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Alexander Duncan,1 Angela Kellum,2 Skye Peltier,3 David L Cooper,4 Hossam Saad4 1Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA; 2Louisiana Center for Bleeding and Clotting Disorders, Tulane University, New Orleans, LA, USA; 3Center for Bleeding and Clotting Disorders, University of Minnesota Medical Center – Fairview, Minneapolis, MN, USA; 4Novo Nordisk Inc., Plainsboro, NJ, USACorrespondence: Alexander DuncanEmory University School of Medicine, Atlanta, GA, USATel +1 404 712 4637Fax +1 404 712 4632Email aduncan@emory.eduPurpose: Glanzmann’s thrombasthenia (GT) is a rare bleeding disorder caused by a mutation in the αIIbβ 3 integrin essential for optimal platelet function and hemostasis. The aim of this study was to identify the burden of GT on patients and caregivers through better understanding of the management and psychosocial impact of this disorder.Patients and Methods: Participants for this online survey were recruited using a rare disease specialty recruiter from Comprehensive Health Education Services. Data were collected from January 31 through March 12, 2019. The questionnaire was designed to collect information regarding demographics, diagnosis, treatment, and psychosocial impact.Results: Of the 45 respondents (24 patients and 21 caregivers), the majority were female (58%), white (64%), and employed full-time (53%) and had no family history of GT (64%). Many patients reported significant bruising at birth (76%), and the mean age at diagnosis was 2.6 years. About half of the patients experienced 1 bleed per day, and 13% had over 500 bleeds of any severity per year. Most bleeds were skin bruising or mouth bleeds, but patients also reported joint/muscle and gastrointestinal bleeds. Most patients reported receiving a platelet transfusion (82%), and some had developed platelet refractoriness (38%) or antibodies (32%). Common treatments were antifibrinolytics (82%) and recombinant activated factor VII (rFVIIa) (42%), likely due to the presence of antibodies. Many (58%) patients experienced issues with excessive bleeding at school; 38% reported missing school as a result. Female patients struggled to find a gynecologist with knowledge of the management of GT. Most patients were satisfied with the support they receive from their current partner (65%) and their friends (76%).Conclusion: Most patients with GT are diagnosed early. Patients experience considerable psychosocial impact. Patient and physician education concerning treatment alternatives and the support of the GT community are critical.Keywords: bleeding disorder, psychosocial impact, recombinant activated factor VII, platelet transfusion, platelet antibodies

Skye Peltier,1 Angela Kellum,2 Janet Brewer,3 Alexander Duncan,4 David L Cooper,5 Hossam Saad5 1Center for Bleeding and Clotting Disorders, University of Minnesota Medical Center - Fairview, Minneapolis, MN, USA; 2Louisiana Center for Bleeding and Clotting Disorders, Tulane University, New Orleans, LA, USA; 3Comprehensive Health Education Services, Hanson, MA, USA; 4Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA; 5Novo Nordisk Inc., Plainsboro, NJ, USACorrespondence: Skye PeltierCenter for Bleeding and Clotting Disorders, University of Minnesota Medical Center – Fairview, Minneapolis, MN, USATel +1 612-273-5047Fax +1 612-273-5018Email speltie1@fairview.orgPurpose: Congenital factor VII (FVII) deficiency is a rare bleeding disorder of variable phenotype with predominantly mucocutaneous bleeding. The aim of this study was to identify the burden of FVII deficiency on patients and caregivers through a better understanding of the management and psychosocial impact of this disease.Materials and Methods: A rare disease specialty recruiter from Comprehensive Health Education Services recruited participants for this online survey, which was conducted from January 31 to March 12, 2019. A moderator-assisted questionnaire was used to collect data on demographics, diagnosis, treatment, and psychosocial impact.Results: Of the 45 respondents (25 patients and 20 caregivers), the majority were female (56%). Respondents reported a wide variety of initial bleeding symptoms, including bruising (58%), epistaxis (56%), and menorrhagia (36% of females). Because symptoms varied between individuals and were not always severe, diagnosis was often delayed. Mean time to obtain a diagnosis was 6.5 years and mean age at first diagnosis was 12.9 years. One-quarter (24%) of the respondents reported more than 100 bleeds of any severity over the previous year. When treating bleeds, 44% of patients reported using antifibrinolytics, and 42% reported using recombinant activated factor VII. Almost 31% of respondents reported missing schooldays as children, and 16% reported losing or resigning from a job in adulthood as a direct result of their disease. Notably, 29% of caregivers and 10% of their partners had also experienced issues with employment. Forty percent of respondents reported not participating in contact sports during childhood, and 22% continued to avoid contact sports in adulthood.Conclusion: Overall, FVII deficiency has a substantial psychosocial impact, but most patients are satisfied with their disease management and are optimistic about their future. Patients desire additional educational, social, and financial support.Keywords: bleeding disorder, psychosocial impact, recombinant activated factor VII, survey

Shilpa Jain,1,2 Jennifer Donkin,3 Mary-Jane Frey,4 Skye Peltier,5 Sriya Gunawardena,6 David L Cooper6 1Hemophilia Center of Western New York, Buffalo, NY, USA; 2Department of Pediatrics, Division of Pediatric Hematology-Oncology, John R. Oishei Children’s Hospital, University of Buffalo, Buffalo, NY, USA; 3Hemostasis and Thrombosis Center, Children’s Hospital Los Angeles, Los Angeles, CA, USA; 4Children’s Hospital of Michigan, Detroit, MI, USA; 5Center for Bleeding and Clotting Disorders, University of Minnesota, Minneapolis, MN, USA; 6Clinical Development, Medical and Regulatory Affairs, Novo Nordisk Inc., Plainsboro, NJ, USA Background: One of the most common rare inherited bleeding disorders, congenital factor VII (FVII) deficiency typically has a milder bleeding phenotype than other rare bleeding disorders. Categorizing severity in terms of factor activity associated with hemophilia (severe

Healing of complex wounds requires dressings that must, at least, not hinder and should ideally promote the activity of key healing cells, in particular fibroblasts. This in vitro study assessed the effects of three wound‐dressings (a pure Ca2+ alginate: Algostéril®, a Ca2+ alginate + carboxymethylcellulose: Biatain alginate® and a polyacrylate impregnated with lipido‐colloid matrix: UrgoClean®) on dermal fibroblast activity. The results showed the pure calcium alginate to be non‐cytotoxic, whereas the other wound‐dressings showed moderate to strong cytotoxicity. The two alginates stimulated fibroblast migration and proliferation, whereas the polyacrylate altered migration and had no effect on proliferation. The pure Ca2+ alginate significantly increased the TGF‐β‐induced fibroblast activation, which is essential to healing. This activation was confirmed by a significant increase in Vascular endothelial growth factor (VEGF) secretion and a higher collagen production. The other dressings reduced these fibroblast activities. The pure Ca2+ alginate was also able to counteract the inhibitory effect of NK cell supernatants on fibroblast migration. These in vitro results demonstrate that tested wound‐dressings are not equivalent for fibroblast activation. Only Algostéril was found to promote all the fibroblast activities tested, which could contribute to its healing efficacy demonstrated in the clinic. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Microscopy is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The effects of periodic crosshatch roughness (k+ = 160) on a Mach 4.9 turbulent boundary layer (Reθ = 63 000) are examined using particle image velocimetry. The roughness elements generate a series of alternating shock and expansion waves, which span the entire boundary layer, causing significant (up to +50% and -30%) variations in the Reynolds shear stress field. Evidence of the hairpin vortex organization of incompressible flows is found in the comparative smooth-wall boundary layer case (Reθ = 47 000), and can be used to explain several observations regarding the rough-wall vortex organization. In general, the rough-wall boundary layer near-wall vortices no longer appear to be well-organized into streamwise-aligned packets that straddle relatively low-speed regions like their smooth-wall counterpart; instead, they lean farther away from the wall, become more spatially compact, and their populations become altered. In the lower half of the boundary layer, the net vortex swirling strength and outer-scaled Reynolds stresses increase relative to the smooth-wall case, and actually decrease in the outer half of the boundary layer, as ejection and entrainment processes are strengthened and weakened in these two regions, respectively. A spectral analysis of the data suggests a relative homogenizing of the most energetic scales near Λ = ∼0.5δ across the rough-wall boundary layer. [ABSTRACT FROM AUTHOR]

Mastication is one of the most important orofacial functions. The neurobiological mechanisms of masticatory control have been investigated in animal models, but less so in humans. This project used functional connectivity magnetic resonance imaging (fcMRI) to assess the positive temporal correlations among activated brain areas during a gum-chewing task. Twenty-nine healthy young-adults underwent an fcMRI scanning protocol while they chewed gum. Seed-based fcMRI analyses were performed with the motor cortex and cerebellum as regions of interest. Both left and right motor cortices were reciprocally functionally connected and functionally connected with the post-central gyrus, cerebellum, cingulate cortex, and precuneus. The cerebellar seeds showed functional connections with the contralateral cerebellar hemispheres, bilateral sensorimotor cortices, left superior temporal gyrus, and left cingulate cortex. These results are the first to identify functional central networks engaged during mastication. [ABSTRACT FROM PUBLISHER]

Background: Vitamin D is a nutrient long considered as essential for skeletal health but is now attracting interest from medical and nutritional communities as knowledge emerges of its biological function and its association with decreased risk of many chronic diseases. Results: A question emerges: How much more vitamin D do we need for these new functions of vitamin D? This review discusses vitamin D physiology and hypovitaminosis D and presents two vitamin D dietary policies: that according to regulatory authorities and that of nutrition scientists. Scientific evidence suggests that 25(OH)D serum levels should be over 75 nmol/L; otherwise, there is no beneficial effect of vitamin D on long-latency diseases. Current regulatory authority recommendations are insufficient to reach this level of adequacy. Observational and some prospective data show that vitamin D has a role in the prevention of cancer as well as immunity, diabetes and cardiovascular and muscle disorders, which supports the actions of 1α,25(OH)2D at cellular and molecular levels. The recent assessments done by the European Food Safety Authority should lead to new health claims. Conclusions: Vitamin D, through food fortification and supplementation, is a promising new health strategy and thus provides opportunities for food industry and nutrition researchers to work together towards determining how to achieve this potential health benefit. [ABSTRACT FROM AUTHOR]

The effects of convex curvature on the outer structure of a Mach 4.9 turbulent boundary layer (Reθ = 4.7 × 104) are investigated using condensate Rayleigh scattering and analyzed using spatial correlations, intermittency, and fractal theory. It is found that the post-expansion boundary layer structure morphology appears subtle, but certain features exhibit a more obvious response. The large-scale flow structures survive the initial expansion, appearing to maintain the same physical size. However, due to the nature of the expansion fan, a differential acceleration effect takes place across the flow structures, causing them to be reoriented, leaning farther away from the wall. The onset of intermittency moves closer towards the boundary layer edge and the region of intermittent flow decreases. It is likely that this reflects the less frequent penetration of outer irrotational fluid into the boundary layer, consistent with a boundary layer that is losing its ability to entrain freestream fluid. The fractal dimension of the turbulent/nonturbulent interface decreases with increasing favorable pressure gradient, indicating that the interface's irregularity decreases. Because fractal scale similarity does not encompass the largest scales, this suggests that the change in fractal dimension is due to the action of the smaller-scales, consistent with the idea that the small-scale flow structures are quenched during the expansion in response to bulk dilatation. [ABSTRACT FROM AUTHOR]

Analysis of the amplitude of low frequency BOLD signal fluctuations (ALFF) in the resting state has recently been used to study the dynamics of intrinsic neural activity. Several studies have also suggested its potential as a biomarker for neuropsychiatric disease. In the current study, we quantified ALFF to determine changes in intrinsic neural oscillations in patients with Parkinson's disease (PD) on and off L-DOPA. Twenty-four PD patients and 24 healthy age-matched controls participated in the study. PD patients underwent two resting state fMRI sessions, either ON a controlled dose of L-DOPA or following a placebo pill (OFF). Control participants underwent one test session. We found that there was increased amplitude of low frequency BOLD signal oscillations for PD patients OFF L-DOPA in the primary and secondary motor areas, and in the middle and medial prefrontal cortices. L-DOPA significantly reduced the amplitude of low frequency oscillations within these regions. The degree of ALFF in the premotor cortex predicted patients' motor performance as measured by the Grooved Pegboard task, such that greater ALFF was associated with poorer performance. These results are in line with the pathophysiology of PD, which shows changes in neural oscillations. Thus, frequency domain analyses of resting state BOLD fMRI signals may provide a useful means to study the pathophysiology of PD and the physiology of the brain's dopaminergic pathways. [ABSTRACT FROM AUTHOR]

The bolus intravenous administration of a novel medium-chain triglyceride: fish oil emulsion (MCT:FO) to normal subjects was recently found to increase within 60 min the amount of long-chain polyunsaturated ω3 fatty acids (ω3) in platelet and leukocyte phospholipids and, hence, was proposed as a tool to prevent such pathological events as cardiac arrhythmia in selected patients who have to undergo urgent anesthesia and/or surgery. This study investigates whether other cells located outside the vascular bed may also benefit from this procedure for replenishing phospholipids with ω3. For such a purpose, the MCT:FO emulsion (1.0 ml) was injected into normal or ω3-depleted rats examined, one hour later, for the content and fatty acid pattern of liver triglycerides and phospholipids. Control experiments included the administration of saline or a medium-chain triglyceride:olive oil emulsion. The results reveal that the bolus intravenous injection of MCT:FO to the ω3-depleted rats resulted in the enrichment of liver phospholipids in ω3 and a marked reduction in hepatic steatosis. In conclusion, it is proposed that such a procedure may indeed allow a rapid supply of ω3 not only to circulating and vascular endothelial cells but also to extravascular cells, with a resulting correction of the biochemical and biophysical defects linked to a deficiency in these fatty acids. [ABSTRACT FROM AUTHOR]

The article focuses on a study on the intermittent field test10x45s/15s (IFT45/15) for identifying peak oxygen uptake as well as the comparison of the performance in the test and the 30-second Wingate test (WT) in young physical education students. It also details the methodology and laboratory tests used in the study. The statistical analysis of the measurement of mean maximal speed value of the peak oxygen uptake is discussed. A correlation matrix was created between mean maximal IFT speed and anaerobic capacity, mean and peak power output.

Resting state low frequency (<0.08 Hz) fluctuations in MR timecourses that are temporally correlated between functionally related areas have been observed in recent studies. These fluctuations have been assumed to arise from spontaneous blood oxygenation level-dependent (BOLD) oscillations. This work examines the T2* characteristics of the low frequency fluctuations (functional connectivity) and compares them to those of task activation induced signal changes. Multi-echo spiral data were fit using a mono-exponential decay model to generate T2* and intensity (I0) parameter timecourses. Resultant correlation maps show that both functional connectivity and BOLD activation modulate T2*, not I0. Regression analysis also finds that both have a linear dependence on echo time. Thus, functional connectivity and task activation MR signal changes appear to arise from the same BOLD-related origins. [Copyright &y& Elsevier]

Introduction À l'échelle planétaire, il est estimé que près de 592 millions de personnes seront atteintes de diabète de type 2 (DT2) en 2035, ce qui rend fondamental l'identification de nouvelles thérapeutiques pour freiner le développement de cette maladie. Des expérimentations préliminaires nous ont permis d'identifier une nouvelle formulation (Valedia) susceptible de retarder l'apparition du DT2. L'objet de ce travail était d'étudier les effets d'un traitement chronique au Valedia chez la souris db/db. Matériels et Méthodes Des souris mutantes db/db ont été nourries ad libitum durant 6 semaines avec un régime contrôle ou incorporant la composition Valedia (2,6 %). Le poids, la prise alimentaire et la glycémie à jeun ont été mesurés chaque semaine. En fin de traitement, l'homéostasie glucidique a été évaluée au travers d'un test oral de tolérance au glucose (OGTT), d'un test de tolérance à l'insuline (ITT) et de la quantification de l'hémoglobine glyquée (HbA 1c ). La composition corporelle était estimée par echo-MRI et des prélèvements tissulaires ont été réalisés pour explorer les mécanismes d'action du Valedia à l'échelon cellulaire. Résultats La composition Valedia a induit une diminution de la prise de poids (− 18,8 %, p < 0,01) après 6 semaines de traitement) associée à une moindre masse grasse (− 26,8 %, p < 0,01), tandis que la masse maigre et la prise alimentaire n'étaient pas modifiées significativement. Alors que les souris contrôles ont rapidement développé un diabète, la glycémie à jeun est restée stable dans le groupe Valedia (141 ± 16 mg/dL en fin de traitement vs 437 ± 26 mg/dL pour les souris contrôles). Les aires sous la courbe (AUC) de la glycémie au cours de l'OGTT (− 53 % vs contrôles, p < 0,0001) et de l'ITT (− 73 % vs contrôles, p < 0,0001) étaient diminuées chez les souris traitées avec Valedia, de même que l'HbA 1c (− 49 % vs contrôles, 0,0001). Un mécanisme d'action lié à une augmentation de l'AMPK au niveau hépatique a été identifié. Conclusions Le Valedia est une nouvelle formulation permettant de limiter l'augmentation de la masse grasse, du poids corporel et le développement du DT2 chez la souris db/db par un mécanisme cellulaire faisant intervenir l'AMPK. [ABSTRACT FROM AUTHOR]

Abstract Background Carbohydrates (CHOs), branched-chain amino acids (BCAAs) and caffeine are known to improve running performance. However, no information is available on the effects of a combination of these ingredients on performance and neuromuscular function during running. Methods The present study was designed as a randomized double-blind cross-over placebo-controlled trial. Thirteen trained adult males completed two protocols, each including two conditions: placebo (PLA) and Sports Drink (SPD: CHOs 68.6 g.L-1, BCAAs 4 g.L-1, caffeine 75 mg.L-1). Protocol 1 consisted of an all-out 2 h treadmill run. Total distance run and glycemia were measured. In protocol 2, subjects exercised for 2 h at 95% of their lowest average speeds recorded during protocol 1 (whatever the condition). Glycemia, blood lactate concentration and neuromuscular function were determined immediately before and after exercise. Oxygen consumption (V˙O2), heart rate (HR) and rate of perceived exertion (RPE) were recorded during the exercise. Total fluids ingested were 2 L whatever the protocols and conditions. Results Compared to PLA, ingestion of SPD increased running performance (p = 0.01), maintained glycemia and attenuated central fatigue (p = 0.04), an index of peripheral fatigue (p = 0.04) and RPE (p = 0.006). Maximal voluntary contraction, V˙O2, and HR did not differ between the two conditions. Conclusions This study showed that ingestion of a combination of CHOs, BCAAs and caffeine increased performance by about 2% during a 2-h treadmill run. The results of neuromuscular function were contrasted: no clear cut effects of SPD were observed. Trial registration ClinicalTrials.gov, http://www.clinicaltrials.gov, NCT00799630

TOTUM-070 is a botanical complex with demonstrated efficacy to reduce LDL-cholesterol in several preclinical models. This clinical trial aims to assess, for the first time in humans, the efficacy of TOTUM-070 on plasma lipids concentration in subjects with moderate hypercholesterolemia. Our hypothesis is that Totum-070 taken daily for 24 weeks will decrease fasting blood LDL-cholesterol compared to placebo. This multicentric randomized, double-blind, placebo-controlled trial included 120 subjects (men and women, aged 18–70 years), with moderate hypercholesterolemia (between 130 and 190 mg/dL), who were not receiving cholesterol-lowering medication. Subjects were randomly assigned to consume TOTUM-070 or placebo for 24 weeks. The primary outcome was the fasting blood LDL-cholesterol concentration after 24 weeks (V3). Secondary outcomes included other plasma lipid parameters such as triglycerides, total cholesterol, non-HDL-cholesterol, and apolipoproteins. Intermediate analysis was scheduled after 12 weeks of supplementation (V2). Atherogenic index was calculated using the log10 (TG/HDL-chol) equation. Safety markers were also measured. Analysis was performed by intention to treat. The HEART study is registered at ClinicalTrials.gov: NCT04760951. Blood LDL-cholesterol concentration was reduced by −13% and −9% compared to placebo after 12 and 24 weeks of supplementation, respectively (from 146 ± 26 mg/dL at baseline to 127 ± 18 mg/dL after 12 weeks, P < 0.001; and 133 ± 21 mg/dL after 24 weeks, P < 0.01). In addition, TOTUM-070 consumption reduced blood levels of total cholesterol (−15% at 12 weeks P < 0.05; −16% at 24 weeks, P < 0.01), non-HDL-cholesterol (−14% at 12 weeks, P < 0.01; and −17% at 24 weeks, P < 0.0001), triglycerides (−5% vs. placebo at both 12 and 14 weeks, P < 0.05), apolipoprotein B (−7% at V2 and V3, P < 0.01) and apolipoprotein B/apolipoprotein A1 ratio (−3% after 12 weeks, P = 0.06; −4% after 24 weeks, P < 0.05) when compared to placebo. Moreover, the atherogenic index decreased −6% after 12 and 24 weeks when compared to placebo (P < 0.05). In addition, safety markers showed that TOTUM-070 was well tolerated. In conclusion, this Phase II clinical trial showed that daily intake of TOTUM-070 lowers LDL-cholesterol in subjects with moderate hypercholesterolemia. TOTUM-070 is safe, well tolerated, and has additional favorable effects on other lipid parameters. TOTUM-070 might be a promising candidate for cardiac risk prevention. [ABSTRACT FROM AUTHOR]

Introduction Les fonctions des macrophages dépendent de leur phénotype qui fluctue entre un état pro-inflammatoire (M1) ou anti-inflammatoire (M2a et M2c) après polarisation induite par l’environnement tissulaire. Les macrophages ont été impliqués dans la réparation tissulaire et le remodelage. Cependant, la participation des macrophages dans la réparation alvéolaire reste peu connue chez l’homme en particulier au cours du SDRA. Nos objectifs étaient in vitro : – d’étudier l’effet de l’environnement alvéolaire de patients avec ou sans critères de SDRA sur la polarisation de macrophages; – d’évaluer les conséquences de cette polarisation sur la réparation épithéliale alvéolaire. Matériel et méthodes Étude prospective bicentrique non interventionnelle ayant obtenu l’avis favorable du Comité d’évaluation de l’éthique des projets de recherche biomédicale (CEERB) du GHU Nord (n o 12-087). Des monocytes humains issus de témoins sains ont été cultivés et différenciés in vitro en macrophages en présence de rhGM-CSF et de rhM-CSF pendant 3 jours. Les macrophages étaient ensuite polarisés après 3 jours supplémentaires de culture en présence soit de cytokines induisant les phénotypes : M1 (rh-IFNγ), M2a (rh-IL-4) et M2c (rh-IL-10), soit de Liquide Broncho Alvéolaire (LBA) (25 % vol/vol) issus de patients à la phase précoce de SDRA ( n = 12), de témoins ventilés (TV, n = 10) ou de témoins non ventilés (TNV, n = 4). La caractérisation de la polarisation des macrophages a été réalisée par qPCR à l’aide des marqueurs CD80 (M1), CD200R (M2a) et CD163 (M2c). L’effet des surnageants de macrophages (SM) sur la réparation épithéliale a été déterminé dans un modèle de plaie épithéliale calibrée (insert) utilisant une monocouche de cellules pulmonaires A549. L’implication de l’IL-1β dans cet effet a été spécifiquement évaluée à l’aide d’un anticorps monoclonal anti IL-1β. Résultats Le LBA de patients en SDRA favorisait la polarisation M1, alors que le LBA de TV induisait une polarisation M2c. Le LBA des TNV n’avait pas d’effet spécifique sur la polarisation. Les SM recueillis après polarisation M1 par rh-IFNγ ou par le LBA de SDRA augmentaient la vitesse de fermeture de la plaie, respectivement de 39 % ( p = 0,01) et 36 % ( p < 0,001) par rapport à la condition basale. Au contraire les SM recueillis après polarisation M2c induite par rh IL-10 ou LBA de TV ne la modulaient pas. L’anticorps anti IL-1β diminuait de 44 % ( p = 0,004) la fermeture induite par les SM recueillis après polarisation M1 via le LBA de patients en SDRA ( n = 7). Discussion L’environnement alvéolaire au cours du SDRA induit une polarisation des macrophages vers un profil M1. Nous montrons pour la première fois chez l’homme que la polarisation M1 influence la réparation alvéolaire en induisant la migration épithéliale, à l’inverse de la polarisation M2c. L’IL-1β sécrétée par les macrophages M1 est un médiateur important impliqué dans cet effet, mais d’autres médiateurs sont susceptibles d’être impliqués et restent à déterminer. [ABSTRACT FROM AUTHOR]

Background: Our previous research showed evidence of compromised cognitive function prior to adjuvant chemotherapy for breast cancer, with fatigue as a contributory factor. Fatigue is a common symptom reported by women treated for breast cancer, yet its association with neurocognitive function has not been systematically examined. In this prospective study, we examined possible alterations in neurocognitive responses, namely, working memory, from pre- to post- adjuvant treatment during functional magnetic resonance imaging (fMRI) and further investigated whether early fatigue might be linked to cognitive alterations over time. Methods: Women treated with either adjuvant chemotherapy (anthracyline-based combination regimen, n=29) or radiotherapy (n = 37) for localized breast cancer (Stages 0-IIIa) and age-matched healthy controls (n = 32) were enrolled. Participants performed a verbal working memory task (VWMT) with varying levels of demand for cognitive control during fMRI scanning and provided self-reports of fatigue (FACT-F) at two time points coincident with pre- and one-month post chemotherapy assessments. Imaging data were analyzed with general linear models using SPM5; comparative statistics were used to determine group differences, and correlational analyses addressed relationships of fatigue and neurocognitive measures. Findings: The chemotherapy group reported significantly greater severity of fatigue (p < .05) and performed less accurately on the VWMT both pre- and one-month post-treatment than the other groups. Greater fatigue was correlated with poorer performance on the VWMT at both time points across groups, with stronger correlation post-treatment (r = -.22, p = .03). A 2 time-point (pre- vs. post-treatment) x 2 group (chemotherapy vs. controls) x 2 demand-level contrasts (high minus low vs. medium minus low) analytic model showed a significant group x time interaction (p < .05), mainly due to lower pre-treatment activation in an area of the prefrontal cortex supporting working memory , the anatomical left inferior frontal gyrus (LiFG), at higher task demand in the chemotherapy group. The radiotherapy group scored between the other two groups with intermediate activation of those contrasts. Of interest, lower pre-treatment activation in the LiFG in the high-low demand contrast predicted severity of fatigue across all participants at the post-treatment assessment (r = -.27, p < .01), linking early compromise in neurocognitive performance with greater fatigue over time. Discussion: Neurocognitive alterations during a working memory task and greater fatigue were evident before any adjuvant chemotherapy for breast cancer . Notably, functional alterations in working memory processes were evident with fMRI before adjuvant chemotherapy and predicted severity of post-treatment fatigue. Importantly, across all participants, greater fatigue over time was correlated with reduced cognitive performance. Taken together , these findings indicate that pre-treatment neurocognitive compromise and fatigue are key contributors to the cognitive impact often attributed solely to chemotherapy . Early therapeutic interventions targeting fatigue may improve cognitive function and reduce the distress of "chemo brain" throughout the course of adjuvant treatment. [ABSTRACT FROM AUTHOR]