New insights into the tetrameric family of the Fur metalloregulators.

The ferric uptake regulator (Fur) belongs to the family of the metal-responsive transcriptional regulators. Fur is a global regulator found in all proteobacteria. It controls the transcription of a wide variety of genes involved in iron metabolism but also in oxidative stress or virulence factor synthesis. As a general view, Fur proteins were considered to be dimeric proteins both in solution and when bound to DNA. However, our recent data demonstrate that Fur proteins can be classified into two subfamilies, according to their quaternary structure. The group of dimers is represented by E. coli, V. cholerae and Y. pestis Fur and the group of highly stable tetramers by P. aeruginosa and F. tularensis Fur. Here, another tetrameric structure of a PaFur mutant containing manganese and zinc metal ions is described. Through biochemical, structural and computational studies, we have deciphered the important structural characteristics of the tetramers and studied the main interactions responsible for their strength. Potential or mean force calculations for tetramer formation have been determinant to quantify these interactions. Moreover calculations allow us to propose that some conserved residues prevent the tetramerization in the subfamily of dimeric Fur.

Updated European Consensus Statement on diagnosis and treatment of adult ADHD.

Background Attention-deficit/hyperactivity disorder (ADHD) is among the most common psychiatric disorders of childhood that often persists into adulthood and old age. Yet ADHD is currently underdiagnosed and undertreated in many European countries, leading to chronicity of symptoms and impairment, due to lack of, or ineffective treatment, and higher costs of illness. Methods The European Network Adult ADHD and the Section for Neurodevelopmental Disorders Across the Lifespan (NDAL) of the European Psychiatric Association (EPA), aim to increase awareness and knowledge of adult ADHD in and outside Europe. This Updated European Consensus Statement aims to support clinicians with research evidence and clinical experience from 63 experts of European and other countries in which ADHD in adults is recognized and treated. Results Besides reviewing the latest research on prevalence, persistence, genetics and neurobiology of ADHD, three major questions are addressed: (1) What is the clinical picture of ADHD in adults? (2) How should ADHD be properly diagnosed in adults? (3) How should adult ADHDbe effectively treated? Conclusions ADHD often presents as a lifelong impairing condition. The stigma surrounding ADHD, mainly due to lack of knowledge, increases the suffering of patients. Education on the lifespan perspective, diagnostic assessment, and treatment of ADHD must increase for students of general and mental health, and for psychiatry professionals. Instruments for screening and diagnosis of ADHD in adults are available, as are effective evidence-based treatments for ADHD and its negative outcomes. More research is needed on gender differences, and in older adults with ADHD.

Structural and functional studies of the metalloregulator Fur identify a promoter-binding mechanism and its role in Francisella tularensis virulence.

Francisella tularensis is a Gram-negative bacterium causing tularaemia. Classified as possible bioterrorism agent, it may be transmitted to humans via animal infection or inhalation leading to severe pneumonia. Its virulence is related to iron homeostasis involving siderophore biosynthesis directly controlled at the transcription level by the ferric uptake regulator Fur, as presented here together with the first crystal structure of the tetrameric F. tularensis Fur in the presence of its physiological cofactor, Fe2+. Through structural, biophysical, biochemical and modelling studies, we show that promoter sequences of F. tularensis containing Fur boxes enable this tetrameric protein to bind them by splitting it into two dimers. Furthermore, the critical role of F. tularensis Fur in virulence and pathogenesis is demonstrated with a fur-deleted mutant showing an attenuated virulence in macrophage-like cells and mice. Together, our study suggests that Fur is an attractive target of new antibiotics that attenuate the virulence of F. tularensis.

[Health related quality of life in chronic venous disease: Systematic literature review]. / Évaluation de la qualité de vie liée à l'insuffisance veineuse chronique (IVC). Revue systématique de la littérature.

OBJECTIVE: Excepting life-threatening situations, improvement of health-related quality-of-life is the main therapeutic goal in chronic disease. The purpose of this review was to study the different ways of assessing Quality-of-Life (QoL) in patients with chronic venous disease (CVD) (CEAP classes C3 to C6). METHODS: A literature search was conducted with three databases: MEDLINE, WEB OF SCIENCE and COCHRANE LIBRARY in order to identify articles with the PRISMA reporting guidelines. Then we compared psychometric performance of general and specific QoL questionnaires for a French population with CVD. RESULTS: A total of 481 articles were identified, from which 25 were selected and analyzed. CIVIQ 20, CIVIQ 14 and VEINES Qol/sym are the specific health related QoL scales validated for a French population with CVD. VEINES Qol/sym was specifically validated in patients with leg ulcer or post-thrombotic syndrome (PTS). CIVIQ 14 is a CIVIQ 20 optimized to be used more widely in international studies and validated in milder forms of the CVD spectrum (C0 à C4). The general health related QoL scales are SF-36, SF-12 and EQ-5D. EQ-5D is simple and provides health state utility values. CONCLUSION: CIVIQ 14 is a simple specific health-related QoL scale for less severe CVD. VEINES Qol/sym was developed for severe CVD and PTS but clinically relevant point scales remain to be assessed. EQ-5D is a generic scale to be preferred to assess economic impact based on a cost-utility analysis.

Abnormal amplitude and kinetics of digital postocclusive reactive hyperemia in systemic sclerosis.

OBJECTIVES: Postocclusive reactive hyperemia is mediated by two major mediators: sensory nerves and endothelium-derived hyperpolarizing factors. We hypothesized that the skin microvascular response to 5 min ischemia would differ depending upon the hand location in patients with systemic sclerosis (SSc), primary Raynaud's phenomenon (PRP) and healthy controls. METHODS: Fifteen patients with SSc, 15 sex- and age-matched patients with PRP and healthy controls were enrolled. Their right hands were subjected to 5 min ischemia followed by a postocclusive hyperemia test, with local microcirculation monitoring by laser speckle contrast imaging on the dorsal face of the hand. RESULTS: Postocclusive reactive hyperemia was abnormal in terms of peak and area under the curve (AUC) on all fingers except the thumb in patients with SSc and PRP compared with controls. In contrast, the kinetics of the response was longer only in SSc patients, with mean (SD) time to peak on the index, middle and ring finger were respectively 72 (58), 73 (51) and 67 (47) s for SSc; 40 (20), 40 (20) and 36 (19) s for PRP; and 34 (30), 34 (30) and 29 (24) s for controls (P=0.009 for interaction). CONCLUSIONS: We observed decreased distal digital microvascular perfusion following 5 min of ischemia in patients presenting with PRP or SSc, while the kinetics was prolonged only in SSc. A dynamic assessment of digital skin blood flow using laser speckle contrast imaging following 5 min ischemia could be used as a tool to assess microvascular abnormalities in patients with Raynaud's phenomenon secondary to SSc.

The digital thermal hyperemia pattern is associated with the onset of digital ulcerations in systemic sclerosis during 3 years of follow-up.

OBJECTIVES: One of the most important skin complications in systemic sclerosis (SSc) is digital ulceration. Local thermal hyperemia (LTH) in the skin is a biphasic response to local heating involving both neurovascular and endothelial responses. Since LTH is abnormal in SSc patients, we aimed at testing whether LTH could be a prognostic tool for the onset of digital ulcers. METHODS: We prospectively enrolled 51 patients with SSc. Nailfold capillaroscopy and LTH were recorded at baseline, and patients were followed for 3 years. RESULTS: No patient with a LTH peak/plateau ratio ≥1 (n=19) developed digital ulcerations during the 3 year follow-up (100% negative predictive value), while 6 out of 32 patients with a LTH peak/plateau ratio <1 at enrolment presented with finger pad ulcerations within 3 years (p=0.05). In contrast, when lidocaine/prilocaine was applied to the finger pad, no relationship between thermal hyperemia and digital ulcerations was observed. CONCLUSIONS: A LTH peak/plateau ratio on the finger pad greater than 1, which can easily be determined in routine clinical practice, could be used to reassure patients, whatever the subtype of SSc, about the low probability of future digital ulceration. However, the prognostic value of this parameter should be confirmed in a larger cohort.

Use of bosentan for digital ulcers related to systemic sclerosis: a real-life retrospective French study of 89 patients treated since specific approval.

OBJECTIVES: Ischaemic digital ulcers (DUs) are a common complication of systemic sclerosis (SSc). This study aimed to characterize patients with SSc and ongoing DUs treated with the endothelin receptor antagonist bosentan in clinical practice in France. METHOD: An observational, retrospective, longitudinal study was conducted in 10 French expert centres. Medical records from randomly selected adult SSc patients who received treatment with bosentan for DU prevention from March 2007 to December 2010 were analysed. The primary objective was to determine the profile of patients at treatment initiation. Secondary objectives were to monitor bosentan dosing, treatment schedule, and reasons for treatment termination. RESULTS: The study included 89 patients (mean age 52 years, 69% female, 44% diffuse cutaneous SSc). At bosentan treatment initiation, the mean duration of Raynaud's phenomenon was 15 ± 12 years, and the mean time since first episode with DU was 6.5 ± 7 years. Most patients had a history of at least two episodes with DUs, separated by < 12 months (61%), and had received intravenous iloprost (63%). Previous DU complications included auto-amputation (8%), surgical amputation (6%), osteitis (6%), and gangrene (4.5%). Active smokers (25%) had a history of significantly more surgical amputation (p = 0.004) and osteitis (p = 0.004) than non-smokers. At least one active DU at bosentan initiation was detected in 82% of patients. Bosentan was used according to prescription guidelines and was well tolerated; six patients (7%) withdrew from treatment because of raised liver enzymes. CONCLUSIONS: Patients treated with bosentan for DU prevention in France have severe, refractory, ongoing ulcerative disease. Active smoking was correlated to a history of DU complications. Tolerance of bosentan was comparable to previous studies.

[Lyme disease acrodermitis chronica atrophicans: misleading vascular signs]. / Acrodermatite atrophiante de Lyme : des signes vasculaires parfois trompeurs.

Lyme disease acrodermatitis chronica atrophicans is a tertiary form of Lyme borrelliosis. It occurs at least six months, but also up to several years, after a tick bite. This rare condition is probably underestimated because of the difficult diagnosis. Clinical presentations of acrodermatitis chronic atrophicans are quite variable depending upon the duration of the disease. Complimentary explorations are difficult to interpret and rarely specific. Only rare configurations allow formal diagnosis of Borrelia burgdoferi infection. We present a patient who exhibited an atypical clinical presentation of Lyme disease acrodermatitis chronic atrophicans. The clinical outcome was quite favorable with treatment, confirming the diagnosis. Such treatments, which are well tolerated and highly effective, are essential since an untreated disease can lead to potentially severe neurological involvement.

[Addiction from a developmental perspective: the role of conduct disorder and ADHD in the development of problematic substance use disorders]. / Verslaving in ontwikkelingsperspectief: de rol van antisociale gedragsstoornis en ADHD in de ontwikkeling van problematisch middelengebruik.

BACKGROUND: The externalising disorders conduct disorder (CD) and ADHD occur frequently in patients suffering from substance use disorders. These disorders play an important role in the onset and development of addiction. AIM: To examine the influence of CD and ADHD on the current problems and the psychiatric comorbidity of patients with a chronic addiction. METHOD: A group of 193 opiate-addicted patients receiving methadone maintenance treatment were evaluated extensively in the following areas: functioning, quality of life, psychiatric comorbidity (including CD and ADHD) and comorbid addictions. Standardised interviews were used to check for the presence of CD and ADHD. RESULTS: A history of CD was demonstrated in the majority of participants (60.1%). Persistent ADHD was ascertained in 24.9%. Participants with CD and/or ADHD had a more severe addiction, characterised by more psychiatric comorbidity, more serious dysfunctioning and reduced quality of life. A history of CD predisposed patients particularly to antisocial behaviour and personality disorders. ADHD increased the risk of psychiatric comorbidity. CONCLUSION: Psychiatric comorbidity is part and parcel of addiction and reduces the quality of life of addicted patients. Behaviour problems in childhood play a major role in the development of severe addictions. Although CD is the biggest risk factor, the combination of ADHD with CD increases this risk, possibly through increased vulnerability to further psychiatric comorbidity.

Cutaneous iontophoresis of treprostinil in systemic sclerosis: a proof-of-concept study.

Ischemic digital ulcer (DU) is a serious complication of systemic sclerosis (SSc). Intravenous prostanoids are the only approved treatment for active DUs, but they induce dose-limiting side effects and require hospitalization. Our objective was to evaluate the effect of iontophoresis (a noninvasive drug delivery method) of treprostinil in SSc patients. Three studies were conducted: a pharmacokinetic study in 12 healthy volunteers showed that peak dermal concentration was reached at 2 hours, whereas plasma treprostinil was undetected. Then, a placebo-controlled, double-blind incremental dose study assessed the effect of treprostinil on digital skin blood flow in 22 healthy subjects. The effect of the highest dose was then compared with that of placebo in 12 SSc patients. Treprostinil significantly increased skin blood flow in healthy subjects (P = 0.006) and in SSc patients (P = 0.023). In conclusion, digital iontophoresis of treprostinil is feasible, is well tolerated, and increases digital skin perfusion. It could be tested as a treatment for SSc-related DUs.

[Secretan's syndrome: myth or pathomimia?]. / Le syndrome de Secrétan : mythe ou pathomimie ?

UNLABELLED: Secretan's syndrome is a rare condition involving generally trauma-induced hard edema of the dorsal aspect of the hand. The cause is poorly understood but factitious trauma is often suspected. CASE REPORT: A 42-year-old woman presented with a fortuitous edema on the back of the right hand. The minimally depressible edema was associated with moderately intense mechanical pain. Routine laboratory tests were normal. An extensive imaging work-up (bone x-ray of the hand and wrist, bone scintigraphy, computed tomography phlebography, lymphoscintigraphy, magnetic resonance imaging) was equally non-contributive. The diagnosis of self-inflected trauma was suggested by the atypical nature of the edema, the absence of any organic disorder on the tests performed, and the patient's attitude concerning her disease. In this clinical context, the diagnosis of Secretan's syndrome was retained. Outcome was compatible, with secondary development of complex regional pain syndrome. DISCUSSION: Three forms of Secretan's syndrome have been recently described: benign; hyperplastic; and mixed. The cause remains poorly defined. Certain authors report that it is most likely related to pathomimia. Treatment can combine physiotherapy and psychological counseling. CONCLUSION: Secretan's syndrome is a poorly-understood and rarely-described condition that may be underdiagnosed. Physicians specialized in vascular medicine should be aware of this syndrome and its difficult diagnosis by elimination.

[Arterial bypass iterative thrombosis and cancer: three cases]. / Thromboses itératives de pontages artériels et cancer : à propos de trois cas.

Cancer associated with venous thromboembolic disease has been recognized since Trousseau, but a link between cancer and iterative arterial thrombosis is rarely described. We report three cases of patients with iterative bypass thrombosis in whom cancer was subsequently diagnosed: lung cancer in one patient and hepatocarcinoma and bladder cancer in the others. Smoking and hypertension were risk factors in both patients. The link between arterial thrombosis and cancer is probably multifactorial. In case of iterative arterial bypass thrombosis, the search for cancer is as useful as the control of cardiovascular risk factors and the search for antiphospholipid syndrome, since patient management can be affected.

[Substance use disorders and ADHD: an overview of recent Dutch research]. / Verslaving en ADHD: een overzicht van recent Nederlands onderzoek.

BACKGROUND: ADHD is an important risk factor for the development of substance use disorders (SUD). AIM: To provide an overview of recent Dutch research into the prevalence of ADHD in SUD populations and the neurobiological substrate of the reduced effect of pharmacological treatment of this patient group. METHOD: We describe three studies: a meta-analysis and meta-regression analysis of the prevalence of ADHD in 6689 SUD patients; a cross-sectional study of the prevalence of ADHD and several other psychiatric disorders in 193 methadon maintenance patients, and finally a study in which the availability and occupation of dopamine transporters before and after methylphenidate treatment were measured using SPECT scans in 24 ADHD patients with and without cocaine addiction. RESULTS: The prevalence of ADHD in SUD patients is estimated to be 23.1% (95% confidence interval 19.4-27.2). This prevalence is influenced by the diagnostic instrument for ADHD and by the substance of abuse: cocaine is associated with a lower ADHD prevalence than other substances. The prevalence found among methadone maintenance patients was similar, namely 24.9%; additional comorbid psychiatric disorders were also frequently present. In the imaging study, lower availability of dopamine transporters and lower occupation by methylphenidate were found in cocaine-dependent ADHD patients than in ADHD patients without SUD. CONCLUSION: These studies confirm the high prevalence of ADHD in SUD patients, and provide a possible explanation for the reduced efficacy of methylphenidate in this patient population.

[Minimal work-up for Raynaud syndrome: a consensus report. Microcirculation working group of the Société française de médecine vasculaire]. / Bilan étiologique minimal du phénomène de Raynaud : un consensus d'experts.

About ten to fifteen percent of the French population suffer from Raynaud's phenomenon. Most of the time, it is considered as primary Raynaud's phenomenon, without underlying disease. The aim of this expert consensus from the "microcirculation group" for the French Society of Vascular Medicine and the French Society for Microcirculation, was to define clinical guidelines in patients consulting for Raynaud's phenomenon. The recommended minimal screening includes clinical examination, nailfold capillaroscopy and antinuclear antibodies. In particular, the aim of this screening is to identify patients with a significant risk for scleroderma, who would need a careful follow up.

[Chromametry, a promising technique for the quantification of skin changes in chronic venous disorders]. / La chromamétrie, une technique prometteuse pour la quantification de l'atteinte cutanée dans l'insuffisance veineuse chronique.

OBJECTIVE: The development and validation of new clinimetric tools is essential for the progress of clinical research in the field of chronic venous insufficiency. Chromametry is a simple, quick and non-invasive technique that measures the color of the skin. The aim of this study was to evaluate the ability of this technique to quantify skin pigmentation as a marker of severity of chronic venous disease and to assess the variability of measurements obtained in this condition. METHODS: Chomametry was performed on three different sites on each lower limb in 42 patients undergoing a spa treatment in La Léchère (Savoie) for chronic venous disorders (CVD). Four series of measurements were taken by two investigators for each patient, at two sessions two to four days apart. RESULTS: The chromameter readily measured the pigmentation index (PI). The PI increased with higher clinical class (CEAP classification) for measurements made at the malleolar level (r=0.48; P<0.001) and the supra-malleolar area (r=0.55; P<0.001), but not at the level of the anterior tibial tuberosity (r=-0.09; P=0.45). The repeatability and the intra- and inter-observer reproducibility of this PI index were 15%, 18% and 21% respectively of the mean of the observed difference at the malleolar level. The chromameter also provided an erythema index, which appears to be less relevant and more variable than the PI, but which might add potentially useful information regarding the characterization of skin inflammation related to the venous disease. CONCLUSION: This study shows that chromametry can be used in clinical research studies to quantify skin changes associated with CVD. Whether it can also be useful for early detection and follow-up of patients with venous trophic changes remains to be investigated.

Shared and unique genetic contributions to attention deficit/hyperactivity disorder and substance use disorders: a pilot study of six candidate genes.

The shared genetic basis of attention deficit/hyperactivity disorder (ADHD) and substance use disorders (SUDs) was explored by investigating the association of candidate risk factors in neurotransmitter genes with both disorders. One hundred seven methadone maintenance treatment patients, 36 having an ADHD diagnosis, 176 adult patients with ADHD without SUDs, and 500 healthy controls were genotyped for variants in the DRD4 (exon 3 VNTR), DRD5 (upstream VNTR), HTR1B (rs6296), DBH (rs2519152), COMT (rs4680; Val158Met), and OPRM1 (rs1799971; 118A>G) genes. Association with disease was tested using logistic regression models. This pilot study was adequately powered to detect larger genetic effects (OR≥2) of risk alleles with a low frequency. Compared to controls, ADHD patients (with and without SUDs) showed significantly increased frequency of the DBH (rs2519152: OR 1.73; CI 1.15-2.59; P=0.008) and the OPRM1 risk genotypes (rs1799971: OR 1.71; CI 1.17-2.50; P=0.006). The DBH risk genotype was associated with ADHD diagnosis, with the association strongest in the pure ADHD group. The OPRM1 risk genotype increased the risk for the combined ADHD and SUD phenotype. The present study strengthens the evidence for a shared genetic basis for ADHD and addiction. The association of OPRM1 with the ADHD and SUD combination could help to explain the contradictory results of previous studies. The power limitations of the study restrict the significance of these findings: replication in larger samples is warranted.

[Minimal work-up for Raynaud syndrome: a consensus report. Microcirculation Working Group of the French Vascular Medicine Society]. / Bilan étiologique minimal du phénomène de Raynaud : un consensus d'experts.

About ten to fifteen percent of the French population suffer from Raynaud's phenomenon. Most of the time, it is considered as primary Raynaud's phenomenon, without underlying disease. The aim of this expert consensus from the "microcirculation group" for the French Society of Vascular Medicine and the French Society for Microcirculation, was to define clinical guidelines in patients consulting for Raynaud's phenomenon. The recommended minimal screening includes clinical examination, nailfold capillaroscopy and antinuclear antibodies. In particular, the aim of this screening is to identify patients with a significant risk for scleroderma, who would need a careful follow up.