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Iron and magnesium are essential nutrients for most microorganisms. In the environment, the availability of iron is low relative to that of magnesium. Microorganisms have developed various iron acquisition systems, which have been well studied, whereas few studies have examined magnesium acquisition. The production of siderophores is one of the efficient strategies widely used to sustain iron nutritional requirements. Many studies have shown that minerals, such as clays, iron oxides, and silicates, can serve as nutrient sources for bacteria. Asbestos, a natural fibrous silicate present in soil contains iron and/or magnesium, depending on the species of asbestos. Our aim was to study the acquisition of iron and magnesium from flocking asbestos waste by Pseudomonas aeruginosa and the involvement of the siderophores, pyoverdine and pyochelin. Flocking asbestos waste promoted growth under iron- and magnesium-limited conditions, together with a decrease in pyoverdine production, correlating with the dissolution of iron from the waste. In long-term experiments, flocking asbestos waste provided these two essential elements for bacterial growth and resulted in a decrease of iron in asbestos fibers. Among the enzymes required for pyochelin and pyoverdine synthesis, PchA and PvdJ were tagged with the fluorescent protein mCherry to analyze the expression patterns of proteins involved in siderophore production. Both enzymes were produced in the presence of flocking asbestos waste, suggesting a role of the pyoverdine and pyochelin pathway in asbestos dissolution. We investigated the involvement of each siderophore in iron and magnesium removal using mutants in one or both siderophore pathways. We observed a significant increase in iron extraction in the presence of siderophores and the absence of one of the two siderophores could be compensated by the other. Flocking asbestos waste represents an iron and magnesium source for P. aeruginosa, with iron removal linked to a siderophore-driven mechanism., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Although the technological and economic benefits of engineered nanomaterials are obvious, concerns have been raised about adverse effects if such material is inhaled, ingested, applied to the skin or even released into the environment. Here we studied the cytotoxic effects of the most abundant nanomaterial, silica nanoparticles (SiO 2 -NPs), in murine RAW264.7 macrophages. SiO 2 -NPs dose-dependently induce membrane leakage and cell death without obvious involvement of reactive oxygen species. Interestingly, at low concentrations SiO 2 -NPs trigger autophagy, evidenced by morphological and biochemical hallmarks such as autophagolysosomes or increased levels of LC3-II, which serves to protect cells from cytotoxicity. Hence SiO 2 -NPs initiate an adaptive stress response which dependent on dose serve to balance survival and death and ultimately dictates the cellular fate., (Copyright © 2017 Elsevier B.V. All rights reserved.)

This phase 3 trial evaluated the safety and hemostatic efficacy of a recombinant von Willebrand factor (rVWF) for treatment of bleeds in severe von Willebrand disease (VWD). rVWF was initially administered together with recombinant factor VIII (rFVIII) and subsequently alone, as long as hemostatic factor VIII activity (FVIII : C) levels were maintained. Pharmacokinetics (PK) were evaluated in a randomized cross-over design (rVWF vs rVWF:rFVIII at 50 IU VWF:ristocetin cofactor activity [RCo]/kg). Bleed control for all treated bleeds (N = 192 bleeds in 22 subjects) was rated good or excellent (96.9% excellent; 119 of 122 minor, 59 of 61 moderate, and 6 of 7 major bleeds) on a 4-point scale (4 = none to 1 = excellent). A single infusion was effective in 81.8% of bleeds. Treatment success, defined as the number of subjects with a mean efficacy rating of <2.5, was 100%. The PK profile of rVWF was not influenced by rFVIII (mean VWF:RCo terminal half-life: 21.9 hours for rVWF and 19.6 hours for rVWF:rFVIII). FVIII : C levels increased rapidly after rVWF alone, with hemostatic levels achieved within 6 hours and sustained through 72 hours after infusion. Eight adverse events (AEs; 6 nonserious AEs in 4 subjects and 2 serious AEs [chest discomfort and increased heart rate, without cardiac symptomatology] concurrently in 1 subject) were associated with rVWF. There were no thrombotic events or severe allergic reactions. No VWF or FVIII inhibitors, anti-VWF binding antibodies, or antibodies against host cell proteins were detected. These results show that rVWF was safe and effective in treating bleeds in VWD patients and stabilizes endogenous FVIII : C, which may eliminate the need for rFVIII after the first infusion. This trial was registered at www.clinicaltrials.gov as #NCT01410227., (© 2015 by The American Society of Hematology.)

The objective of this study was to evaluate the potential of the partial plastination technique in minimizing material slippage and to discuss the effects on the tensile properties of thin dense connective tissue. The ends of twelve iliotibial tract samples were primed with polyurethane resin and covered by plastic plates to provide sufficient grip between the clamps. The central part of the samples remained in an anatomically unfixed condition. Strain data of twelve partially plastinated samples and ten samples in a completely anatomically unfixed state were obtained using uniaxial crosshead displacement and an optical image tracking technique. Testing of agreement between the strain data revealed ongoing but markedly reduced material slippage in partially plastinated samples compared to the unfixed samples. The mean measurement error introduced by material slippage was up to 18.0% in partially plastinated samples. These findings might complement existing data on measurement errors during material testing and highlight the importance of individual quantitative evaluation of errors that come along with self-made clamping techniques., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Comparison of the pharmacokinetics (PK) of a coagulation factor between groups of patients can be biased by differences in study protocols, in particular between blood sampling schedules. This could affect clinical dose tailoring, especially in children. The aim of this study was to describe the relationships of the PK of factor VIII (FVIII) with age and body weight by a population PK model. The potential to reduce blood sampling was also explored. A model was built for FVIII PK from 236 infusions of recombinant FVIII in 152 patients (1-65 years of age) with severe hemophilia A. The PK of FVIII over the entire age range was well described by a 2-compartment model and a previously reported problem, resulting from differences in blood sampling, to compare findings from children and adults was practically abolished. The decline in FVIII clearance and increase in half-life with age could be described as continuous functions. Retrospective reduction of blood sampling from 11 to 5 samples made no important difference to the estimates of PK parameters. The obtained findings can be used as a basis for PK-based dose tailoring of FVIII in clinical practice, in all age groups, with minimal blood sampling.

Background: The use of cell-culture technologies for the manufacture of influenza vaccines might contribute to improved strain selection and robust vaccine supplies. We investigated the safety, immunogenicity, and protective efficacy of a Vero-cell-culture-derived influenza vaccine, and assessed the correlation between vaccine efficacy and haemagglutination inhibition antibody titre., Methods: In a double-blind, placebo-controlled, phase 3 trial undertaken in 36 centres in the USA, healthy adults (aged 18-49 years) were randomly assigned in a 1:1 ratio to one injection of either placebo or Vero-cell-culture-derived influenza vaccine during the 2008-09 season. Randomisation was done in blocks by use of the random number generator algorithm, and participants were allocated by use of a centralised telephone system. The primary objective was the efficacy of the vaccine in preventing cell-culture-confirmed influenza infection with viruses that were antigenically matched to one of the vaccine strains. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00566345., Findings: 7250 participants were randomly assigned to vaccine (n=3626) and placebo (n=3624). 7236 were analysed for the primary outcome (n=3619 and n=3617, respectively). Overall protective efficacy for antigenically matched influenza infection was 78·5% (95% CI 60·8-88·2). The vaccine was well tolerated with no treatment-related serious adverse events. Adverse events were mainly mild and transient. An HI titre of at least 1:15 provided a reliable correlate of cell-culture-derived influenza vaccine-induced protection; no additional benefit was noted with titres greater than 1:30., Interpretation: The data indicate that existing correlates of protection afforded with egg-derived seasonal influenza vaccines also apply to this vaccine., Funding: Federal (US Government) funds from the Office for Preparedness and Response, Biomedical Advanced Research and Development Authority, under contract to DynPort Vaccine Company., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Dose tailoring of coagulation factors requires reliably estimated and reproducible pharmacokinetics (PK) in the individual patient., Objectives: To investigate the contribution of both biological and methodological factors to the observed variability of factor VIII (FVIII) PK, with the focus on differences between children and adults, and to examine the implications for dosing., Patients: Data from 52 1-6-year-old and 100 10-65-year-old patients with hemophilia A (FVIII < or = 2 IU dL(-1)) in three clinical studies were included., Results: In vivo recovery was lower, weight-adjusted clearance was higher and FVIII half-life was on average shorter in children than in adults. However, a reduced blood sampling schedule for children was estimated to account for up to one half of the total observed differences. Intrapatient variance in PK was smaller than interpatient variance in 10-65-year-olds. Age and ratio of actual to ideal weight only showed weak relationships with PK parameters. Variance in PK caused large variance in the calculated dose required to maintain a target FVIII trough level during prophylactic treatment., Conclusion: Differences in blood sampling schedules should be taken into account when results from different PK studies are compared. However, even with this consideration, PK cannot be predicted from observable patient characteristics but must be determined for the individual. Because the influence of reducing the blood sampling was minor in comparison to the true variance between patients, a reduced blood sampling protocol can be used. Low intrapatient variability supports the use of PK measurements for dose tailoring of FVIII.

The aim of this research work was focused on the replacement of the time-consuming soaking of cork stoppers which is mainly used as screening method for cork lots in connection with sensory analysis and/or analytical methods to detect releasable 2,4,6-trichloroanisole (TCA) of natural cork stoppers. Releasable TCA from whole cork stoppers was analysed with the application of a microwave assisted extraction method (MAE) in combination with stir bar sorptive extraction (SBSE). The soaking of corks (SOAK) was used as a reference method to optimise MAE parameters. Cork lots of different quality and TCA contamination levels were used to adapt MAE. Pre-tests indicated that an MAE at 40 degrees C for 120 min with 90 min of cooling time are suitable conditions to avoid an over-extraction of TCA of low and medium tainted cork stoppers in comparison to SOAK. These MAE parameters allow the measuring of almost the same amounts of releasable TCA as with the application of the soaking procedure in the relevant range (<25 ng L(-1) releasable TCA from one cork) to evaluate the TCA level of cork stoppers. Stable isotope dilution assay (SIDA) was applied to optimise quantification of the released TCA with deuterium-labelled TCA (TCA-d(5)) using a time-saving GC-MS technique in single ion monitoring (SIM) mode. The developed MAE method allows the measuring of releasable TCA from the whole cork stopper under improved conditions and in connection with a low use of solvent and a higher sample throughput., (Copyright 2009 Elsevier B.V. All rights reserved.)

Background: Prophylactic factor (F)VIII has been shown to reduce bleeds and arthropathy in patients with severe hemophilia A., Objectives: Assuming that the trough FVIII level is an important determinant of the efficacy of prophylaxis, this paper addresses the effect of the inter-patient variability in pharmacokinetics and different dosing regimens on trough levels., Methods: Simulations used FVIII half-lives and in vivo recoveries (IVR), observed during clinical trials with Advate [Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method], and commonly used prophylactic regimens to calculate their effect on FVIII levels during prophylaxis., Results and Conclusions: Half-life and dose frequency had a larger effect on trough FVIII and time per week with FVIII<1 IU dL(-1) than IVR and infused dose per kg. The combined effect of these parameters resulted in substantial inter-patient variability in the amount of FVIII required to sustain a desired trough level. Prophylactic regimens based on Monday, Wednesday, Friday dosing were less cost effective in maintaining a desired trough level throughout the week. Dose escalation on Friday to cover the weekend would require potentially harmful doses of FVIII in many patients, especially in young children where more than 50% would require a Friday dose of over 100 IU kg(-1) and some would require more than 400 IU kg(-1). Knowledge of individual patients' half-lives and alteration of frequency of infusions may allow the more cost-effective use of FVIII and potentially expand access to prophylaxis to a greater number of patients, especially in regions where healthcare resources are scarce.

Mutations in the NPM1 gene represent the most frequent genetic alterations in patients with acute myeloid leukemia (AML) and are associated with a favorable outcome. In 690 normal karyotype (NK) AML patients the complete remission rates (CRs) and the percentage of patients with adequate in vivo blast cell reduction 1 week after the end of the first induction cycle were significantly higher in NPM1(+) (75% and 80%, respectively) than in NPM1(-) (57% and 57%, respectively) patients, but were unaffected by the FLT3-ITD status. Multivariate analyses revealed the presence of a NPM1 mutation as an independent positive prognostic factor for the achievement of an adequate day-16 blast clearance and a CR. In conclusion, NPM1(+) blast cells show a high in vivo sensitivity toward induction chemotherapy irrespective of the FLT3-ITD mutation status. These findings provide insight into the pathophysiology and help to understand the favorable clinical outcome of patients with NPM1(+) AML.

Background: The role of prophylactic factor VIII (FVIII) to decrease hemophilic bleeding and arthropathy is well established. The rationale for this strategy is to convert patients with severe hemophilia A to a moderate clinical phenotype by reducing time spent with a FVIII level <1 IU dL(-1). Studies to date, however, have not demonstrated a strong link between FVIII level and the bleeding rate., Objectives: To assess the effect of FVIII level on break-through bleeding in patients with severe hemophilia A on prophylaxis., Patients/methods: This study analysed data from 44 patients aged 1-6 and 99 patients aged 10-65 years with severe hemophilia A (FVIII <1 IU dL(-1)) who were treated with prophylactic FVIII as part of clinical studies assessing pharmacokinetics, safety and efficacy of a recombinant FVIII (Advate). Each patient had pharmacokinetic measurements and FVIII infusions recorded, and these were used to calculate time spent with a FVIII below 1, 2 and 5 IU dL(-1)., Results: The data demonstrate that increasing time with a FVIII below 1 IU dL(-1) is associated with increased total bleeds and hemarthroses. Lack of adherence to the intended frequency of FVIII infusion was the most important determinant of low FVIII and increased bleeding. In children aged 1-6 years, the rate of bleeding was also influenced by FVIII half-life and clearance., Conclusions: These data have important implications for the management of patients with severe hemophilia.

Laparoscopic surgery has gained wide acceptance. However, there is still debate as to its role in assessment and staging of gastrointestinal malignancies(1)since it may promote dissemination of cancer cells.(2)We report the first case of a low-grade mesenteric nodal lymphoma for laparoscopic hernia repair, complicated by distant implants both on the peritoneum and wall mesh., (Copyright 1999 Harcourt Publishers Ltd.)

We report here the results of a 2-year study on the prenatal diagnosis of viral infections in Strasbourg. This screening was carried out by virus isolation, by PCR assay, or by detection of IgM fetal antibody for 98 pregnant women at risk of transmitting one of the viruses that causes fetal disease such as parvovirus B19 (B19), Herpesviruses [cytomegalovirus (CMV), varicella-zoster virus, herpes simplex virus] and rubella virus. A viral etiology was proven in 7 out 98 cases: PCR applied to B19 DNA detection was positive in 5 amniotic fluids (AF), 2 fetal serums and one ascitic liquid. The diagnosis of 2 cases of CMV infection was obtained by both PCR and virus isolation in AF from twins fetuses. The detection of specific IgM in maternal serum or fetal serum is useful to achieve the diagnosis but serological tests on other samples have no efficiency. No virus was found in any other specimen, but the genome of Toxoplasma gondii was detected by PCR in 1 of 17 AF samples analyzed at the Institut de Parasitologie. These findings show that PCR assay is a sensitive method for the positive diagnosis of intrauterine infection and promises to careful follow-up of the pregnancy.

Objective: To review the literature on somatoform disorders in children and adolescents relevant to recertification by the American Board of Psychiatry and Neurology., Method: The psychiatric, pediatric, and psychological literatures were searched for clinical or research articles in the past 10 years dealing with somatization and somatoform disorders., Results: Somatizing presentations are organized conceptually; somatization disorder, body dysmorphic disorder, hypochondriasis, conversion disorder, vocal cord dysfunction, pain disorder, and recurrent abdominal pain are described in children and adolescents; empirical evidence for treatment efficacy is scant, but clinically reasonable approaches are applied., Conclusion: More developmentally appropriate diagnostic schemas and better outcome studies are needed in all the somatoform disorders for children and adolescents.

Background: Thoracoscopic sympathectomy is the most effective treatment for upper limb hyperhidrosis. However, this is offset by the occurrence of a high rate of side effects, such as embarrassing compensatory sweating. Anticipating that a technique that respects the sympathetic chain and divides only the rami communicantes may lead to fewer side effects, we assessed the technique described by R. Wittmoser, comparing it with conventional thoracoscopic sympathecomy., Methods: A total of 240 thoracoscopic sympathectomies were performed in 124 patients suffering from upper limb hyperhidrosis. Fifty-four patients underwent a conventional sympathectomy (group TS), 62 underwent division of the rami communicantes with respect to the main trunk (group SS), and 8 underwent both procedures (group TS/SS) because of accidental division of the chain during dissection. The mean follow-up is 8 months., Results: No recurrence was observed in group TS whereas six (5%) occurred in group SS (p < 0.05). The global rate of compensatory sweating was about the same in both groups: 72.2% in group TS and 70.9% in group SS. However, the rate of embarrassing or disabling compensatory sweating was significantly higher in group TS (50%) than in group SS (21%) (p < 0.001)., Conclusions: Although selective division of the rami communicantes results in a significant decrease in the rate of disturbing side effects, it also leads to recurrences that are usually not observed at that level in patients treated with the conventional technique. Therefore other means of achieving the ideal operation should be explored, that is, a technique associated with a high success rate but a minimal number of side effects.

Objective: To assess the results and the morbidity of thoracoscopy compared with conventional mediastinoscopy for the approach of mediastinal solid masses and lymph nodes, we have performed a prospective study about the respective yields, complication rates, and the length of hospital stay for patients., Material and Methods: We have included 114 patients in the study. The criteria of inclusion were the accessibility of the lymph nodes and/or mass to cervical mediastinoscopy through CT scan view. There were 2 groups: 52 patients underwent a mediastinoscopy (group M) and 62 underwent a thoracoscopy (group T)., Results: There were 3 failures in group M (5.7%) and 5 failures in group T (8.1%) (not significant; NS). In group M, the three procedures were converted to anterior mediastinotomy (two cases) and to thoracoscopy (one case). In group T, the five procedures were converted to anterior mediastinotomy (two cases), mediastinoscopy (two cases), and thoracotomy (one case). The diagnostic yield was 94.3% in group M and 91.9% in group T (NS). After conversion, a diagnosis was reached in all patients in group M (100%) and in all but 1 patient in group T (98.3%) (NS). There was no intraoperative complication in group M, while 2 complications occurred in group T (3.2%) (p < 0.05). The overall morbidity was zero in group M and 4.8% in group T (p < 0.05)., Conclusion: The diagnostic yield of mediastinoscopy is comparable to thoracoscopy. Complication rate and hospital stay of patients undergoing mediastinoscopy are significantly inferior. Thoracoscopy should be indicated only for lesions that are not within the reach of the mediastinoscope or when multiple biopsy specimens are necessary.