Treatment of Eosinophilic Annular Erythema: Retrospective multicenter study and literature review.

BACKGROUND: Eosinophilic annular erythema (EAE) is a rare eosinophil-related skin disease which typically manifests with annular erythematous plaques and severe pruritus. Besides the diagnosis, the treatment of EAE is challenging since relevant published data are sparse. METHODS: The aim of this study was to assess the underlying diseases, treatments and outcomes of patients with EAE. To this end, we conducted a retrospective multicenter study and a systematic review of the MEDLINE database. RESULTS: We included 18 patients with EAE followed in 8 centers. The MEDLINE database search yielded 37 relevant publications reporting 55 cases of EAE with 106 treatment sequences. The most common and efficient treatments included topical or systemic corticosteroids, hydroxychloroquine and dapsone. In refractory patients, a combination of systemic corticosteroids with hydroxychloroquine was associated with 88% of complete clinical response. DISCUSSION: To improve the management of EAE patients, we discuss the following treatment strategy: in topical steroid-resistant patients, hydroxychloroquine can be given as first-line systemic treatment. Dapsone, hydroxychloroquine or systemic corticosteroids are second-line options to consider. Last, monoclonal antibodies or JAK inhibitors targeting type 2 inflammation could represent promising last-resort options in refractory patients.

T helper 2 inflammatory markers are associated with recurrence in chronic rhinosinusitis with nasal polyps after endoscopic sinus surgery.

BACKGROUND: Despite maximum medical treatment and endoscopic sinus surgery (ESS), chronic rhinosinusitis with nasal polyps (CRSwNP) can require revision surgery. With a growing literature on the diversity of cytokine inflammation patterns in CRSwNP, an endotype-driven approach could lead to the identification of cytokine profiles that predict recurrence. METHODS: A monocentric longitudinal study was carried out until June 2019 following CRSwNP patients who underwent surgery for the first time between December 2010 and January 2012. The biomarker profiles were established on blood and nasal secretions at the time of the first surgery (Interleukin (IL)-5, IgE, IgA, eosinophilic cationic protein (ECP) and eosinophilic- derived neurotoxin (EDN)). Profiles were compared between the patients still controlled by medical treatment and the patients requiring revision surgery during the course of the follow-up period. RESULTS: Among the 48 patients initially enrolled in our study, 8 required revision surgery (16,7%). Clinical features (asthma, allergy, aspirin intolerance, active smoking) and levels of blood markers measured at the time of the first surgery were comparable between the 2 groups of patients. Levels of IL-5, IgE and ECP in nasal secretions were significantly increased in the group of patients needing revision surgery. CONCLUSIONS: Based on simple approach of nasal secretions sampling, we showed that a predominant T helper 2 proteins expression profile can be associated with recurrent CRSwNP after ESS. Initial immunoprofiling in CRSwNP disease may contribute to better predict the therapeutic response to optimal medical and surgical treatment, and help define the role of innovative targeted treatment, beside corticosteroids and ESS.

Long term use of metformin in idiopathic cyclic edema, report of thirteen cases and review of the literature.

INTRODUCTION: Idiopathic cyclic edema (ICE) is a rare cause of edema. To date, there is no standard of care. The physiopathology of ICE could be explained by an impairment of capillary permeability. In 1995, a study demonstrated the efficacy of metformin on symptoms and capillary permeability. We evaluated ICE-patients who were treated with metformin in our department. METHODS: We retrospectively included patients diagnosed for ICE between January 1997 and October 2013. ICE was diagnosed in the presence of edema after excluding other etiologies. LANDIS test was used to support ICE diagnosis in all patients. The absence of edema at follow-up was considered as complete response (CR), partial decreased was considered as partial response (PR). Adverse events were recorded. RESULTS: Thirteen patients have accepted to use metformin. The median treatment duration was 28.5 months [8-167] and the median follow-up of treated patients was 40.5 months [14-167]. CR was reached in 10 patients (77%), and PR in 2 patients (15%). Two patients reported side-effects as diarrheas and one of them stopped the treatment due to mild diarrhea. CONCLUSION: We report the interest and tolerance of the long-term use of metformin in ICE. No severe adverse events were noticed. A prospective study is needed to confirm the efficacy of metformin in ICE-patients.

In situ real time infrared spectroscopy of sorption of (poly)molybdate ions into layered double hydroxides.

The sorption of (poly)molybdate ions into layered double hydroxides (LDHs), with Zn(2+) and Al(3+) cations, has been followed by in situ infrared spectroscopy using the attenuated total reflection technique. The exchange between solution molybdate species and interlayer anions has been followed in real time, illustrating the different behavior of molybdate ions and polymolybdate species. In a first part, the Mo(VI) speciation in solution was performed by comparison of thermodynamical calculations and infrared spectroscopy of solutions with different pH. Decomposition of bands between 800 to 1000 cm(-1), corresponding to the (Mo-O) stretching vibration, has permitted to identify major (poly)molybdate species. In the presence of LDH, the measurements have shown a high affinity for heptamolybdate (Mo7O24(6-)) species, and its preferential sorption in comparison with molybdate ions or other protonated polymolybdate species even if it represents very small fractions. From these measurements, the affinity series Mo7O24(6-) > CO3(2-) > MoO4(2-) > SO4(2-) have been directly obtained.

Chromatin structure, epigenetic mechanisms and long-range interactions in the human insulin locus.

Regulation of gene expression in eukaryotes is largely dependent on variations in chromatin structure. More recently, it has become clear that this may involve not only local chromatin organization but also distant regulatory elements that participate in large-scale chromatin architecture within the nucleus. We describe recent methods that make possible the detection of such structures and apply them to analysis of the human insulin (INS) locus in pancreatic islets. We show that the INS gene is part of an extended 'open' chromatin domain that includes adjacent genes as well. We also find that in islets, the INS promoter is in physical contact with distant sites on the same human chromosome and notably, with the SYT8 gene, located nearly 300 kb away. The strength of the contact between INS and SYT8 is increased by glucose, and this results in stimulation of SYT8 expression. Inhibition of INS transcription decreases SYT8 expression. Furthermore, downregulation of SYT8 results in decreased secretion of insulin. Our results thus establish the existence of a regulatory network between the INS gene and other distant genes through long-range physical interactions, and suggest that such networks may have general importance for insulin biology and diabetes.

Poor performance of albumin or protein-adjusted plasma calcium to diagnose dyscalcemia in hospitalized patients: A confirmatory study in a general internal medicine department.

INTRODUCTION: Hypo- and hypercalcemia are common and some causes require urgent diagnosis and treatment. Measurement of ionized calcium is the reference test to diagnose calcium disorders but total calcium adjusted for protein or albumin concentration is more often used. METHODS: Patients hospitalised in a general internal medicine department from September 2013 to December 2015 who had a total plasma calcium concentration and a serum albumin or protein concentration measured within 24h of a ionized calcium blood measurement were included. Total calcium was adjusted for protein or albumin concentration using widely used formulas and compared to ionized calcium as the gold standard. RESULTS: Among 210 included patients, 46 (22%) had hypocalcemia, 124 (59%) normocalcemia and 40 (19%) hypercalcemia according to ionized calcium concentration. Total calcium had 50% sensitivity and 95% specificity to diagnose hypocalcemia and a 93% sensitivity and 89% specificity to diagnose hypercalcemia. Adjusting total calcium for protein or albumin concentrations did not increase and sometimes decreased diagnostic accuracy. CONCLUSION: Total calcium, with or without albumin/protein adjustment, is poorly sensitive to screen for hypocalcemia. Unadjusted total calcium is as sensitive as protein- or albumin-adjusted total calcium to screen for hypercalcemia. These data argue against the use of albumin- or protein-adjusted calcium. Ionized calcium measurement should be performed to confirm dyscalcemia in patients with abnormal total calcium concentration and to rule out hypocalcemia in patients with total calcium concentration in the lower range of normal values.

[GATA2 gene mutations: 3 cases]. / Mutations du gène GATA2 : à propos de 3 cas.

INTRODUCTION: Heterozygous germline mutations of GATA2 gene (guanine-adenine-thymine-adenine binding protein 2) are hereditary mutations that can be pathogenic, sometimes occurring sporadically, responsible for a florid clinical-biological picture, sometimes serious and quickly leading to the death. CASE REPORTS: We reported two women and one man with germline mutations in the GATA2 gene. The first patient, aged 19, initially presented with monocytopenia and chronic lymphedema of the four limbs, suggestive of Emberger syndrome. The second patient, 28-years-old, presented with a disseminated atypical mycobacterium (Mycobacterium kansasii) infection, raising suspicion of an immune deficiency such as MonoMAC syndrome (deficiency syndrome of dendritic cells, monocytes, B lymphocytes and NK cells). The last patient, 30-years-old, presented with pancytopenia, leading to the diagnosis of a family form of myelodysplastic syndromes and acute myeloid leukemia characterized by a mutation of the GATA2 gene. CONCLUSIONS: Each case illustrates a typical clinical presentation of GATA2 deficiency, although the evolution of these syndromes ultimately reveals a complex, heterogeneous and intricate picture of hematological, dermatological, infectious, pulmonary, ENT or oncological symptoms. Mutations in the GATA2 gene remain a diagnostic and therapeutic challenge for the internist, and require multidisciplinary management given the florid picture that can be of interest to all specialties. The clinical spectrum of these GATA2 mutations as well as the latest management recommendations from the recent litterature and the "GATA2 club" are described in this article.

[Telomeropathies: A study of 15 cases]. / Téloméropathies de recrutement hématologique : étude de 15 cas.

INTRODUCTION: Telomeres are composed of a repeated sequence of double-stranded nucleotides TTAGGG and numerous proteins including the Shelterin complex. Their main role is to maintain the stability of the genome during cell replication through a mechanism of copying the repeted sequence by the telomerase complexe. All the diseases involving a deregulation of this complex are now grouped together under the term telomeropathies. They are difficult to diagnose and manage. Our objective was to describe the clinico-biological characteristics and treatments used, in patients affected by telomeropathies previously seen by an hematologist followed at the Lille University Hospital Center. METHODS: This is a retrospective, single-center study carried out within the department of internal medicine-clinical immunology, Reference center for rare autoimmune and systemic diseases at Lille University Hospital Center between 2005 and 2020 including all patients followed for telomeropathy. RESULTS: Probands and relatives were included. Fifteen patients were studied from 10 independant families. Sixty percent had an heterozygous TERC gene mutation. Sixty seven percent had haematological diseases including macrocytosis, anemia and/or thrombocytopenia, 20 % had a fibrotic hepatic disease, 27 % had a fibrotic pulmonary disease. Lymphocyte immunophenotyping showed a double negative T lymphocyte population with γδ TCR expression in 5 (33 %) patients. Forty-seven percent of the patients had not received any treatment. Twenty-seven percent were on androgen therapy. Twenty percent had received cyclosporine and 13 % anti-lymphocyte serum in the context of initial misdiagnosis. CONCLUSION: It is important to be aware of the complexity of telomeropathies, a differential diagnosis of immune aplastic anemia, in order to optimize management and avoid inappropriate treatments. Allografting of hematopoietic stem cells is the only potentially curative treatment. Our analysis found particularities in immunophenotyping lymphocyte not previously described to our knowledge, whose physiopathological imputability remains to be demonstrated.

Thrombotic events during long-term follow-up of obstetric antiphospholipid syndrome patients.

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by arterial and/or venous thromboses and/or pregnancy-associated morbidity. Some patients develop only obstetric complications (obstetric APS), but data on the frequency of thrombotic events during the follow-up of these patients are scarce. This study was undertaken to evaluate the rate of thrombotic events after obstetric APS diagnosis according to the 2006 revised criteria. In total, 32 obstetric APS patients were retrospectively studied, with mean follow-up of 50 ± 37 months. After delivery, aspirin was prescribed to all patients as primary thrombosis prevention. The thrombosis rate was 3.3/100 patient-years and was 4.6, 4.5 and 10/100 patient-years when we considered at least two antiphospholipid antibody positivities (among lupus anticoagulant, anticardiolipin and anti-ß2-glycoprotein-I), antinuclear antibody positivity or systemic lupus erythematosus-associated APS patients, respectively. The thrombosis rate was high after obstetric APS diagnosis, even for patients taking aspirin. Larger, prospective studies are needed to confirm this high frequency and determine the associated risk factors.

Is procalcitonin a marker of invasive bacterial infection in acute sickle-cell vaso-occlusive crisis?

Fever is often present during painful vaso-occlusive crisis (VOC) in sickle-cell disease (SCD), but does not always indicate infection. The aim of our study was to test procalcitonin as a marker of invasive bacterial infection in VOC. Consecutive SCD adults hospitalized for VOC were included. Data were collected at admission and within 24 h after the onset of fever. We distinguished patients with clinically defined and microbiologically documented invasive bacterial infection from patients with no evidence of invasive bacterial infection and who fared well without antibiotics. One hundred and twelve patients were enrolled (61% females, median age 23 years, 88% homozygous SCD). All patients with procalcitonin (PCT) level ≥1 µg/L had an invasive bacterial infection, but two patients (33%) with an invasive bacterial infection had a PCT level <1 µg/L. High levels of PCT indicate invasive bacterial infection. However, a single low PCT level without follow-up measurement cannot rule out an invasive bacterial infection and should not withhold the prescription of antibiotics.

A fibered laser system for the MIGA large scale atom interferometer.

We describe the realization and characterization of a compact, autonomous fiber laser system that produces the optical frequencies required for laser cooling, trapping, manipulation, and detection of 87Rb atoms - a typical atomic species for emerging quantum technologies. This device, a customized laser system from the Muquans company, is designed for use in the challenging operating environment of the Laboratoire Souterrain à Bas Bruit (LSBB) in France, where a new large scale atom interferometer is being constructed underground - the MIGA antenna. The mobile bench comprises four frequency-agile C-band Telecom diode lasers that are frequency doubled to 780 nm after passing through high-power fiber amplifiers. The first laser is frequency stabilized on a saturated absorption signal via lock-in amplification, which serves as an optical frequency reference for the other three lasers via optical phase-locked loops. Power and polarization stability are maintained through a series of custom, flexible micro-optic splitter/combiners that contain polarization optics, acousto-optic modulators, and shutters. Here, we show how the laser system is designed, showcasing qualities such as reliability, stability, remote control, and flexibility, while maintaining the qualities of laboratory equipment. We characterize the laser system by measuring the power, polarization, and frequency stability. We conclude with a demonstration using a cold atom source from the MIGA project and show that this laser system fulfills all requirements for the realization of the antenna.

Raising rare disease awareness using red flags, role play simulation and patient educators: results of a novel educational workshop on Raynaud phenomenon and systemic sclerosis.

BACKGROUND: As lack of awareness of rare diseases (RDs) among healthcare professionals results in delayed diagnoses, there is a need for a more efficient approach to RD training during academic education. We designed an experimental workshop that used role-play simulation with patient educators and focused on teaching "red flags" that should raise the suspicion of an RD when faced with a patient with frequently encountered symptoms. Our objective was to report our experience, and to assess the improvement in learners' knowledge and the satisfaction levels of the participants. RESULTS: The workshop consisted of 2 simulated consultations that both started with the same frequent symptom (Raynaud phenomenon, RP) but led to different diagnoses: a frequent condition (idiopathic RP) and an RD (systemic sclerosis, SSc). In the second simulated consultation, the role of the patient was played by a patient educator with SSc. By juxtaposing 2 seemingly similar situations, the training particularly highlighted the elements that help differentiate SSc from idiopathic RP. When answering a clinical case exam about RP and SSc, students that had participated in the workshop had a higher mean mark than those who had not (14 ± 3.7 vs 9.6 ± 5.5 points out of 20, p = 0.001). Participants mostly felt "very satisfied" with this training (94%), and "more comfortable" about managing idiopathic RP and SSc (100%). They considered the workshop "not very stressful" and "very formative" (both 71%). When asked about the strengths of this training, they mentioned the benefits of being put in an immersive situation, allowing a better acquisition of practical skills and a more interactive exchange with teachers, as well as the confrontation with a real patient, leading to a better retention of semiological findings and associating a relational component with this experience. CONCLUSIONS: Through the use of innovative educational methods, such as role-play simulation and patient educators, and by focusing on teaching "red flags", our workshop successfully improved RP and SSc learning in a way that satisfied students. By modifying the workshop's scenarios, its template can readily be applied to other clinical situations, making it an interesting tool to teach other RDs.

Corticotropin-releasing factor stimulates accumulation of adenosine 3', 5'-monophosphate in rat pituitary corticotrophs.

The presence of synthetic ovine corticotropin-releasing factor leads to a rapid and marked stimulation of adenosine 3', 5'-monophosphate accumulation in an enriched population of rat pituitary corticotrophs in primary culture. The increase, observed as early as 60 seconds after the addition of corticotropin-releasing factor, suggests that changes in the intracellular concentration of the cyclic nucleotide coincide with or precede the secretion of adrenocorticotropic hormone in response to corticotropin-releasing factor.

Diagnostic value of procalcitonin in acutely hospitalized elderly patients.

The aim of this study was to evaluate procalcitonin as an adjunct to diagnose bacterial infections in older patients. One hundred seventy-two patients admitted to an acute-care geriatric unit during a 6-month period were prospectively included, 39 of them with an invasive bacterial infection. The best cut-off value to rule in a bacterial infection was 0.51 microg/l with sensitivity 64% and specificity 94%. The best cut-off value to rule out a bacterial infection was 0.08 microg/l with sensitivity 97% and specificity 20%. Procalcitonin was inconclusive (between 0.08 and 0.51 microg/l) for 112 admissions. Procalcitonin over 0.51 microg/l was useless 22 times out of 33 (infection already ruled in on clinical grounds) and misleading in eight of the 11 remaining cases (no infection). Procalcitonin below 0.08 microg/l was useless 23 times out of 27 (infection already ruled out on clinical grounds) and misleading in one of the four remaining cases (infection). Despite a good overall diagnostic accuracy, the clinical usefulness of PCT to diagnose invasive bacterial infections in elderly patients hospitalized in an acute geriatric ward appears to be very limited.

Pharmacokinetics of a novel transdermal rivastigmine patch for the treatment of Alzheimer's disease: a review.

BACKGROUND: Cholinesterase inhibitors have all been available in oral formulations, but a rivastigmine transdermal patch has now been developed and is approved in many countries worldwide for the treatment of mild-to-moderate Alzheimer's disease (AD) (including the USA, Latin America, Europe and Asia). OBJECTIVES: To review the available pharmacokinetic data that supported the rationale behind the development of the rivastigmine transdermal patch and its clinical effects in dementia therapy. This article will also discuss how the patch may alter the treatment paradigm for patients with AD. RESULTS: The 9.5 mg/24 h rivastigmine patch was shown to provide comparable exposure to the highest recommended doses of capsules (12 mg/day) with significantly lower maximum plasma concentration (Cmax 8.7 vs. 21.6 ng/ml) and slower absorption rate (tmax 8.1 vs. 1.4 h). In a clinical trial of 1195 AD patients, this translated into similar efficacy with three times fewer reports of nausea and vomiting (7.2% vs. 23.1%, and 6.2% vs. 17.0% respectively). Consequently, more patients in the 9.5 mg/24 h patch group achieved their target therapeutic dose at the end of the study, compared with those in the 12 mg/day capsule group (95.9% vs. 64.4%). CONCLUSION: The rivastigmine patch provides continuous drug delivery over 24 h and similar efficacy to the highest recommended dose of oral rivastigmine with improved tolerability. This may allow patients to achieve optimal therapeutic doses and to benefit from a longer duration of treatment.

[NT-proBNP in practice: from chemistry to medicine]. / NT-proBNP en pratique "de la biologie à la clinique".

Since introduction of routine assay for natriuretic peptides, there are a growing number of clinical applications for those new tests. Numerous studies have defined analytical characteristics and clinical interest of NT-proBNP assay. Originally limited to acute heart failure diagnosis in the emergency room, NT-proBNP assay has now a wide number of applications. This review presents the "state of art" of this marker, detailing NT-proBNP physiological recent knowledge and its recognized or investigated clinical applications.

Intrauterine growth restriction, soluble fms-like tyrosine kinase-1 to placental growth factor ratio increase and preeclampsia.

BACKGROUND: Intrauterine growth restriction (IUGR) and preeclampsia (PE) share common features such as ischemic placental disease but also differ in their clinical expression regarding maternal diseases. The reason why IUGRremains isolated in some cases yet is followed by clinical manifestations of PE in other cases remains unexplained. CASE REPORT: A 40-year old woman, gravida two, para one, experienced early-onset IUGR with a significant increase in the ratio of soluble fms-like tyrosine kinase 1 (sFlt-1) to placental growth factor (PlGF) but, surprisingly, without any maternal clinical manifestations of PE. CONCLUSION: IUGR and a significant increase in sFlt-1/PlGF ratio without PE raise the issue of a missing factor enabling IUGR, a significant increase in sFlt-1/PlGF ratio, and PE to be linked. TEACHING POINTS: (1) Early-onset IUGR and a significant increase in sFlt-1/PlGF ratio do not necessarily mean the onset of PE. (2) Combining early-onset IUGR and a significant increase in sFlt-1/PlGF ratio without PE raises the question of an additional factor responsible for the onset of PE.

An unexpected asymptomatic epiglottal site of Kimura disease.

INTRODUCTION: Kimura disease (KD) is a chronic lymphoproliferative disorder of unknown etiology that affects the skin and lymph nodes, mostly observed in males of Asian descent. The natural history of asymptomatic epiglottal KD remains unknown. This rare site of KD is often only diagnosed when tumor growth starts to obstruct the upper airways. OBSERVATION: A 34-year-old North African male presented with fatigue and multiple, slowly progressive, fluctuating skin nodules in the right mandibular and retroauricular regions. Computed tomography of the head and neck revealed a large soft tissue tumor close to the right mandibular body and unexpected thickening of the epiglottis. Transnasal laryngoscopy confirmed the CT findings and showed thickening of the epiglottis. The diagnosis of KD was based on histological examination of biopsy specimens taken from the right mandibular tumor, a cervical lymph node, and the epiglottis. DISCUSSION: Most cases of KD with epiglottal involvement present with dysphonia and dysphagia. No consensus guidelines are available concerning the complementary investigations that should be performed. This case report raises the question of whether patients with suspected KD should be systematically screened for lesions in unusual and potentially dangerous anatomic sites.

[Isolated right ventricular acute myocardial infarction mimicking anterior infarction]. / Infarctus isolé du ventricule droit mimant un infarctus antérieur.

Isolated right ventricular acute myocardial infarction is rare and its presentation can sometimes mimic an anterior ST-segment elevation myocardial infarction. We reported two cases of isolated right ventricular acute myocardial infarction presenting with a ST-elevation in anterior leads. The first case was admitted for an out-of-hospital cardiac arrest due to ventricular fibrillation. The patient died from neurologic consequences of the cardiac arrest, despite a successful prehospital thrombolysis, followed by a percutaneous angioplasty of the right coronary artery. The second case occurred after a complex percutaneous angioplasty of the right coronary artery, complicated by a total occlusion of a right marginal branch. These two cases illustrate the limits of the ECG for the diagnosis of isolated right ventricular acute infarction, and the difficulties of the differential diagnosis with anterior infarction, which may determine the treatment and the prognosis.

[Analytical evaluation of NT-proBNP assay on Cardiac Reader]. / Evaluation analytique du dosage du NT-proBNP sur Cardiac Reader.

We evaluated a natriuretic peptide NT-proBNP assay on total blood, thanks to unit strips read by an apparatus of delocalized biology, the Cardiac Reader (Roche Diagnostics). Using the principle of immuno-chromatography, (with reading of colour intensity) this test measures concentrations of NT-proBNP from 60 to 3.000 pg/mL. The evaluation of this test shows an excellent repeatability, the absence of hook effect for very high values of NT-proBNP, the absence of BNP recognition and a robustness compared to the interferences classically checked: haemolysis and turbidity. The correlation of this total blood assay with a plasmatic assay by electrochemiluminescence of NT-proBNP is excellent, as well at the analytical level as on the level of the respect of the clinical decisional thresholds classically used. The test's analytical qualities make it an interesting alternative to the assay usually practised on automats in central laboratory. Nevertheless, the provision of this assay in delocalized biology (point of care) must be done according to strict rules of use, to take into account certain analytical constraints guaranteeing results of quality, compared to the therapeutic decisions that can result from.