings underscore that the search for cancer should be performed in these patients.
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October 2013

The predictive value of treatment response using FDG PET performed on day 21 of chemoradiotherapy in patients with oesophageal squamous cell carcinoma. A prospective, multicentre study (RTEP3).

Eur J Nucl Med Mol Imaging 2013 Sep 29;40(9):1345-55. Epub 2013 May 29.

Department of Nuclear Medicine, Faculty of Medicine, Henri Becquerel Cancer Center and Rouen University Hospital, & QuantIF - LITIS (EA 4108), University of Rouen, Rouen, France.

Purpose: FDG PET has been suggested to have predictive value in the prognosis of oesophageal carcinoma. However, the retrospective studies reported in the literature have shown discordant results. Additionally, only four studies have evaluated FDG PET during chemoradiotherapy (CRT) in patients with different histological lesions. The purpose of this study was to investigate the predictive value of FDG PET performed early during CRT (on day 21) in a population of patients with oesophageal squamous cell carcinoma.

Methods: Included in this prospective study were 57 patients with a histological diagnosis of squamous cell carcinoma of the oesophagus. Of these 57 patients, 48 (84%) were evaluated (aged 63 ± 11 years; 44 men, 4 women). Each patient underwent FDG PET (4.5 MBq/kg) before CRT, according to the Herskovic protocol (t0; PET₁) and on day 21 ± 3 from the start of CRT (d21; PET₂). The response assessment included a clinical examination, CT scan or FDG PET and histological analysis 3 months and 1 year after PET₁. The patients were classified as showing a complete response (CR) or a noncomplete response. A quantitative analysis was carried out for PET₁ and PET₂ using the following parameters: SUVmax, SUVmean (with SUVmean40 as the 3-D volume at an SUVmax threshold of 40% and SUVmeanp as that defined by a physician), tumour volume (TV, with TV40 defined as the TV at 40% of SUVmax, and TVp as that defined by a physician); and the total lesion glycolysis (TLG, SUVmean × TV, with TLG₄₀ defined as the TLG at 40% of SUVmax, and TLGp as that defined by a physician). The differences in responses at 3 months and 1 year between PET₁ (t0) and PET₂ (d21) were assessed in terms of variations in SUV, TV and TLG using a repeated measures of variance (ANOVA).

Results: SUVmax, SUVmean and TLG decreased significantly between PET₁ (t0) and PET₂ (d21; p < 0.0001). The TV significantly decreased only when assessed as TVp (p = 0.02); TV₄₀ did not decrease significantly. With respect to the predictive value of PET₁, only TV40_1 and TVp_1 values, and therefore TLG40_1 and TLGp_1, but not the SUV values, were significantly lower in patients with CR at 3 months. SUVmax1, TVp_1 and TLGp_1 were significantly lower in patients with CR at 1 year. With respect to the predictive value of PET₂, only TV40_2 and TVp_2 values, and therefore TLG40_2 and TLGp_2, but not the SUV values, were significantly lower in patients with CR at 3 months. None of the PET₂ parameters had significant value in predicting patient outcome at 1 year. The changes in SUVmax, TV₄₀, TVp, TLG₄₀ and TLGp between PET₁ and PET₂ had no relationship to patient outcome at 3 months or 1 year.

Conclusion: This prospective, multicentre study performed in a selected population of patients with oesophageal squamous cell cancer demonstrates that the parameters derived from baseline PET₁ are good predictors of response to CRT. Specifically, a high TV and TLG are associated with a poor response to CRT at 3 months and 1 year, and a high SUVmax is associated with a poor response to CRT at 1 year. FDG PET performed during CRT on day 21 appears to have less clinical relevance. However, patients with a large functional TV on day 21 of CRT have a poor clinical outcome ( NCT 00934505).
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September 2013

Baseline laboratory test abnormalities are common in early arthritis but rarely contraindicate methotrexate: study of three cohorts (ESPOIR, VErA, and Brittany).

Semin Arthritis Rheum 2013 Apr 24;42(5):474-81. Epub 2013 Jan 24.

Rheumatology Unit and Immunology Department, CHU Brest, Université Bretagne Occidentale, Brest-Cedex, France.

Objective: To evaluate the prevalence of baseline abnormalities in standard laboratory tests in patients with early arthritis and their impact on selection of disease-modifying antirheumatic drugs according to American College of Rheumatology (ACR) recommendations and/or of nonsteroidal anti-inflammatory drugs.

Methods: In three cohorts of patients with early arthritis (the ESPOIR, VErA, and Brittany cohorts), we evaluated the prevalence of anemia (hemoglobin <1 3 g/dL in men and 12 g/dL in women), leukopenia (<3500 per mm(3)), thrombocytopenia (<150000 per mm(3)), renal dysfunction (mild, creatinine clearance [CrCl]=60-89.9 mL/min; moderate, CrCl=30-59.9 mL/min; or severe, CrCl<30 mL/min), liver cytolysis (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]>N or>2N), and systemic inflammation (erythrocyte sedimentation rate [ESR]>20 and C-reactive protein [CRP]>6).

Results: We evaluated 1393 patients (1018 women and 375 men). Anemia was present in 363/1366 (26.5%) patients, leukopenia in 18/1372 (1.3%), and thrombocytopenia in 13/1371 (0.9%). ESR elevation was seen in 50.4% of patients and CRP elevation in 62.7%. The level of AST was above normal in 4% and of ALT in 10% of patients. No patient had severe renal dysfunction, 5.6% had moderate renal dysfunction, and 42.6% had mild renal dysfunction. Among the 1094 patients who had undergone all the tests, only 18 (1.64%, 95% confidence interval, 1-2.64) had a formal contraindication to methotrexate therapy according to ACR recommendations (4 had leukopenia, 12 had high ALT levels, and 2 had high ALT and AST levels).

Conclusion: Patients with recent-onset arthritis often have anemia, mild or moderate renal dysfunction, and abnormal liver function. However, fewer than 2% have laboratory test abnormalities contraindicating methotrexate therapy.
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April 2013

Delayed gastric emptying determined using the 13C-octanoic acid breath test in patients with systemic sclerosis.

Arthritis Rheum 2012 Jul;64(7):2346-55

Department of Internal Medicine, Rouen University Hospital, Rouen, France.

Objective: To determine the prevalence of delayed gastric emptying using the 13C-octanoic acid breath test in unselected patients with systemic sclerosis (SSc), to evaluate whether findings of the 13C-octanoic acid breath test are associated with clinical digestive manifestations, gastric mucosal abnormalities detected by gastroscopy, motor activity dysfunction detected by antroduodenal manometry, and esophageal motor impairment and extradigestive manifestations of SSc, and to develop a risk prediction score of gastric emptying in SSc.

Methods: Consecutive patients with SSc (n=57) underwent the 13C-octanoic acid breath test. All of the patients with SSc completed a questionnaire on digestive symptoms, and a global symptom score (GSS) was calculated.

Results: The prevalence of delayed gastric emptying was 47.4% in patients with SSc. A marked correlation was observed between a GSS of digestive symptoms≥5 and the presence of delayed gastric emptying (P<0.00001). The sensitivity of a GSS≥5 for predicting delayed gastric emptying was as high as 0.93, while the specificity was 0.73. Moreover, a GSS≥5, mucosal gastric abnormalities, severe esophageal motor impairment, and interstitial lung disease were factors that were independently associated with the presence of delayed gastric emptying, and these variables were used to create a risk prediction score. The area under the receiver operating characteristic curve for the risk prediction score was 0.90; the sensitivity of this score for the prediction of delayed gastric emptying was 0.93, while the specificity was 0.77.

Conclusion: The results indicate that delayed gastric emptying occurs often in patients with SSc. Interestingly, using risk models with routine clinical characteristics, a simple risk prediction score can be calculated, allowing prediction of the occurrence of delayed gastric emptying in patients with SSc.
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July 2012

Can sacral neuromodulation improve minor incontinence symptoms in doubly incontinent patients successfully treated for major incontinence symptoms?

Urology 2012 Jan 17;79(1):80-5. Epub 2011 Nov 17.

Urology Department, Rouen University Hospital, Rouen, France.

Objective: To describe the effect of sacral nerve modulation (SNM) on less severe types of incontinence in patients who were successfully implanted for either urinary or fecal incontinence, and who presented with double incontinence. When conservative treatments fail, SNM is a first-line treatment for patients with urge urinary or fecal incontinence.

Methods: All patients who received SNM between 2005 and 2010 at 5 hospitals and who still had the implant were included in our survey. All received a urinary and fecal change and quality of life questionnaire by mail to complete.

Results: Of the 51 questionnaires sent out, 37 were returned, for a 72.5% response rate. The population was composed of 97.3% women, with a mean age of 56.8 years (SD 14). The main indication for SNM was urge urinary incontinence in 15 patients (40.5%) and fecal incontinence in 22 patients (59.5%). Eighteen patients (48.7%) had improvements in both urinary and fecal incontinence symptoms. The percentage increased to 53.3% (16/30) in the group of patients with urge urinary incontinence associated with fecal incontinence. Patients who reported an improvement in double incontinence symptoms complained more often of urge urinary incontinence than other patients (P=.04).

Conclusions: Of the doubly incontinent patients who were successfully implanted for a predominant type of incontinence (ie, urinary or fecal incontinence), 48.7% had an improvement in the other type of incontinence. Patients with urge urinary incontinence associated with fecal incontinence were more likely to report an improvement in double incontinence than the other patients.
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January 2012

Short-term and long-term outcome of anti-Jo1-positive patients with anti-Ro52 antibody.

Semin Arthritis Rheum 2012 Jun 9;41(6):890-9. Epub 2011 Nov 9.

Department of Internal Medicine, CHU Rouen, and INSERM U 905, University of Rouen IFRMP, Institute for Biochemical Research, Rouen, France.

Objectives: The aims of the present study were to (1) assess clinical features and long-term outcome in anti-Jo1-positive patients with anti-Ro52 antibody; (2) compare characteristics of anti-Jo1-positive patients with and without anti-Ro52 antibody; and (3) compare features of anti-Ro52-positive patients with and without anti-Jo1 antibody.

Methods: The medical records of 89 consecutive anti-Jo1-positive patients with antisynthetase syndrome (ASS) were reviewed; 36 of these patients had coexistent anti-Ro52 antibody. Furthermore, the medical records of 13 consecutive anti-Ro52-positive patients without anti-Jo1 antibody were also reviewed.

Results: Nine anti-Jo1-positive patients (25%) with anti-Ro-52 antibody achieved remission of ASS, whereas 19 other patients (52.8%) improved and 8 patients (22.2%) worsened their clinical status. Anti-Jo1-positive patients with anti-Ro52 antibody experienced ASS-related complications: interstitial lung disease (n = 28), esophageal dysfunction (n = 9), and joint manifestations (n = 25), including periarticular hydroxyapatite calcifications and erosions of metacarpophalangeal and interphalangeal joints and wrists (n = 3); 7 anti-Ro52-positive patients (19.4%) had cancer. Anti-Jo1-positive patients with anti-Ro52 antibody, compared with those without, more commonly experienced deterioration of myositis and joint involvement, symptomatic form of ILD, and cancer; they also had decreased survival rate (P = 0.05). We further found that anti-Ro52-positive patients with anti-Jo1 antibody, compared with those without, were younger and more frequently exhibited ILD with poorer prognosis.

Conclusions: Our series underlines that the presence of anti-Ro52 antibody is associated with a particular phenotype of ASS, leading to more severe myositis and joint impairment. Moreover, the coexistence of anti-Ro52 antibody seems to be associated with an increased risk of cancer. We therefore suggest that anti-Jo1-positive patients should routinely undergo the search for anti-Ro52 antibody, as this autoantibody appears to impact patients' prognosis.
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June 2012

The expression and the cellular distribution of the tight junction proteins are altered in irritable bowel syndrome patients with differences according to the disease subtype.

Am J Gastroenterol 2011 Dec 18;106(12):2165-73. Epub 2011 Oct 18.

Department of Gastroenterology, Rouen University Hospital, France.

Objectives: Recent studies have suggested that an increased intestinal permeability is involved in the pathophysilogy of irritable bowel syndrome (IBS). However, the differential expression of tight junctions (TJs) proteins according to IBS subtypes and symptoms remained unknown. The objective of this study was to study zonula occludens-1 (ZO-1), occludin, and claudin-1 in the colonic mucosa of patients with IBS.

Methods: Fifty IBS patients fulfilling the Rome III criteria and 31 controls were included. All types of IBS patients participated with predominant diarrhea (IBS-D, n=19), predominant constipation (IBS-C, n=14), constipation alternating with diarrhea (IBS-A, n=15), or unclassified (IBS-U, n=2). IBS symptom intensity was quantified on 10-cm Visual Analog Scale (VAS). TJ proteins (claudin-1, ZO-1, occludin) were quantified by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), western blot, while their localization was determined by immunofluorescence.

Results: ZO-1 and occludin expression was lower in IBS patients compared with controls, whereas only a trend for a decrease of claudin-1 was observed. The mRNA levels remained unaffected. In the subgroup analyses, occludin and claudin-1 expression was decreased in IBS-D patients but not in IBS-C and IBS-A patients. The subcellular distribution of these three proteins was altered in IBS-C and IBS-D patients. Occludin (r=0.40, P<0.01) and claudin-1 (r=0.46, P<0.01) expression was correlated with the duration of symptoms. The expression of occludin was lower in patients with an abdominal pain intensity higher than 6 on the VAS (P<0.05).

Conclusions: Occludin and claudin-1 appeared markedly affected in IBS-D patients. In addition, our results suggest that alteration of TJ proteins may be involved in the initiation of IBS and contribute to visceral hypersensitivity.
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December 2011

Combining anti-cyclic citrullinated peptide with the American College of Rheumatology 1987 criteria failed to improve early rheumatoid arthritis diagnosis in the community-based very early arthritis cohort.

Rheumatology (Oxford) 2011 Oct 12;50(10):1901-7. Epub 2011 Jul 12.

Rheumatology Department, Rouen University Hospital and Inserm Unit 905, University of Rouen,, France.

Objectives: To test the performances of combining anti-CCP second generation (CCP2) with ACR 1987 classification criteria and to diagnose early RA in a community-based very early arthritis (VErA) patient cohort.

Methods: The VErA cohort comprised 310 patients (median age 52 years; 68.1% women; median symptom duration 4.2 months; glucocorticoid- and DMARD naïve) conservatively treated during the first 2 years. At 6 years of follow-up, a three-expert committee classified the patients into three groups: RA, other classified arthritis (OCA) or unclassified arthritis (UA). We calculated the performances of the different sets, including anti-CCP2 positivity, while retaining or deleting RF and rheumatoid nodule components with ACR 1987 criteria for early RA diagnosis. Models were subjected to receiver operating characteristics curve and logistic regression analyses to try to identify relevant sets able to classify very early RA.

Results: At 6 years, 149 patients were diagnosed as RA and 119 as non-RA (95 OCA and 24 UA). The original ACR 1987 criteria had 77.9% sensitivity and 64.7% specificity for the RA diagnosis at 6 years. The modified set excluding rheumatoid nodules, including anti-CCP2 positivity and retaining RF performed significantly better than ACR 1987 criteria, with 79.9% sensitivity and 64.7% specificity and with a larger area under the curve. However, in the zone of interest, i.e., ≥4/7 criteria, the curves for these sets were superimposed.

Conclusions: Adding anti-CCP2 positivity and deleting rheumatoid nodules failed to improve the performances of ACR 1987 classification criteria for the diagnosis of early RA.
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October 2011

Role of toll-like receptor 4 in the inflammation reaction surrounding silicone prosthesis.

Acta Biomater 2011 May 25;7(5):2047-52. Epub 2011 Jan 25.

Department of Plastic and Reconstructive Surgery, Rouen University Hospital, Rouen, France.

The inflammation which occurs around the silicone prosthesis is a complex process that can provoke the failure of the device and compromise the health of the implanted patient. Toll-like receptors (TLRs), which are transmembrane proteins, are now known to act in the innate immune response and in endogenous inflammation. The aim of our study was to assess the role of TLR4 in the foreign body reaction to a silicone shell prosthesis. Disks of shell silicone prosthesis were implanted in the subcutaneous tissue of C57BL6-TLR4-/- and C57BL6-WT mice. At day 14, inflammatory cell infiltrate and vessel sections around the prosthesis were less numerous in TLR4-/- than in WT mice. A histomorphometric analysis showed that the capsule around the implant was 1.96-fold less thick in depleted TLR4 than in wild-type mice. In addition, vascular endothelial growth factor and transforming growth factor 1 were underexpressed in the surrounding tissue of the prosthesis in TLR4-/- mice. Our study suggests, from this foreign body response model against silicone in mice, that TLR4 plays a key role in the reaction process around silicone implants.
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May 2011

Simultaneous positron emission tomography (PET) assessment of metabolism with ¹⁸F-fluoro-2-deoxy-d-glucose (FDG), proliferation with ¹⁸F-fluoro-thymidine (FLT), and hypoxia with ¹⁸fluoro-misonidazole (F-miso) before and during radiotherapy in patients with non-small-cell lung cancer (NSCLC): a pilot study.

Radiother Oncol 2011 Jan 4;98(1):109-16. Epub 2010 Nov 4.

Department of Nuclear Medicine, Henri Becquerel Cancer Center and Rouen University Hospital, France.

Objectives: To investigate the changes in tumour proliferation (using FLT), metabolism (using FDG), and hypoxia (using F-miso) during curative (chemo-) radiotherapy (RT) in patients with non-small-cell lung cancer (NSCLC).

Patients And Methods: Thirty PET scans were performed in five patients (4 males, 1 female) that had histological proof of NSCLC and were candidates for curative-intent RT. Three PET-CT (Biograph S16, Siemens) scans were performed before (t(0)) and during (around dose 46 Gy, t(46)) RT with minimal intervals of 48 h between each PET-CT scan. The tracers used were (18)fluoro-2deoxyglucose (FDG) for metabolism, (18)fluorothymidine (FLT) for proliferation, and (18)F-misonidasole (F-miso) for hypoxia. The 3 image sets obtained at each time point were co-registered (rigid: n=9, elastic: n=1, Leonardo, TrueD, Siemens) using FDG PET-CT as reference. VOIs were delineated (40% SUV(max) values were used as a threshold) for tumours and lymph nodes on FDG PET-CT, and they were automatically pasted on FLT and F-miso PET-CT images. ANOVA and correlation analyses were used for comparison of SUV(max) values.

Results: Four tumours and twelve nodes were identified on initial FDG PET-CT images. FLT SUV(max) values were significantly lower (p<0.0006) at t(46) in both tumours and nodes. The decrease in FDG SUV(max) values had a trend towards significance (p=0.048). F-Miso SUV(max) values were significantly higher in tumours than in nodes (p=0.02) and did not change during radiotherapy (p=0.39). A significant correlation was observed between FLT and FDG uptake (r=0.56, p<10(-4)) when all data were pooled together, and they remained similar when the before and during RT data were analysed separately. FDG and F-miso uptakes were significantly correlated (r=0.59, p=0.0004) when all data were analysed together. The best fit was obtained after adjusting for lesion type (tumour vs. node). This correlation was observed for the SUV(max) measured during RT (r=0.70, p=0.008) but not for the pre-RT data (r=0.19, p=0.35). The weak correlation between FLT and F-miso uptakes only became significant (r=0.66, p=0.002) when the analysis was restricted to the data acquired during RT.

Conclusion: Three different PET acquisitions can be performed quasi-simultaneously (4-7 days) before and during radiotherapy in patients with NSCLC. Our results at 46 Gy suggest that a fast decrease in the proliferation of both tumours and nodes exists during radiotherapy with differences in metabolism (borderline significant decrease) and hypoxia (stable).
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January 2011

Infectious complications in polymyositis and dermatomyositis: a series of 279 patients.

Semin Arthritis Rheum 2011 Aug 2;41(1):48-60. Epub 2010 Nov 2.

Department of Internal Medicine, CHU Rouen, Rouen, France.

Objectives: To assess the prevalence and characteristics of severe pyogenic, nonpyogenic, and opportunistic infections in polymyositis and dermatomyositis (PM/DM) patients and to evaluate the predictive values for infections on clinical presentation and biochemical findings of PM/DM to detect patients at risk for such infections.

Methods: The medical records of 279 consecutive PM/DM patients in 3 medical centers were reviewed.

Results: One hundred four severe infections occurred in our patients (37.3%), ie, pyogenic (n = 71) and nonpyogenic/opportunistic infections (n = 33). Pyogenic infections were mainly due to aspiration pneumonia (n = 46) and calcinosis cutis infection. Thirty-three PM/DM patients developed nonpyogenic/opportunistic infections that were due to the following: Candida albicans, Pneumocystis jiroveci, Aspergillus fumigatus, Geotrichum capitatum, Mycobacterium (avium-intracellulare complex, xenopi, marinum, peregrinum, tuberculosis), Helicobacter heilmanii, cytomegalovirus, herpes simplex and zoster virus, hepatitis B and C, JC virus, Leishmania major, Strongyloides stercoralis. Esophageal dysfunction, ventilatory insufficiency, malignancy, and lymphopenia were significantly more frequent in the group of PM/DM patients with infections.

Conclusion: Our study underscores the high frequency of infections in PM/DM, resulting in an increased mortality rate. Our results suggest that prophylaxis against pyogenic infections should be routinely recommended for patients with PM/DM, including regular physical examination of lungs to depict aspiration pneumonia as well as risk factors of aspiration pneumonia. Finally, because a great variety of micro-organisms may be responsible for opportunistic infections, it seems difficult to initiate primary prophylaxis in PM/DM patients exhibiting risk factors for opportunistic infections.
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August 2011

Serum IgA rheumatoid factor and pyridinoline in very early arthritis as predictors of erosion(s) at two years: a simple model of prediction from a conservatively treated community-based inception cohort.

Arthritis Care Res (Hoboken) 2010 Dec;62(12):1739-47

INSERM Unit 905 and Rouen University Hospital, Rouen, France.

Objective: To identify, in conservatively treated, very early arthritis patients, predictors of ≥1 erosion(s) at 2 years, and to construct a prediction model.

Methods: Community-based adults (n=310) who had never taken disease-modifying antirheumatic drugs (DMARDs) or steroids with swelling of ≥2 joints persisting for >4 weeks and lasting <6 months were recruited. Erosion status was assessed at 0, 6, 12, and 24 months; evaluations were comprised of clinical criteria (Disease Activity Score, Health Assessment Questionnaire), C-reactive protein level, erythrocyte sedimentation rate, autoantibodies, bone and cartilage markers, hand densitometry, and HLA class II shared epitopes. Patients meeting American College of Rheumatology rheumatoid arthritis (RA) criteria or with undifferentiated arthritis (UA) were followed and treated conservatively: one-third of RA patients and three-fourths of UA patients received no DMARDs during 2 years; a biologic agent was given to 1.8% of the patients during the first year. The main judgment criterion was ≥1 erosion(s) at 2 years.

Results: At 2 years, 219 patients were assessed; 31.3% with RA and 10.6% with UA had ≥1 erosion(s). Logistic regression analysis at that time showed erosion(s) strongly associated with serum IgA rheumatoid factor (IgA-RF) and pyridinoline levels for the 190 patients with no baseline erosions, with the corresponding receiver operating characteristic curve having an area under the curve of 0.77 (95% confidence interval 0.64-0.86). A prediction model was constructed with IgA-RF thresholds of 5 and 25 IU/ml and a pyridinoline threshold of 10 nM/liter; odds ratios ranged from 1 for IgA-RF<5 IU/ml and pyridinoline <10 nM/liter to 50.75 for the association of IgA-RF≥5 IU/ml and pyridinoline≥10 nM/liter.

Conclusion: This model, using serum IgA-RF and pyridinoline concentrations, was able to predict≥1 erosion(s) at 2 years in very early arthritis patients.
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December 2010

Prenatal exposure to tobacco and risk for schizophrenia: a retrospective epidemiological study.

Compr Psychiatry 2010 Mar-Apr;51(2):106-9. Epub 2009 May 5.

Department of Psychiatry, Rouen University Hospital, Rouen 76031, France.

Introduction: In animal studies, long-term prenatal nicotinic exposure alters the development of dopaminergic neurons. To determine whether prenatal smoking exposure was associated with schizophrenia, using a retrospective design study, we compared the prevalence of tobacco use during pregnancy in mothers of subjects with and without schizophrenia.

Methods: One hundred patients with schizophrenia, 100 nonschizophrenic-matched subjects, and their respective mothers were interviewed. The prevalence of smoking was measured in these individuals as well as in their respective mothers during the pregnancy.

Results: Patients with schizophrenia smoked more often compared with controls (73% vs 57%). In contrast, the prevalence of smoking during pregnancy did not differ between the groups of mothers. Indeed, the amount of tobacco used was significantly lower in mothers of patients with schizophrenia vs mothers of nonpsychotic subjects.

Conclusion: This study did not show any association between prenatal tobacco exposure and further development of schizophrenia.
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August 2010

Small intestinal bacterial overgrowth in systemic sclerosis.

Rheumatology (Oxford) 2009 Oct 20;48(10):1314-9. Epub 2009 Aug 20.

Department of Internal Medicine, Rouen University Hospital, 76301 Rouen Cedex, France.

Objectives: The aims of this study were to: (i) determine the prevalence of small intestinal bacterial overgrowth (SIBO) in unselected patients with SSc; (ii) assess both clinical presentation and outcome of SIBO; and (iii) make predictions about which SSc patients are at risk for SIBO.

Methods: Fifty-one consecutive patients with SSc underwent glucose hydrogen and methane (H(2)/CH(4)) breath test. All SSc patients also completed a questionnaire for intestinal symptoms, and a global symptomatic score (GSS) was calculated. SSc patients with SIBO were given rotating courses of antibiotics (norfloxacin/metronidazole) for 3 months; glucose H(2)/CH(4) breath test was performed at 3-month follow-up.

Results: The prevalence of SIBO was 43.1% in our SSc patients. After logistic regression, we identified the following risk factors for SIBO: presence of diarrhoea and constipation. Interestingly, we observed a marked correlation between values of GSS of digestive symptoms (> or =5) and the presence of SIBO (P = 10(-6)); indeed, both sensitivity and specificity of GSS > or =5 to predict SIBO were as high as 0.909 and 0.862, respectively. Finally, eradication of SIBO was obtained in 52.4% of the SSc patients with a significant improvement of intestinal symptoms.

Conclusion: Our study underscores that SIBO often occurs in SSc patients. We further suggest that GSS may be systematically performed in SSc patients; since we found a correlation between GSS of digestive symptoms > or =5 and SIBO, we suggest that glucose H(2)/CH(4) breath test may be performed in the subgroup of SSc patients exhibiting GSS > or =5.
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October 2009

The role of coagulation marker fibrin D-dimer in early diagnosis of catatonia.

Psychiatry Res 2009 Jun 17;168(1):78-85. Epub 2009 May 17.

Service Hospitalo-Universitaire de Psychiatrie de Rouen, Centre Hospitalier du Rouvray, 4 rue Paul Eluard, 76300 Sotteville-lès-Rouen, France.

Catatonia is a common but under-diagnosed neuropsychiatric syndrome characterized by the occurrence in a single patient of concomitant affective, motor and behavioral symptoms with a hazardous outcome (called lethal catatonia: LC). Deaths by thromboembolic disease have been previously reported in LC. A 2-year prospective study was carried out to examine D-dimer levels, an early and sensitive coagulation marker, in patients with catatonic disorders. Twenty-five acute catatonic patients and 50 psychiatric control patients - matched on age, gender, psychiatric diagnosis, general psychopathology and neuroleptic medication matched - were investigated and considered in relation to D-dimer blood levels and other biological variables (serum iron, creatine phosphokinase, leukocytosis). All catatonic patients had high D-dimer levels and mean levels were significantly higher in catatonics than in non-catatonic patients, independently of age, gender, immobility, comorbid diagnosis, general psychopathology and neuroleptic medication. No significant association was observed with other biological parameters investigated. These preliminary and exploratory results suggest that catatonia is associated with early coagulation activation.
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June 2009

Paradoxical adverse events of anti-tumour necrosis factor therapy for spondyloarthropathies: a retrospective study.

Rheumatology (Oxford) 2009 Jul 24;48(7):761-4. Epub 2009 Apr 24.

Department of Pharmacy, University of Medicine-Pharmacy, Rouen University Hospital and Inserm U905 (IFRMP 23), Institute for Biomedical Research, University of Rouen, Rouen,France.

Objectives: Several paradoxical adverse events (PAEs), e.g. IBDs, acute anterior uveitis (AAU) and psoriasis, have been described in patients taking anti-TNF drugs. This retrospective study aimed to describe the different PAEs that have occurred in a population of SpA patients treated with anti-TNF drugs, and to determine whether they are drug specific.

Methods: Since 2000, we have followed 296 patients with SpA [198 AS, 21 SpA associated with IBD (9 ulcerative colitis, 12 Crohn's disease) and 77 psoriatic arthritis] treated with at least one anti-TNF drug (infliximab, etanercept or adalimumab), and 112 SpA patients treated only with conventional DMARDs who served as controls. Considering the cumulative time of exposure to each anti-TNF agent, the frequencies of new-onset PAEs in exposed patients were calculated.

Results: Respective cumulative exposure times were 287, 290 and 62 patient-years for infliximab, etanercept and adalimumab. We observed the following PAEs: five psoriasis (three under infliximab and one with etanercept or adalimumab), three AAU (1/100 patient-years, all under etanercept) and four IBD (three under etanercept and one under infliximab). There was no significant association among any of these PAEs and a specific anti-TNF agent; nor significant difference in the overall PAEs among patients receiving anti-TNF drugs or controls (P = 0.303), the latter experiencing two psoriasis and three AAU.

Conclusions: Undesirable side effects--IBD, AAU and psoriasis--may appear with anti-TNF drugs. Even if they are, a priori, paradoxical, no evidence supports any PAEs to be anti-TNF agent-specific in SpA.
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July 2009

Prognostic value of sympathetic innervation and cardiac asynchrony in dilated cardiomyopathy.

Eur J Nucl Med Mol Imaging 2008 Nov 6;35(11):2074-81. Epub 2008 Aug 6.

Nuclear Medicine, Rouen University Hospital-Henri Becquerel Center, 1 rue d'Amiens, 76038, Rouen, France.

Purpose: The purpose of the study is to examine prognostic values of cardiac I-123 metaiodobenzylguanidine (MIBG) uptake and cardiac dyssynchrony in patients with dilated cardiomyopathy (DCM).

Materials And Methods: Ninety-four patients with non-ischemic DCM underwent I-123 MIBG imaging for assessing cardiac sympathetic innervation and equilibrium radionuclide angiography. Mean phase angles and SD of the phase histogram were computed for both right ventricular (RV) and left ventricular (LV). Phase measures of interventricular (RV-LV) and intraventricular (SD-RV and SD-LV) asynchrony were computed.

Results: Most patients were receiving beta-blockers (89%) and angiotensin-converting enzyme inhibitors (88%). One patient (1%) was lost to follow-up, six had cardiac death (6.4%), eight had heart transplantation (8.6%), and seven had unplanned hospitalization for heart failure (7.5%; mean follow-up: 37 +/- 16 months). Patients with poor clinical outcome were older, had higher The New York Heart Association functional class, impaired right ventricular ejection fraction and left ventricular ejection fraction, and impaired cardiac I-123 MIBG uptake. On multivariate analysis, I-123 MIBG heart-to-mediastinum (H/M) uptake ratio <1.6 was the only predictor of both primary (cardiac death or heart transplantation, RR = 7.02, p < 0.01) and secondary (cardiac death, heart transplantation, or recurrent heart failure, RR = 8.10, p = 0.0008) end points.

Conclusions: In patients receiving modern medical therapy involving beta-blockers, I-123 MIBG uptake, but not intra-LV asynchrony, was predictive of clinical outcome. The impact of beta-blockers on the prognostic value of ventricular asynchrony remains to be clarified.
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November 2008