High-frequency ultrasound quantification of acute radiation dermatitis: pilot study of patients undergoing radiotherapy for breast cancer.

BACKGROUND: Acute radiation dermatitis (ARD) is a frequent complication after breast cancer radiotherapy and is usually assessed by semi-quantitative clinical scores, which may be subject to inter-observer variability. High-frequency ultrasound imaging of the skin can reliably quantify thickness and edema in diseased skin. We aimed to compare the relative increase in dermal thickness of the irradiated zone in breast-cancer patients undergoing radiotherapy, with clinical severity. METHODS: A consecutive series of patients undergoing treatment for breast cancer by lumpectomy and radiotherapy in a 6-month period also underwent clinical and ultrasound evaluation of ARD. RESULTS: We included 34 female patients 17 had grade 1 (group 1), 17 had grade 2 or grade 3 ARD (group 2). The mean relative increase in dermal thickness in irradiated skin (RIDTIS) was greater for group 2 than 1: 0.53 vs 0.29 mm (P=.023). On univariate analysis, ARD was associated with skin phototype, breast volume and RIDTIS, and on multivariable analysis, breast volume and age remained predictive of the disease. CONCLUSION: Patients with more severe dermatitis showed significantly increased dermal thickness. Dermal thickness is a quantitative variable that could help quantify the efficacy of drugs and improve the treatment of this disease in patients undergoing radiotherapy.

Prospective observational study of the effect of dual antiplatelet therapy with tranexamic acid treatment on platelet function and bleeding after cardiac surgery.

BACKGROUND: The bleeding impact of dual antiplatelet therapy (DAPT), aspirin and clopidogrel, maintained until coronary artery bypass graft surgery (CABG), is still a matter of debate. The lack of preoperative antiplatelet activity measurement and heterogeneity of antifibrinolytic protocols in prior studies make the conclusions questionable. The aim of this prospective study was to determine, after preoperative antiplatelet activity measurement, if the maintenance of DAPT until CABG increases bleeding in patients treated with tranexamic acid (TA). METHODS: This observational study included 150 consecutive patients, 89 treated with aspirin and 61 treated with DAPT, undergoing a first-time planned on-pump CABG with TA treatment. Antiplatelet activity was measured with platelet aggregation tests and quantification of VASP phosphorylation. Postoperative bleeding at 24 h was recorded and propensity score analysis was performed. RESULTS: Based on VASP assay, 54% of patients showed high on-clopidogrel platelet activity inhibition. Postoperative bleeding at 24 h increased by 22% in the DAPT group, compared with the aspirin group (680 [95% CI: 360-1670] vs 558 [95%CI: 267-1270] ml, P < 0.01), consistent with increased blood transfusion (21% vs 7%, P = 0.01); a higher incidence of mediastinitis did not reach statistical significance (15% vs 4%, P = 0.05). Bleeding correlated with the extent of clopidogrel antiplatelet effect, with the best correlation for the VASP assay. CONCLUSIONS: Maintenance of DAPT until the day of CABG in patients treated with TA, increased postoperative bleeding at 24 h in parallel with preoperative antiplatelet activity induced by clopidogrel.

Multifaceted bench comparative evaluation of latest intensive care unit ventilators.

BACKGROUND: Independent bench studies using specific ventilation scenarios allow testing of the performance of ventilators in conditions similar to clinical settings. The aims of this study were to determine the accuracy of the latest generation ventilators to deliver chosen parameters in various typical conditions and to provide clinicians with a comprehensive report on their performance. METHODS: Thirteen modern intensive care unit ventilators were evaluated on the ASL5000 test lung with and without leakage for: (i) accuracy to deliver exact tidal volume (VT) and PEEP in assist-control ventilation (ACV); (ii) performance of trigger and pressurization in pressure support ventilation (PSV); and (iii) quality of non-invasive ventilation algorithms. RESULTS: In ACV, only six ventilators delivered an accurate VT and nine an accurate PEEP. Eleven devices failed to compensate VT and four the PEEP in leakage conditions. Inspiratory delays differed significantly among ventilators in invasive PSV (range 75-149 ms, P=0.03) and non-invasive PSV (range 78-165 ms, P<0.001). The percentage of the ideal curve (concomitantly evaluating the pressurization speed and the levels of pressure reached) also differed significantly (range 57-86% for invasive PSV, P=0.04; and 60-90% for non-invasive PSV, P<0.001). Non-invasive ventilation algorithms efficiently prevented the decrease in pressurization capacities and PEEP levels induced by leaks in, respectively, 10 and 12 out of the 13 ventilators. CONCLUSIONS: We observed real heterogeneity of performance amongst the latest generation of intensive care unit ventilators. Although non-invasive ventilation algorithms appear to maintain adequate pressurization efficiently in the case of leakage, basic functions, such as delivered VT in ACV and pressurization in PSV, are often less reliable than the values displayed by the device suggest.

[Short-term efficacy and safety of lurasidone in the treatment of schizophrenia]. / Efficacité et tolérance à court terme de la lurasidone dans la prise en charge de la schizophrénie.

Lurasidone is a new second-generation antipsychotic approved in October 2010 by the Food and Drug Administration and in March 2014 by the European Medicines Agency for the treatment of schizophrenia. Like other second-generation antipsychotics, lurasidone is an antagonist of D2 dopamine and 5HT2A serotonin receptors, but differs from the other second-generation antipsychotics in its action profile for certain receptors. Lurasidone is the second-generation antipsychotic with the greatest affinity for 5HT7 receptors and has a low affinity for α1 and α2C-adrenergic and 5HT2C serotonin receptors, and no affinity for histaminergic H1 or muscarinic M1 receptors. Lurasidone has demonstrated its efficacy in several short-term studies in acute schizophrenia with significantly reducing total scores of Positive and Negative Syndrome Scale (PANSS) and Brief Psychiatric Rating Scale (BPRS) compared with placebo. Early improvement was observed by days 3-7 for the 80-160 mg/day doses. Two studies with several methodological limitations showed that lurasidone might be involved in the improvement of cognitive performance in schizophrenic patients. Post hoc analysis of four pooled short-term studies showed significantly better effects on improving depressive symptoms associated with schizophrenia in patients treated with lurasidone as compared to patients treated with placebo. Lurasidone differs from the other second-generation antipsychotics by a good tolerability profile, in particular in terms of metabolic and cardiovascular profiles. Although results of the preclinical studies suggested that lurasidone had a low potential for causing clinically significant extrapyramidal symptoms, these were observed with a higher frequency than expected. It seems to have a significant though moderate link with the occurrence of akathisia, extrapyramidal symptoms, and hyperprolactinemia during initiation of treatment. This new tolerance profile greatly broadens the scope of second-generation antipsychotics and supports the view of some authors that the term second-generation antipsychotic is now outdated. Other therapeutic perspectives of lurasidone have been assessed, in particular in bipolar depression.

Mapping of electron-hole excitations in the charge-density-wave system 1T-TiSe2 using resonant inelastic x-ray scattering.

In high-resolution resonant inelastic x-ray scattering at the Ti L edge of the charge-density-wave system 1T-TiSe(2), we observe sharp low energy loss peaks from electron-hole pair excitations developing at low temperature. These excitations are strongly dispersing as a function of the transferred momentum of light. We show that the unoccupied bands close to the Fermi level can effectively be probed in this broadband material. Furthermore, we extract the order parameter of the charge-density-wave phase from temperature-dependent measurements.

Tocilizumab and COVID-19: Timing of administration assessment.

Recent evidence showed greater efficacy of tocilizumab (TCZ) in the subgroups of COVID-19 patients who presented with symptoms for less than 7 days and in those only receiving oxygen. We retrospectively analyzed a compassionate use cohort to determine the best timing for TCZ injection. We showed no association between the timing of injection after symptom onset and the efficacy of TCZ on mortality. We then investigated whether the oxygen level at the time of TCZ injection impacted the mortality rate. Our study finally suggested that TCZ could be less effective when oxygen requirement is >11L/min and we hypothesized that earlier administration could be associated with better outcome. However, randomized clinical trials are required to confirm this hypothesis.

[Reprint of: Severe pre-eclampsia: guidelines for clinical practice from the French Society of anesthesiology and intensive care (SFAR) and the French College of gynaecologists and obstetricians (CNGOF)]. / Republication de : recommandations formalisées d'experts. Prise en charge de la patiente avec une pré-éclampsie sévère­RFE communes Société française d'anesthésie-réanimation (SFAR)­Collège national des gynécologues et obstétriciens français (CGNOF).

OBJECTIVE: To provide national guidelines for the management of women with severe preeclampsia. DESIGN: A consensus committee of 26 experts was formed. A formal conflict of interest (COI) policy was developed at the onset of the process and enforced throughout. The entire guidelines process was conducted independently of any industrial funding. The authors were advised to follow the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE®) system to guide assessment of quality of evidence. The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasized. METHODS: The last SFAR and CNGOF guidelines on the management of women with severe preeclampsia was published in 2009. The literature is now sufficient for an update. The aim of this expert panel guidelines is to evaluate the impact of different aspects of the management of women with severe preeclampsia on maternal and neonatal morbidities separately. The experts studied questions within 7 domains. Each question was formulated according to the PICO (Patients Intervention Comparison Outcome) model and the evidence profiles were produced. An extensive literature review and recommendations were carried out and analyzed according to the GRADE® methodology. RESULTS: The SFAR/CNGOF experts panel provided 25 recommendations: 8 have a high level of evidence (GRADE 1±), 9 have a moderate level of evidence (GRADE 2±), and for 7 recommendations, the GRADE method could not be applied, resulting in expert opinions. No recommendation was provided for 3 questions. After one scoring round, strong agreement was reached between the experts for all the recommendations. CONCLUSIONS: There was strong agreement among experts who made 25 recommendations to improve practices for the management of women with severe preeclampsia.

Identification of a stimulator of steroid hormone synthesis isolated from testis.

Gonadal steroidogenesis is regulated by pituitary gonadotropins and a locally produced, unidentified factor. A 70-kilodalton (kD) protein complex secreted from rat Sertoli cells was isolated. The complex, composed of 28- and 38-kD proteins, stimulated steroidogenesis by Leydig cells and ovarian granulosa cells in a dose-dependent and adenosine 3',5'-monophosphate-independent manner. The follicle-stimulating hormone-induced 28-kD protein appeared to be responsible for the bioactivity, but the 38-kD protein was indispensable for maximal activity. The 28- and 38-kD proteins were shown to be identical to the tissue inhibitor of metalloproteinase-1 (TIMP-1) and the proenzyme form of cathepsin L, respectively. Thus, a TIMP-1-procathepsin L complex is a potent activator of steroidogenesis and may regulate steroid concentrations and, thus, germ cell development in both males and females.

ß LACTA test performance for detection of extended-spectrum ß-lactamase-producing Gram-negative bacilli directly on bronchial aspirates samples: a validation study.

OBJECTIVES: Incidence of extended-spectrum ß-lactamase-producing Gram-negative bacilli (ESBL-PE-GNB)-related infections is worryingly increasing worldwide. ESBL-PE-GNB detection directly on bronchial aspirate samples (BAS) performed for suspected pneumonia may help save empirical carbapenems. Our objectives were to optimize ß-LACTA™ test (BLT) realization and evaluate BLT performance for ESBL-PE-GNB detection directly on BAS. METHODS: We studied BLT technical optimization using BAS of different matrix types spiked with increasing concentrations of CTX-M-15-producing Klebsiella pneumoniae; in vitro validation of BLT diagnostic performance on 17 ESBL enzymes, belonging to CTX-M, SHV, TEM, OXA, GES, VEB and PER groups; and clinical validation of BLT performance on 126 BAS prospectively collected from seven intensive care units. RESULTS: After optimization, BLT detected with 100% sensitivity the presence of CTX-M-15-producing K. pneumoniae spiked in sterile BAS for inoculums upon two or more GNB per field upon microscopic Gram staining examination (MGSE). The BLT accurately detected the 17 ESBLs tested at 106 CFU/mL and all ESBLs except Pseudomonas aeruginosa-related OXA-14 at 104 CFU/mL. Among the 126 BAS of the validation cohort, 21 (17%) gave positive BLT (ten in BAS positive and 11 in BAS negative on MGSE). All BLT-positive BAS grew with ESBL-PE-GNB, including five hyper-L2-producing Stenotrophomonas maltophilia strains. BLT detected ESBL-PE-GNB directly on clinical BAS positive for GNB on MGSE and/or growing with ≥104 CFU/mL with 100% sensitivity, specificity, and positive and negative predictive values. CONCLUSIONS: BLT is an accurate tool for ESBL-PE-GNB detection directly on BAS. Further studies are needed to evaluate the impact of BLT-guided early antimicrobial de-escalation strategies.

[VIVOPTIM: Feedback of an e-Health experimental program of primary prevention of cardiovascular risk on 30 to 70 years old volunteers]. / VIVOPTIM : retour d'expérience d'un programme expérimental de e-santé et de prévention primaire du risque cardiovasculaire global chez des sujets volontaires âgés de 30 à 70 ans.

Today by the e-health and the telemedicine, many people are more and more interested by the improvement of disease knowledge on cardiovascular diseases and associated risk factors, personalized self management support follow-up and e-Health monitoring. MGEN is a not-for-profit complementary health insurance gave itself the ways to use the new digital tools in health. MGEN developed an original and personalized program VIVOPTIM for the primary prevention of the cardiovascular risks for their members. The VIVOPTIM Pilot program is based upon digital services and was experimented by November 2015 to December, 2017 with 8000 members of the MGEN, from 30 to 70 years old and resident in two French areas (Occitanie and Bourgogne Franche-Comté). The assessment of the experiment VIVOPTIM e -health program was positive for the personalized cardiovascular support and for their health. Therefore, the MGEN generalized the VIVOPTIM program of cardiovascular prevention, to the whole France on July 11th, 2018.

Lyme borreliosis incidence in two French departments: correlation with infection of Ixodes ricinus ticks by Borrelia burgdorferi sensu lato.

We conducted a prospective study to estimate the Lyme borreliosis incidence in two rural French departments, Meuse and Puy-de-Dôme. Concurrently, we investigated the prevalence of ticks infected with Borrelia burgdorferi sensu lato (sl) and Anaplasma phagocytophilum. The incidence of Lyme borreliosis decreased from 156 to 109/100,000 inhabitants in Meuse and from 117 to 76/100,000 inhabitants in Puy-de-Dôme in 2004 and 2005, respectively, corresponding to a decrease in the density of Ixodes ricinus nymphs infected with B. burgdorferi sl. During the same period, the density of adult ticks increased. Interestingly, B. valaisiana, a nonpathogenic species, infected adult ticks more often than nymphs. These results confirmed the correlation between the Lyme borreliosis incidence and the density of infected nymphs, a stage preferentially infected with B. afzelii. In contrast, we found a low rate of infection by A. phagocytophilum, ranging from 0% to 0.4% in Puy-de-Dôme and from 0.8% to 1.4% in Meuse, suggesting a low risk for humans.

Inhibition of cyclin-dependent kinases, GSK-3beta and CK1 by hymenialdisine, a marine sponge constituent.

BACKGROUND: Over 2000 protein kinases regulate cellular functions. Screening for inhibitors of some of these kinases has already yielded some potent and selective compounds with promising potential for the treatment of human diseases. RESULTS: The marine sponge constituent hymenialdisine is a potent inhibitor of cyclin-dependent kinases, glycogen synthase kinase-3beta and casein kinase 1. Hymenialdisine competes with ATP for binding to these kinases. A CDK2-hymenialdisine complex crystal structure shows that three hydrogen bonds link hymenialdisine to the Glu81 and Leu83 residues of CDK2, as observed with other inhibitors. Hymenialdisine inhibits CDK5/p35 in vivo as demonstrated by the lack of phosphorylation/down-regulation of Pak1 kinase in E18 rat cortical neurons, and also inhibits GSK-3 in vivo as shown by the inhibition of MAP-1B phosphorylation. Hymenialdisine also blocks the in vivo phosphorylation of the microtubule-binding protein tau at sites that are hyperphosphorylated by GSK-3 and CDK5/p35 in Alzheimer's disease (cross-reacting with Alzheimer's-specific AT100 antibodies). CONCLUSIONS: The natural product hymenialdisine is a new kinase inhibitor with promising potential applications for treating neurodegenerative disorders.

[Acid sphingomyelinase deficiency and spleen trauma: splenectomy or not splenectomy?]. / Déficit en sphingomyélinase acide et rupture splénique : splénectomie ou traitement conservateur ?

INTRODUCTION: Acid sphingomyelinase deficiency leads to a severe infantile disease (Niemann-Pick disease type A) or an attenuated form of the disease encountered in adults (Niemann-Pick type B), including pulmonary fibrosis and splenomegaly. CASE REPORT: A 52-year-old man with Niemann-Pick disease type B was admitted with splenic rupture. Embolization of the splenic artery was initially performed. Three months later, the splenic volume had increased and functional asplenia was diagnosed. Splenic scintigraphy showed 20% of functional splenic tissue. Splenectomy was finally performed because of complete necrosis of the spleen. CONCLUSION: Despite its theoretical contra-indication in Niemann-Pick disease due to a risk of respiratory insufficiency, splenectomy must sometimes be considered.

Fructose utilization and phytopathogenicity of Spiroplasma citri.

Spiroplasma citri is a plant-pathogenic mollicute. Recently, the so-called nonphytopathogenic S. citri mutant GMT 553 was obtained by insertion of transposon Tn4001 into the first gene of the fructose operon. Additional fructose operon mutants were produced either by gene disruption or selection of spontaneous xylitol-resistant strains. The behavior of these spiroplasma mutants in the periwinkle plants has been studied. Plants infected via leafhoppers with the wild-type strain GII-3 began to show symptoms during the first week following the insect-transmission period, and the symptoms rapidly became severe. With the fructose operon mutants, symptoms appeared only during the fourth week and remained mild, except when reversion to a fructose+ phenotype occurred. In this case, the fructose+ revertants quickly overtook the fructose- mutants and the symptoms soon became severe. When mutant GMT 553 was complemented with the fructose operon genes that restore fructose utilization, severe pathogenicity, similar to that of the wild-type strain, was also restored. Finally, plants infected with the wild-type strain and grown at 23 degrees C instead of 30 degrees C showed late symptoms, but these rapidly became severe. These results are discussed in light of the role of fructose in plants. Fructose utilization by the spiroplasmas could impair sucrose loading into the sieve tubes by the companion cells and result in accumulation of carbohydrates in source leaves and depletion of carbon sources in sink tissues.

Catharanthus roseus genes regulated differentially by mollicute infections.

A differential display of mRNAs was used to isolate periwinkle cDNAs differentially expressed following infection with one of three mollicutes: Spiroplasma citri, Candidatus Phytoplasma aurantifolia, and stolbur phytoplasma. Twenty-four differentially expressed cDNAs were characterized by Northern blots and sequence analysis. Eight of them had homologies with genes in databanks coding for proteins involved in photosynthesis, sugar transport, response to stress, or pathways of phytosterol synthesis. The regulation of these genes in periwinkle plants infected by additional phloem-restricted bacteria showed that they were not specific to a given mollicute, but correlations with particular symptoms could be established. Expression of transketolase was down regulated following infection with a pathogenic strain of S. citri. No down regulation was observed for the nonphytopathogenic mutant GMT553, which is deficient for fructose utilization.

Acute action of choriogonadotropin on Leydig tumor cells: induction of a higher affinity benzodiazepine-binding site related to steroid biosynthesis.

We previously demonstrated that the mitochondrial peripheral-type benzodiazepine receptor (PBR) is coupled to hormone-activated steroidogenesis by regulating the intramitochondrial cholesterol transport, the rate-determining step of steroid biosynthesis. In the present study we examined whether PBR is the site of hormone action using the hCG-responsive MA-10 mouse Leydig tumor cell line as a model system. Within 15 sec of the addition of hCG to Leydig cells a 3-fold cAMP-dependent increase in PBR binding was observed. This rapid increase returned to basal levels within 60 sec. No effect was observed after 1 min in the continued presence of hCG. Scatchard analysis revealed that in addition to the known high affinity (5.0 nM) benzodiazepine-binding site, a second, hormone-induced, higher affinity (0.2 nM) benzodiazepine-binding site appeared. We then examined whether in such a short time frame steroid synthesis occurs. Fifteen-second incubation of MA-10 cells with the inhibitor of cholesterol metabolism aminoglutethimide together with hCG also resulted in an increased rate of pregnenolone formation by their isolated mitochondria that were washed and incubated in aminoglutethimide-free buffer. The dose response of benzodiazepine binding to hCG closely parallels the increase in steroid formation by the mitochondria of stimulated cells. Addition of the selective inhibitor of cAMP-dependent protein kinase, H-89, completely blocked hormone-induced PBR binding and steroid formation, whereas addition of the inactive analog H-85 was without any effect. The addition of flunitrazepam, a benzodiazepine previously shown to inhibit the trophic hormone action on steroidogenesis, completely abolished the hCG-induced rapid stimulation of steroid synthesis. These results demonstrate that in MA-10 cells, the most rapid effect described thus far of hCG and cAMP, is the transient induction of a higher affinity benzodiazepine-binding site, which occurs concomitantly with an increase in the rate of steroid formation. This, in turn, suggests that these hormones alter PBR to activate cholesterol delivery to the inner mitochondrial membrane and subsequent steroid formation.