Further characterization of clinical and laboratory features in VEXAS syndrome: large-scale analysis of a multicentre case series of 116 French patients.

BACKGROUND: A new autoinflammatory syndrome related to somatic mutations of UBA1 was recently described and called VEXAS syndrome ('Vacuoles, E1 Enzyme, X-linked, Autoinflammatory, Somatic syndrome'). OBJECTIVES: To describe clinical characteristics, laboratory findings and outcomes of VEXAS syndrome. METHODS: One hundred and sixteen patients with VEXAS syndrome were referred to a French multicentre registry between November 2020 and May 2021. The frequency and median of parameters and vital status, from diagnosis to the end of the follow-up, were recorded. RESULTS: The main clinical features of VEXAS syndrome were found to be skin lesions (83%), noninfectious fever (64%), weight loss (62%), lung involvement (50%), ocular symptoms (39%), relapsing chondritis (36%), venous thrombosis (35%), lymph nodes (34%) and arthralgia (27%). Haematological disease was present in 58 cases (50%): myelodysplastic syndrome (MDS; n = 58) and monoclonal gammopathy of unknown significance (n = 12; all patients with MGUS also have a MDS). UBA1 mutations included p.M41T (45%), p.M41V (30%), p.M41L (18%) and splice mutations (7%). After a median follow-up of 3 years, 18 patients died (15·5%; nine of infection and three due to MDS progression). Unsupervised analysis identified three clusters: cluster 1 (47%; mild-to-moderate disease); cluster 2 (16%; underlying MDS and higher mortality rates); and cluster 3 (37%; constitutional manifestations, higher C-reactive protein levels and less frequent chondritis). The 5-year probability of survival was 84·2% in cluster 1, 50·5% in cluster 2 and 89·6% in cluster 3. The UBA1 p.Met41Leu mutation was associated with a better prognosis. CONCLUSIONS: VEXAS syndrome has a large spectrum of organ manifestations and shows different clinical and prognostic profiles. It also raises a potential impact of the identified UBA1 mutation.

Reassessment of inappropriate prescriptions of proton pump inhibitors in elderly in-patients: It's time to take action.

OBJECTIVES: To determine the impact of awareness sessions, proposed by the pharmaceutical team to the hospital physicians, on the reassessment of off-label non-hospital proton pump inhibitor prescriptions dedicated to hospitalized patients in the internal medicine department of a university hospital. METHODS: We conducted a retrospective and comparative cohort study of in-patients aged 65 years old and older with a prescription including a proton pump inhibitor. Patients who were admitted before the implementation of the awareness sessions were enrolled in the control group; others were enrolled in the awareness experimental group. The awareness sessions relating to the appropriate use of proton pump inhibitors involved a presentation about the national consensus guidelines, their side effects, the possible drug interactions with this therapeutic class, and recommendations about proton pump inhibitor discontinuation. Discussions took place around clinical cases during this multidisciplinary meeting. RESULTS: In total, 105 patients were included in the control group, and 52 in the awareness experimental group. In total, 10.8% of the non-hospital prescriptions were in accordance with the guidelines. The spontaneous reassessment of non-hospital proton pump inhibitors prescriptions was significantly higher in the experimental group (55.6%) compared to the control group (35.8%) (P=0.02). At discharge, 66.7% of the off-label non-hospital proton pump inhibitor prescriptions were reassessed in the experimental group versus 28.4% in the control group P<0.01). CONCLUSIONS: This multidisciplinary team meetings on the appropriate use of proton pump inhibitors were proved effective to improve prescription conformity to guidelines in older patients.

Is exposure to night-time traffic noise a risk factor for purchase of anxiolytic-hypnotic medication? A cohort study.

BACKGROUND: Studies suggest that road traffic noise increases risks of sleep disturbances, anxiety and depressive symptoms, but few have focused on psychotropic drug use. We examined whether exposure to night-time road traffic noise in Marseilles (France) is associated with an increased risk of purchasing anxiolytic or hypnotic medications. METHODS: Cohort of 190,617 inhabitants of Marseilles (aged 18-64 years) covered by the National Health Insurance Fund. We used the CadnaA noise propagation prediction model to calculate a potential road noise exposure indicator at dwellings for the night-period: Ln. Association between the number of purchases of anxiolytics-hypnotics in 2008-9 and the Ln was analysed with a zero-inflated negative binomial (ZINB) model adjusted for characteristics of individuals (sociodemographic, consultations with general practitioners, presence of chronic psychiatric disorder), prescribers (demographic, specialty, workload) and neighbourhoods (medical density, complaints filed for environmental noise). Analyses were stratified by the deprivation level of the census block of residence to control for the confounding effects of neighbourhood socio-economic status. RESULTS: The ZINB model showed a small but significant increase in the risk of purchasing higher numbers of anxiolytics-hypnotics for Ln greater than 55 dB(A) only in the low deprivation stratum. CONCLUSION: We found some evidence that potential exposure to night-time road traffic noise might affect individual use of anxiolytics-hypnotics. Further research based on strictly individual approaches is warranted to assess exposure to road traffic noise more precisely and reliably than allowed by noise propagation prediction models.

Transperineal versus transvaginal ultrasound cervical length measurement and preterm labor.

OBJECTIVE: The aim was to evaluate the agreement between and the reproducibility of transperineal and transvaginal ultrasound cervical length measurements performed by the duty obstetrical team in case of preterm labor. The acceptability of transperineal ultrasonography was also assessed. METHODS: Pregnant patients between 25 and 34 weeks of gestation with contractions and a clinically modified cervix were included. Order of ultrasonography examination (transperineal or transvaginal first) and rank of operator (resident or senior) were allocated randomly. Agreement was assessed using the intraclass correlation coefficient (ICC) and the Bland and Altman plot. The patient's discomfort and preference for either method were assessed with a questionnaire. RESULTS: 62 patients admitted for preterm labor between 25 and 34 weeks of gestation were included. Six seniors and nine residents took part in the study. Among the 51 patients with an interpretable transperineal ultrasound scan, median cervical length measurements with the transperineal and the transvaginal technique were, respectively, 25 mm (0-53) and 27 mm (4-51). Concordance was good with an ICC of 0.83 [IC 95 % = (0.73-0.90)]. Transperineal ultrasonography was preferred in 56.5 % of cases. CONCLUSION: In case of preterm labor, cervical length measurement with transperineal ultrasonography seems reproducible and can be performed by the obstetric team on duty.

[McArdle's disease revealed by acute low back pain]. / Une maladie de McArdle révélée par une lombalgie aiguë.

INTRODUCTION: McArdle disease, or glycogen storage disease type V (GSD 5), is a rare metabolic myopathy linked to an autosomal recessive myophosphorylase deficiency. CASE REPORT: We report the case of a 17-year-old male patient who was referred to the emergency department for the management of acute inflammatory low back pain, without traumatic context, associated with an increase of CK at 66,336 UI/L (N<192UI/L) and a CRP at 202mg/L. The immunological assessment was negative and the spinal MRI showed images in favor of necrotizing fasciitis affecting the erector spinae muscles, among others. Faced with the description of difficulties in practicing physical activities since childhood and a non-ischaemic forearm exercise test showing no elevation in lactacidemia, genetic tests were carried out, finding two heterozygous variants in the PYGM gene: c.1963G>A (p.Glu655Lys) class 5 and c.2178-1G>A class 4, confirming the diagnosis of McArdle disease. DISCUSSION: GSD 5 is a disease characterized essentially by muscular fatigability during exercise. The case reported here is original in the clinical circumstances leading to the diagnosis, i.e., inaugural acute low back pain with rhabdomyolysis. This symptomatology had already been described before, but in a patient whose diagnosis was already known. Spinal MRI showed non-specific muscle inflammation and necrosis. Muscle biopsy only found necrosis but no pathological elements typical of the diagnosis. If the symptoms are suggestive, it may be preferable to directly perform a non-ischaemic forearm exercise test, in order to go directly to molecular genetic analysis. There is no specific curative treatment of GSD 5. However, some measures can be implemented to limit the symptoms, such as learning physical exercises, limiting intense efforts and adopting dietary recommendations.

[Fish odor syndrome: A socially disabling disorder]. / Le « Fish odor syndrome ¼ : une maladie socialement invalidante.

INTRODUCTION: Fish odor syndrome (FOS) is a rare metabolic disorder that manifests as "rotten fish" body odor and is caused by the excretion of trimethylamine (TMA) in body fluids. This disease can have a negative impact on the social life of affected patients. CASE REPORTS: We report the case of two female patients complaining about unpleasant body odor. The diagnosis of FOS was confirmed by the demonstration of trimethylaminuria by NMR spectroscopy and by molecular analysis of the FMO3 gene. A restrictive choline diet combined with digestive decontamination reduced odor symptoms and improved the social life of these 2 patients. CONCLUSIONS: Fish odor syndrome is a rare and unrecognized disease that can affect the quality of life of affected persons. Following laboratory diagnosis, treatment is often effective.

Validation of plasma amino acid profile using UHPLC-mass spectrometer (QDa) as a screening method in a metabolic disorders reference centre: Performance and accreditation concerns.

INTRODUCTION: Amino acid (AA) analysis in plasma is essential for diagnosis and monitoring of inborn errors of metabolism (IEM). The efficacy of patient management is governed by the rapidity of AA profile availability, along with the robustness of the method. French quality guidelines and progress made in analytical techniques have led biologists to develop AA profile exploration via mass spectrometry (MS). OBJECTIVES: The aim of this study was to validate an analytical method with a single quadrupole mass spectrometer (MS) and to suggest reference values in regard to French quality and IEM society recommendations. DESIGN AND METHODS: Plasma samples from patients were deproteinised and derivatised with AccqTag™ reagent. Analysis was performed by reverse-phase chromatography coupled to QDA detector. We evaluated accuracy, intra-days and inter-days precision and limit of quantification by the ß-expectation tolerance interval method for 27 AA. Method comparison was performed with the standard method (ion exchange chromatography, IEC) on Jeol Aminotac® and to tandem MS. Reference values were established on AA concentrations of the cohort of patients who had no IEM. RESULTS: Our method allowed the separations of almost all amino acids with a total run time of 12 min. Separation of isoleucine and alloisoleucine was incomplete (R = 0.55) but without impact on biological interpretation. Precision, accuracy and quantification were satisfactory (intra-days coefficient of variation (CV) was <5%, inter-days precision CV <10% and accuracy <15%). The limits of quantification were validated between 1 and 900 µmol/L. Results were comparable between the new method and IEC. CONCLUSION: Ultimately, we validated a rapid method on plasma for quantifying 27 amino acids that can be used in routine practice, according to French quality laboratories and SFEIM (French Society of Inborn Error of Metabolism) recommendations. Furthermore, estimated reference values were similar to those found in published studies focusing on other methods. Despite a lower specificity compared to tandem MS, the simplicity and rapidity of our method are the main advantage of this technique and place it as a major tool in IEM diagnosis and management.

miR-379 links glucocorticoid treatment with mitochondrial response in Duchenne muscular dystrophy.

Duchenne Muscular Dystrophy (DMD) is a lethal muscle disorder, caused by mutations in the DMD gene and affects approximately 1:5000-6000 male births. In this report, we identified dysregulation of members of the Dlk1-Dio3 miRNA cluster in muscle biopsies of the GRMD dog model. Of these, we selected miR-379 for a detailed investigation because its expression is high in the muscle, and is known to be responsive to glucocorticoid, a class of anti-inflammatory drugs commonly used in DMD patients. Bioinformatics analysis predicts that miR-379 targets EIF4G2, a translational factor, which is involved in the control of mitochondrial metabolic maturation. We confirmed in myoblasts that EIF4G2 is a direct target of miR-379, and identified the DAPIT mitochondrial protein as a translational target of EIF4G2. Knocking down DAPIT in skeletal myotubes resulted in reduced ATP synthesis and myogenic differentiation. We also demonstrated that this pathway is GC-responsive since treating mice with dexamethasone resulted in reduced muscle expression of miR-379 and increased expression of EIF4G2 and DAPIT. Furthermore, miR-379 seric level, which is also elevated in the plasma of DMD patients in comparison with age-matched controls, is reduced by GC treatment. Thus, this newly identified pathway may link GC treatment to a mitochondrial response in DMD.

[Mite sensitization in children followed for respiratory allergy in a tropical African environment in Cotonou, Benin]. / Sensibilisation aux acariens chez les enfants suivis pour allergie respiratoire en milieu tropical africain à Cotonou, Bénin.

INTRODUCTION: In tropical Africa, allergies are not well documented. The objective of this work was to evaluate, by two methods, the sensitization to mites in children followed for respiratory allergy. METHODS: Skin prick-test and IgE assay by REAST test with 3 mites: Dermatophagoides pteronyssinus (D. pteronyssinus), Dermatophagoides farinae (D. farinae) and Blomia tropicalis (B. tropicalis) were carried out in children from 3 to 15 years followed up for asthma and/or allergic rhinitis. The positive results of the two tests were compared. RESULTS: Of the 130 (100%) children included, all eligible for the assay, 119 (91.5%) had the prick-test. The mean age and sex ratio (M/F) were 7±1 year, and 1.6. The association of rhinitis and asthma was the most frequent and found in 66 (55.6%). The sensitivity frequencies for the prick-test and assay were respectively 79% versus 36.1% for B. tropicalis, 71.4% versus 33.4% for D. pteronyssinus and 38.7% versus 37.8% for D. farinae. A moderate correlation between mean papule diameter and mean IgE concentration was observed. CONCLUSION: In African tropical environments, dust mite sensitization in children followed for respiratory allergy is frequent, with the order of frequency being: B. tropicalis, D. pteronyssinus, and D. farinae. The prick-test had better sensitivity than the assay for its evaluation.

Heat shock treatment increases engraftment of transplanted human myoblasts into immunodeficient mice.

Myoblast transfer therapy (MTT) is a strategy that has been proposed to treat some striated muscle pathologies. However, the first therapeutic trials using this technique were unsuccessful due to the limited migration and early cell death of the injected myoblasts. Various strategies have been considered to increase myoblast survival in the host muscle after MTT. Overexpression of heat shock proteins (HSPs) in mouse myoblasts has been shown to improve cell resistance against apoptosis in vitro and in vivo. Our objective was to determine whether heat shock (HS) treatment increased the survival of human myoblasts leading to better participation of the injected cells in muscle regeneration. For this study, HS-treated human myoblasts were injected into the tibialis anterior (TA) muscles of immunodeficient RAG-/- gammaC-/- mice. TA muscles were excised at 24 hour and at 1 month after injection. Our results showed that HS treatment increased the expression of the hsp70 protein and protected the cells from apoptosis in vitro. HS treatment dramatically increased the number of human fibers present at 1 month after injection when compared with nontreated cells. Interestingly, HS treatment decreased apoptosis at 24 hour after human myoblast injection, but no differences were observed concerning proliferation, suggesting that the increased fiber formation among the HS-treated group was probably due to decreased cell death. These data suggested that HS treatment might be used in the clinical context to improve the success of MTT.

[Diagnosis and treatment of urea cycle disorders in adult patients]. / Diagnostic et traitement des déficits du cycle de l'urée à l'âge adulte.

Urea cycle disorders (UCDs) are inborn errors of metabolism in which the clinical picture is mostly due to ammonia intoxication. UCD onset may be observed at any age. Acute decompensations of UCDs include neuro-psychiatric symptoms such as headache, confusion, convulsions, ataxia, agitation or delirium, as well as digestive symptoms, namely nausea and vomiting along with abdominal pain. Acute decompensations may lead to an irreversible coma in the absence of specific therapy. The first step is to measure promptly ammonemia in such patients, and start appropriate therapy on an emergency basis.

Myoblast transfer therapy: is there any light at the end of the tunnel?

Myoblast transfer therapy (MTT) was proposed in the 70's as a potential treatment for muscular dystrophies, based upon the early results obtained in mdx mice: dystrophin expression was restored in this model by intramuscular injections of normal myoblasts. These results were quickly followed by clinical trials for patients suffering from Duchenne Muscular Dystrophy (DMD) in the early 90's, based mainly upon intramuscular injections of allogenic myoblasts. The clinical benefits obtained from these trials were minimal, if any, and research programs concentrated then on the various pitfalls that hampered these clinical trials, leading to numerous failures. Several causes for these failures were identified in mouse models, including a massive cell death of myoblasts following their injection, adverse events involving the immune system and requiring immunosuppression and the adverse events linked to it, as well as a poor dispersion of the injected cells following their injection. It should be noted that these studies were conducted in mouse models, not taking into account the fundamental differences between mice and men. One of these differences concerns the regulation of proliferation, which is strictly limited by proliferative senescence in humans. Although this list is certainly not exhaustive, new therapeutic venues were then explored, such as the use of stem cells with myogenic potential, which have been described in various populations, including bone marrow, circulating blood or muscle itself. These stem cells presented the main advantage to be available and not exhausted by the numerous cycles of degeneration/regeneration which characterize muscle dystrophies. However, the different stem candidates have shown their limits in terms of efficiency to participate to the regeneration of the host. Another issue was raised by clinical trials involving the injection of autologous myoblasts in infacted hearts, which showed that limited targets could be aimed with autologous myoblasts, as long as enough spared muscle was available. This resulted in a clinical trial for the pharyngeal muscles of patients suffering from Oculo-Pharyngeal Muscular Dystrophy (OPMD). The results of this trial will not be available before 2 years, and a similar procedure is being studied for Fascio-Scapulo-Humeral muscular Dystrophy (FSHD). Concerning muscular dystrophies which leave very few muscles spared, such as DMD, other solutions must be found, which could include exon-skipping for the eligible patients, or even cell therapy using stem cells if some cell candidates with enough efficiency can be found. Recent results concerning mesoangioblasts or circulating AC133+ cells raise some reasonable hope, but still need further confirmations, since we have learned from the past to be cautious concerning a transfer of results from mice to humans.

[Unilateral isolated Raynaud's phenomenon leading to diagnosis of multifocal giant-cell arteritis complicated with renal ischemia]. / Phénomène de Raynaud unilatéral isolé révélateur d'une artérite à cellules géantes multifocale (maladie de Horton) compliquée d'ischémie rénale.

We report a case of a 76-year-old woman with isolated unilateral Raynaud phenomenon revealing giant-cell arteritis with diffuse arterial lesions and bilateral renal artery stenosis. Doppler ultrasonography showed bilateral stenosis of the subclavian and axillary arteries. Angio-CT PET enlightened diffuse arterial lesions, mainly involving the aorta and the brachial and femoral arteries as well as bilateral renal ostial stenosis with right kidney ischemia. Diagnosis of giant-cell arteritis was made on the temporal artery biopsy. Corticosteroid therapy led to rapid clinical and radiological improvement. Clinical manifestations of giant-cell arteritis may be atypical. Diffuse arterial disease may exist in the absence of cephalic symptoms or significant inflammatory biological features. Ostial renal artery stenosis may induce potentially threatening renal ischemia.

Isolation of HIV-1 from seropositive people living in Cotonou, Benin.

Benin is located in West Africa and is situated between HIV-2 and HIV-1-endemic zones. The first cases of HIV-1 infection in Benin were reported in 1987. Since then, AIDS cases have been diagnosed there and the number of known HIV-seropositive people has rapidly increased. Blood samples were collected from 14 seropositive and 11 seronegative patients living in the main city, Cotonou, and their peripheral blood mononuclear cells were cultured. In seven of the seropositive cases, a retrovirus was detected by measurement of Mg2(+)-dependent reverse transcriptase activity and electron microscopy. HIV-1 antigen assay and genomic analysis indicated that the isolated viruses belong to the first serotype. In each positive case, an HIV-1 DNA probe hybridized to the RNA extracted from the virus and six isolates were found positive by the polymerase chain reaction using HIV-1-specific primers.

Analysis conditions of an industrial Al-Mg-Si alloy by conventional and 3D atom probes.

Industrial 6016 Al-Mg-Si(Cu) alloys are presently regarded as attractive candidates for heat treatable sheet materials. Their mechanical properties can be adjusted for a given application by age hardening of the alloys. The resulting microstructural evolution takes place at the nanometer scale, making the atom probe a well suited instrument to study it. Accuracy of atom probe analysis of these aluminium alloys is a key point for the understanding of the fine scale microstructural evolution. It is known to be strongly dependent on the analysis conditions (such as specimen temperature and pulse fraction) which have been widely studied for ID atom probes. The development of the 3D instruments, as well as the increase of the evaporation pulse repetition rate have led to different analysis conditions, in particular evaporation and detection rates. The influence of various experimental parameters on the accuracy of atom probe data, in particular with regard to hydride formation sensitivity, has been reinvestigated. It is shown that hydrogen contamination is strongly dependent on the electric field at the specimen surface, and that high evaporation rates are beneficial. Conversely, detection rate must be limited to smaller than 0.02 atoms/pulse in order to prevent drastic pile-up effect.

HREM, FIM and tomographic atom probe investigation of Guinier-Preston zones in an Al-1.54at% Cu alloy.

An investigation of Guinier-Preston zones in Al-1.54at% Cu alloy annealed for 30h at 100 degrees C was carried out on the same monocrystal with complementary techniques of high-resolution electron microscopy (HREM) and tomographic atom probe-field ion microscopy (TAP-FIM). HREM results show that majority of GP1 zones are monolayers 1-9nm in size. However, some GP2 zones and particles in an intermediate state of growth between GP1 and GP2 stage were also found. From TAP results it follows that GP1 zones with different Cu concentrations ranging from 40% up to 100% Cu coexist. The residual solid solution is very heterogeneous. In the vicinity of GP particles the Cu content in the matrix falls down to zero, the solid solution in other regions contains from 0.7 to 1at% Cu.

[Pneumomediastinum and subcutaneous emphysema after translaryngeal jet ventilation]. / Pneumomédiastin et emphysème sous-cutané au décours d'une ventilation translaryngée par oxygène pulsé.

The use of emergency transtracheal jet ventilation in a 62 year-old female with laryngeal papillomatosis and respiratory distress is reported. Adequate ventilation of the lungs with an intermittent jet of oxygen under high pressure (5 bar) allowed anaesthesia and surgery to be carried out. Pathogenesis of the mediastinal and subcutaneous emphysema discovered at the end of the procedure is discussed.

[Heart arrest during general anesthesia in a child with unrecognized Duchenne's dystrophy]. / Arrêt circulatoire lors d'une anesthésie générale chez un enfant porteur d'une myopathie de Duchenne méconnue.

A three-year old child was anaesthetized by halothane. Cardiac arrest occurred soon after the injection of suxamethonium. Signs of rhabdomyolysis associated with hyperkalemia were present. The diagnosis of Duchenne muscular dystrophy was obtained afterwards.