Risk factors and outcome of graft failure after HLA matched and mismatched unrelated donor hematopoietic stem cell transplantation: a study on behalf of SFGM-TC and SFHI.

Graft failure remains a severe complication of hematopoietic stem cell transplantation (HSCT). Several risk factors have already been published. In this study, we re-evaluated them in a large cohort who had the benefit of the recent experience in HSCT (2006-2012). Data from 4684 unrelated donor HSCT from 2006 to 2012 were retrospectively collected from centers belonging to the French Society for Stem Cell Transplantation. Among the 2716 patients for whom HLA typing was available, 103 did not engraft leading to a low rate of no engraftment at 3.8%. In univariate analysis, only type of disease and status of disease at transplant for malignant diseases remained significant risk factors (P=0.04 and P<0.0001, respectively). In multivariate analysis, only status of disease was a significant risk factor (P<0.0001). Among the 61 patients who did not engraft and who were mismatched for 1 HLA class I and/or HLA-DP, 5 donor-specific antibodies (DSAs) were detected but only 1 was clearly involved in graft failure, for the others their role was more questionable. Second HSCT exhibited a protective although not statistically significant effect on OS (hazard ratio=0.57 [0.32-1.02]). In conclusion, only one parameter (disease status before graft) remains risk factor for graft failure in this recent cohort.

Predicting pathogen-specific CD8 T cell immune responses from a modeling approach.

The primary CD8 T cell immune response constitutes a major mechanism to fight an infection by intra-cellular pathogens. We aim at assessing whether pathogen-specific dynamical parameters of the CD8 T cell response can be identified, based on measurements of CD8 T cell counts, using a modeling approach. We generated experimental data consisting in CD8 T cell counts kinetics during the response to three different live intra-cellular pathogens: two viruses (influenza, vaccinia) injected intranasally, and one bacteria (Listeria monocytogenes) injected intravenously. All pathogens harbor the same antigen (NP68), but differ in their interaction with the host. In parallel, we developed a mathematical model describing the evolution of CD8 T cell counts and pathogen amount during an immune response. This model is characterized by 9 parameters and includes relevant feedback controls. The model outputs were compared with the three data series and an exhaustive estimation of the parameter values was performed. By focusing on the ability of the model to fit experimental data and to produce a CD8 T cell population mainly composed of memory cells at the end of the response, critical parameters were identified. We show that a small number of parameters (2-4) define the main features of the CD8 T cell immune response and are characteristic of a given pathogen. Among these parameters, two are related to the effector CD8 T cell mediated control of cell and pathogen death. The parameter associated with memory cell death is shown to play no relevant role during the main phases of the CD8 T cell response, yet it becomes essential when looking at the predictions of the model several months after the infection.

Curative vs. preventive management of nitrogen transfers in rural areas: lessons from the case of the Orgeval watershed (Seine River basin, France).

The Orgeval watershed (104 km(2)) is a long-term experimental observatory and research site, representative of rural areas with intensive cereal farming of the temperate world. Since the past few years, we have been carrying out several studies on nitrate source, transformation and transfer of both surface and groundwaters in relation with land use and agriculture practices in order to assess nitrate (NO3(-)) leaching, contamination of aquifers, denitrification processes and associated nitrous oxide (N2O) emissions. A synthesis of these studies is presented to establish a quantitative diagnosis of nitrate contamination and N2O emissions at the watershed scale. Taking this watershed as a practical example, we compare curative management measures, such as pond introduction, and preventive measures, namely conversion to organic farming practices, using model simulations. It is concluded that only preventive measures are able to reduce the NO3(-) contamination level without further increasing N2O emissions, a result providing new insights for future management bringing together water-agro-ecosystems.

Psychological effect of exercise in women with breast cancer receiving adjuvant therapy: what is the optimal dose needed?

BACKGROUND: Several meta-analyses have examined the role of exercise interventions in improving psychological outcomes in cancer survivors but most did not focus on adjuvant therapy period and did not investigate the optimal dose of exercise needed. The present meta-analysis examines the impact of exercise interventions delivered at this particular period on fatigue, anxiety, depression, and quality of life (QoL) as well as dose-response relationships between volume of prescribed exercise and these psychological outcomes. MATERIALS AND METHODS: Randomized, controlled trials that proposed an exercise intervention to patients with breast cancer undergoing chemotherapy and/or radiotherapy were systematically identified and coded. Psychological outcomes effect sizes were calculated and analyzed for trends using linear and quadratic regressions. RESULTS: Pooled effects of the 17 included studies revealed improvement for all outcomes, significant for fatigue, depression, and QoL with pooled estimates ranging from 0.2 to 0.5 favoring intervention. Significant inverse associations of the volume of prescribed exercise with fatigue and QoL were observed. CONCLUSIONS: Exercise intervention improved fatigue, depression, and QoL in patients with breast cancer receiving adjuvant therapy. Prescription of relatively low doses of exercise (<12 MET h/week) consisting in ∼90-120 min of weekly moderate physical exercise seems more efficacious in improving fatigue and QoL than higher doses.

Bubble production mechanism in a microfluidic foam generator.

We present the design and characterization of a microfluidic bubble generator that has the potential of producing monodisperse bubbles in 256 production channels that can operate in parallel. For a single production channel we demonstrate a production rate of up to 4 kHz with a coefficient of variation of less than 1%. We observe a two-stage bubble production mechanism: initially the gas spreads onto a shallow terrace, and then overflows into a larger foam collection channel; pinning of the liquid-gas meniscus is observed at the terrace edge, the result being an asymmetric pinch-off. A semiempirical physical model predicts the scaling of bubble size with fluid viscosity and gas pressure from measurements of the pinned meniscus width.

Zoonotic bacteria, antimicrobial use and antimicrobial resistance in ornamental fish: a systematic review of the existing research and survey of aquaculture-allied professionals.

Using systematic review methodology, global research reporting the frequency of zoonotic bacterial pathogens, antimicrobial use (AMU) and antimicrobial resistance (AMR) in ornamental fish, and human illness due to exposure to ornamental fish, was examined. A survey was performed to elicit opinions of aquaculture-allied personnel on the frequency of AMU and AMR in ornamental fish. The most commonly reported sporadic human infections were associated with Mycobacterium marinum, while Salmonella Paratyphi B var. Java was implicated in all reported outbreaks. Aeromonas spp. were most frequently investigated (n=10 studies) in 25 studies surveying ornamental fish from various sources. High levels of resistance were reported to amoxicillin, penicillin, tetracycline and oxytetracycline, which was also in agreement with the survey respondents' views. Studies on AMU were not found in our review. Survey respondents reported frequent use of quinolones, followed by tetracyclines, nitrofurans, and aminoglycosides. Recommendations for future surveillance and public education efforts are presented.

Repeated therapeutic dosing selects macrolide-resistant Campylobacter spp. in a turkey facility.

AIMS: This study assessed the effects of the therapeutic use of Tylan® in a large-scale turkey production facility on the selection of macrolide-resistant Campylobacter. METHODS AND RESULTS: A flock of production turkeys (c. 30,000 birds) was followed from brooding to slaughter, and the effects of macrolide application was assessed in one half of the flock from finishing stage to final product and compared against the control barn where no macrolide was used. Overall, Campylobacter prevalence in turkeys was almost 100% by 4 weeks of age. When Campylobacter prevalence was assessed in relation to treatment, high levels of macrolide resistance were evident in this group following treatment, with Campylobacter coli becoming the dominant strain type. Over time, and in the absence of a selection agent, the population of resistant strains decreased suggesting that there was a fitness cost associated with macrolide resistance carriage and persistence. Macrolide resistance was detected in the control barn at a very low level (four isolates recovered during the study), suggesting that the creation or selection of macrolide-resistant Campylobacter was correlated with the treatment regime used. Molecular analysis of a selection of macrolide-resistant Campylobacter recovered was assessed using PCR, RFLP and sequence analysis of the 23S rRNA. The majority of isolates displaying high-level macrolide resistance (>256 µg ml(-1)) possessed an A2075G transition mutation in the 23S rRNA and the CmeABC efflux pump. CONCLUSIONS: These studies suggest that macrolide resistance can be promoted through the application of treatment during the grow-out phase and once established in a production facility has the potential to persist and be transferred to final product. SIGNIFICANCE AND IMPACT OF THE STUDY: The study highlights the prudent use of antimicrobials in treatment of disease in poultry. Of significance is the presence of macrolide-resistant Campylobacter in poultry production and finished product as a consequence of macrolide usage.

Microfluidic capillary separation and real-time spectroscopic analysis of specific components from multiphase mixtures.

We present a technique of phase separation suitable for microfluidic systems and demonstrate its efficient integration with a microfluidic optical cell for performing real-time spectrometric measurements on one specific phase from a mixture. We demonstrate that efficient and robust phase separation based on capillarity is possible within a microfluidic chip using either microfabricated capillary channels in polydimethylsiloxane (PDMS) or oil-wet fluoropolymer membranes, allowing for extraction of either the continuous or of the dispersed phases from a multiphase mixture. We analyze the dependence of phase separation efficiency on the operating parameters of the device and observe the presence of a hysteresis cycle during pressure sweeps above a water breakthrough pressure (P(b)); we also observe and analyze the reversibility of the oil-wet state of the membrane upon pressure reduction below a reset pressure (P(r) < P(b)). We test the capillary separation method extensively with several types of organic/water mixtures and emulsions and derive criteria for design and operation of a robust microfluidic capillary separator. As an example of monitoring application we describe the design and manufacturing of a microfluidic spectrometer cell optimized for fast response time, which was used to analyze the oil extracted from an oil/water emulsion using a capillary separator. The complete separator-sensor system is characterized in terms of response and cleanup times to instantaneous changes in the dye concentration of the phase of interest.

Inherited thrombophilias and unexplained pregnancy loss: an incident case-control study.

BACKGROUND: Despite an initial impressive impact, a critical appraisal of the link between pregnancy loss and inherited thrombophilias is currently growing. Furthermore, little is known about the paternal thrombophilic phenotype and pregnancy loss. OBJECTIVE: We sought an association between unexplained pregnancy loss and parental factor V Leiden (FVL) and Prothrombin G20210A (PTG) mutations. METHODS: Design - Incident case-control study. Setting- University Hospital of Brest (France). Patients - Women and their partners from the West Brittany area, consecutively referred for unexplained pregnancy losses (two or more consecutive losses at or before 21 weeks of gestation, or at least one later loss). Controls - Women and their partners with no history of pregnancy loss and at least one normal pregnancy, from the same geographic area, recruited using electoral lists. Statistical analysis - Comparison of FVL and PTG allele frequency between cases and controls using the chi-square test. Separate analyses were performed according to the type of pregnancy loss (early recurrent or later loss). RESULTS: 311 women (mean age: 32.8) and 284 of their partners were enrolled as cases while 599 women (mean age: 34.3) and 297 of their partners were recruited as controls. The prevalence of female, male or couple thrombophilic mutations was not statistically different between cases and controls whatever the definition of pregnancy loss retained. CONCLUSIONS: Presently, there is no clinical indication to routinely test for FVL and likely PTG mutations in women with early recurrent pregnancy loss. Moreover, our results did not reveal that paternal thrombophilic polymorphism should be further explored.

A distinct [18F]MPPF PET profile in amnestic mild cognitive impairment compared to mild Alzheimer's disease.

To date, two positron emission tomography (PET) studies have explored 5-HT(1A) receptor density in the hippocampus of Alzheimer's disease (AD) patients. They showed early changes of 5-HT(1A) receptors in this brain region, known to have a dense serotonergic innervation. These studies only reported measurements in hippocampus. In the present PET study, we used an antagonist of 5-HT(1A) receptors, the [(18)F]MPPF (1) to explore 5-HT(1A) receptor density in the whole brain of AD patients at a mild stage of dementia and amnestic mild cognitive impairment (aMCI) patients compared to a control population; (2) to explore more precisely the 5-HT(1A) receptor density in the limbic brain regions of AD patients and aMCI patients compared to controls. Voxel-based analyses were performed to assess differences in the [(18)F]MPPF binding potential (BP) between AD patients and aMCI patients compared to controls. Analyses of whole-brain [(18)F]MPPF BP showed a global decrease in AD brains in contrast with a global increase in aMCI brains. In AD brains, a significant decrease of BP was detected in hippocampus and parahippocampal gyrus, whereas a significant increase of BP was observed in the inferior occipital gyrus in aMCI brains. These whole brain results are in accordance to hippocampal data reported in a previous study, showing an increase of [(18)F]MPPF binding in the aMCI group contrasting with a decrease in the AD group. Altogether, these results suggest the implication of a compensatory mechanism illustrated by an up regulation of serotonergic metabolism at the aMCI stage before a breakdown of this mechanism at the AD stage. This difference of serotonergic receptor labeling allows to distinguish the groups of aMCI patients from mild AD patients with specific [(18)F]MPPF PET profiles for each patient group.

CFTR mutations in the Algerian population.

The nature and frequency of the major CFTR mutations in the North African population remain unclear, although a small number of CFTR mutation detection studies have been done in Algeria and Tunisia, showing largely European mutations such as F508del, G542X and N1303K, albeit at different frequencies, which presumably emerged via population admixture with Caucasians. Some unique mutations were identified in these populations. This is the first study that includes a genetic and clinical evaluation of CF patients living in Algeria. In order to offer an effective diagnostic service and to make accurate risk estimates, we decided to identify the CFTR mutations in 81 Algerian patients. We carried out D-HPLC, chemical-clamp denaturing gradient gel electrophoresis, multiplex amplification analysis of the CFTR gene and automated direct DNA sequencing. We identified 15 different mutations which account for 58.5% of the CF chromosomes. We used a quantitative PCR technique (quantitative multiplex PCR short fragment fluorescence analysis) to screen for deletion/duplication in the 27 exons of the gene. Taking advantage of the homogeneity of the sample, we report clinical features of homozygous CF patients. As CFTR mutations have been detected in males with infertility, 46 unrelated Algerian individuals with obstructive azoospermia were also investigated.

Vitamin K epoxide reductase genetic polymorphism is associated with venous thromboembolism: results from the EDITH Study.

BACKGROUND: The vitamin K epoxide reductase complex subunit 1 (VKORC1) recycles endogenous vitamin K, a cofactor for vitamin K-dependent coagulation factor synthesis. Common polymorphisms in VKORC1, the gene coding for VKORC1, have been found to affect the dose response to vitamin K antagonists, and to confer an increased risk of vascular diseases in a Chinese population. The aim of this study was to evaluate the association between the VKORC1 1173C > T polymorphism and venous thromboembolism (VTE). METHODS: We report the results of a case-control study designed to evaluate interactions between acquired and inherited risk factors of VTE. We studied 439 cases hospitalized with a first venous thromboembolic event that was not related to a major acquired risk factor for VTE, and 439 matched controls. The VKORC1 1173C > T polymorphism was selected for genotyping as the tagging single-nucleotide polymorphism for previously identified VKORC1 haplotypes. RESULTS: The relationship between VTE and the VKORCI 1173C > T polymorphism was consistent with a recessive model. The frequency of the VKORCI TT genotype was lower in cases than in controls. The odds ratio (OR) (95% CI) was 0.62 (0.41-0.94) for the TT genotype as compared to CT/CC genotypes. Adjustment on cardiovascular diseases, body mass index, factor V (FV) and prothrombin gene mutations did not alter the results. CONCLUSIONS: In this case-control study, the frequency of the VKORCI TT genotype was lower in patients with VTE than in matched controls. The clinical consequence of these results remains to be determined, but gives new perspectives for exploration of the role of VKORCI polymorphism in the pathogenesis of VTE.

Up-regulation of hippocampal serotonin metabolism in mild cognitive impairment.

OBJECTIVE: Recent studies have suggested modifications of serotonin cerebral metabolism and of 5-HT(1A) receptors density in Alzheimer disease (AD). This study aims at exploring hippocampus 5-HT(1A) receptor density in patients at the amnesic mild cognitive impairment (aMCI) and mild AD dementia stages. METHODS: With use of PET with a selective 5-HT(1A) antagonist, 2'-methoxyphenyl-(N-2'-pyridinyl)-p-[(18)F]fluoro-benzamidoethylpiperazine ([(18)F]MPPF), the hippocampus 5-HT(1A) binding potential (BP) was quantified in 10 patients with mild AD, in 11 patients with aMCI, and in 21 aged paired control subjects. To take into account hippocampal atrophy, a partial volume correction was applied to the [(18)F]MPPF data, leading to the calculation of a corrected BP (BP(c)). Comparison of hippocampus BP over populations was performed using Kruskal-Wallis rank analysis. RESULTS: Hippocampus serotonergic receptor binding distinguishes patients from controls and patients with aMCI from patients with AD. In aMCI patients, the mean hippocampus BP(c) was 59% higher than the controls' (p < 0.005), and it was conversely 35% lower in patients with mild AD (p < 0.01). The difference in BP(c) values between patients with aMCI and mild AD was large, resulting in a p value of <0.0005. These differences were not related to hippocampus atrophy. CONCLUSION: A compensatory mechanism illustrated by an up-regulation of serotonergic metabolism has been shown at the stage of amnesic mild cognitive impairment (aMCI) in contrast with a dramatic decrease at later stages of Alzheimer disease (AD). This difference of hippocampus serotonergic receptor labeling allows distinguishing of patients with aMCI from those with mild AD. Exploring 5-HT(1A) receptors with 2'-methoxyphenyl-(N-2'-pyridinyl)-p-(18)F-fluoro-benzamidoethylpiperazine PET seems to be of interest for better understanding pathophysiologic changes at early stages of AD.

Quantum confinement effect on Gd2O3 clusters.

The evolution of the gap of a nanoscaled insulator material, namely, Gd(2)O(3), has been observed by means of vacuum ultraviolet excitation spectra of a dopant (Eu(3+)). The nanoparticles have been synthesized by the low energy cluster beam deposition technique and grown afterward by different annealing steps. A gap shift towards the blue is observed, similar to what is observed in semiconductor nanoparticles. Despite the strong ionic character of the material, the evolution exhibits a behavior similar to covalent materials. The evolution of the gap for Gd(2)O(3) follows the same empiric rule that has been derived for semiconductors (ZnO, CuBr, Si, and CdS). It shows that, in spite of the strong ionic character of the material (0.9 on the scale of Phillips), the amount of covalency is important enough for creating a significant delocalization of the electron with regard to its hole.

Salivary IgA response of triathletes participating in the French Iron Tour.

Athletes are susceptible to upper respiratory tract infections (URTI) during intense training and after major competitions. Secretory IgA, which is the predominant antibody of the mucosal immune system, is the major effector of host-resistance to many microorganisms causing URTI. Previous studies have shown that salivary IgA-mediated immunity decreases after a single short distance triathlon, but the effect of repeated triathlon competitions on secretory IgA levels remains unknown. The purpose of this study was to examine the salivary IgA response of elite triathletes in repeated triathlon races during the 2001 French Iron Tour (FIT). Eight triathletes participated in this study. Saliva samples were collected daily after waking up (fasting basal state), before (pre-race) and after (post-race) each day's competition. Salivary IgA, total protein, and flow rate were measured. Salivary IgA concentrations were measured by an enzyme-linked immunosorbent assay. The salivary flow rate was significantly decreased after each race compared with the fasting basal state (p < 0.01). The salivary IgA concentration of the fasting basal state decreased over the FIT and was even lower than that of the post-race values (p < 0.05). The salivary IgA secretion rate of the fasting basal state decreased by 51.9% over the FIT (p < 0.05). Our data suggest that intense exercise repeated daily has a cumulative negative effect on basal levels of salivary IgA.

High-resolution gamma-ray radiography produced by a laser-plasma driven electron source.

An electron beam from a laser-plasma accelerator is converted into a gamma-ray source using bremsstrahlung radiation in a dense material. The gamma-ray beam has a pointlike source size because it is generated by a high quality electron beam with a small source size and a low divergence. Using this gamma-ray source, the radiography of complex and dense objects with submillimeter resolution is performed. It is the first evidence of a gamma-ray source size of a few hundreds micrometers produced with laser-driven accelerators. This size is consistent with results from Monte Carlo simulations.

Synthesis and properties of europium-based phosphors on the nanometer scale: Eu2O3, Gd2O3:Eu, and Y2O3:Eu.

Nanocrystals of oxides containing europium as the main constituent or as a doping element in RE2O3 ( RE=Y, Gd) have been prepared by direct oxide precipitation in high-boiling polyalcohol solutions and characterized by high-resolution TEM, absorption spectroscopy, and luminescence spectroscopy. The samples obtained consisted of concentrated and colloidally stable suspensions of luminescent oxide nanoparticles with an average grain diameter in the range 2-5 nm. The nanoparticles were found to be highly crystalline despite their ultrasmall size and the low temperature of 180 degrees C applied during the synthesis. Upon UV excitation, the red luminescence relative to the 5D0-->7Fn transition within the cubic form of RE2O3 exhibits some important differences from that usually found in bulk materials.

Seroprevalence of human herpes virus 8 antibody in populations at high or low risk of transfusion, graft, or sexual transmission of viruses.

BACKGROUND: The routes of transmission of human herpes virus 8 (HHV-8) remain unclear. In particular, HHV-8 transmission by blood components and organ transplantation is still debated and raises public health issues. The objective of this study was to determine the prevalence of anti-HHV-8 in selected populations of persons or patients with or without risk factors for the transmission of viral infections, in order to determine the routes of HHV-8 transmission. STUDY DESIGN AND METHODS: A total of 1431 persons or patients at low or high risk of sexually, blood-, or graft-transmitted viral infections were tested by means of a standardized immunofluorescence serologic assay detecting anti-HHV-8. RESULTS: The persons or patients could be classified into three distinct groups according to anti-HHV-8 prevalence: a low prevalence group (0.0% to 5.0%), including healthy blood donors, healthy pregnant women, multiply transfused patients with thalassemia major, and IV drug users; an intermediate prevalence group (5.0% to 20.0%), including organ donors, kidney transplant recipients, and multiply transfused patients with sickle cell disease; a high prevalence group (>20.0%), including HIV-negative persons at high risk of sexually-transmitted viral infections, and HIV-infected homosexual men and heterosexuals. CONCLUSION: The sexual route appears to be the main route of HHV-8 transmission; bloodborne transmission of HHV-8, if it exists, is rare. In contrast, organ transplantation recipients might be exposed to HHV-8 transmission by the transplanted organ, which raises the issue of systematic screening of organ donors.

A combined analysis of the cystic fibrosis transmembrane conductance regulator: implications for structure and disease models.

Over the past decade, nearly 1,000 variants have been identified in the cystic fibrosis transmembrane conductance regulator (CFTR) gene in classic and atypical cystic fibrosis (CF) patients worldwide, and an enormous wealth of information concerning the structure and function of the protein has also been accumulated. These data, if evaluated together in a sequence comparison of all currently available CFTR homologs, are likely to refine the global structure-function relationship of the protein, which will, in turn, facilitate interpretation of the identified mutations in the gene. Based on such a combined analysis, we had recently defined a "functional R domain" of the CFTR protein. First, presenting two full-length cDNA sequences (termed sCFTR-I and sCFTR-II) from the Atlantic salmon (Salmo salar) and an additional partial coding sequence from the eastern gray kangaroo (Macropus giganteus), this study went further to refine the boundaries of the two nucleotide-binding domains (NBDs) and the COOH-terminal tail (C-tail), wherein NBD1 was defined as going from P439 to G646, NBD2 as going from A1225 to E1417, and the C-tail as going from E1418 to L1480. This approach also provided further insights into the differential roles of the two halves of CFTR and highlighted several well-conserved motifs that may be involved in inter- or intramolecular interactions. Moreover, a serious concern that a certain fraction of missense mutations identified in the CFTR gene may not have functional consequences was raised. Finally, phylogenetic analysis of all the full-length CFTR amino acid sequences and an extended set of exon 13--coding nucleotide sequences reinforced the idea that the rabbit may represent a better CF model than the mouse and strengthened the assertion that a long-branch attraction artifact separates the murine rodents from the rabbit and the guinea pig, the other Glires.