The present study aimed to characterize the adrenal response to ACTH. A model was developed that coupled the nonlinear disposition of cortisol with a physiologically based model for cortisol ...secretion by the adrenals. It was assumed that the response to ACTH resulted from two mechanisms: a stimulation of the cortisol secretion rate and control of the duration of the secretion. Seven dose levels of ACTH were tested in horses, a species similar to man as regards adrenal function. The main result was that the secretion rate of the adrenal gland can be modelized by a zero order process that is maximal for a relatively low dose of ACTH (0.1 μg/kg). Beyond this dose, the increasing adrenal gland response is only due to the prolongation of the time of its secretion. The consequences of these different features were explored by simulation to reproduce classical pathophysiological situations encountered in man. Our model was able to reproduce and simply explain many adrenal gland responses that are dimmed by the different nonlinearities of the system.
The present study aimed to characterize the adrenal response to ACTH. A model was developed that coupled the nonlinear disposition of cortisol with a physiologically based model for cortisol ...secretion by the adrenals. It was assumed that the response to ACTH resulted from two mechanisms: a stimulation of the cortisol secretion rate and control of the duration of the secretion. Seven dose levels of ACTH were tested in horses, a species similar to man as regards adrenal function. The main result was that the secretion rate of the adrenal gland can be modelized by a zero order process that is maximal for a relatively low dose of ACTH (0.1 microg/kg). Beyond this dose, the increasing adrenal gland response is only due to the prolongation of the time of its secretion. The consequences of these different features were explored by simulation to reproduce classical pathophysiological situations encountered in man. Our model was able to reproduce and simply explain many adrenal gland responses that are dimmed by the different nonlinearities of the system.
Traumatic brain injury (TBI) leads to a deleterious neuroinflammation, originating from microglial activation. Monitoring microglial activation is an indispensable step to develop therapeutic ...strategies for TBI. In this study, we evaluated the use of the 18-kDa translocator protein (TSPO) in positron emission tomography (PET) and cellular analysis to monitor microglial activation in a mild TBI mouse model. TBI was induced on male Swiss mice. PET imaging analysis with
FFEPPA, a TSPO radiotracer, was performed at 1, 3 and 7 days post-TBI and flow cytometry analysis on brain at 1 and 3 days post-TBI. PET analysis showed no difference in TSPO expression between non-operated, sham-operated and TBI mice. Flow cytometry analysis demonstrated an increase in TSPO expression in ipsilateral brain 3 days post-TBI, especially in microglia, macrophages, lymphocytes and neutrophils. Moreover, microglia represent only 58.3% of TSPO
cells in the brain. Our results raise the question of the use of TSPO radiotracer to monitor microglial activation after TBI. More broadly, flow cytometry results point the lack of specificity of TSPO for microglia and imply that microglia contribute to the overall increase in TSPO in the brain after TBI, but is not its only contributor.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
A new hollow cylinder triaxial cell (60
mm internal diameter and 100
mm external diameter) has been designed to study the behavior of low permeability saturated geo-materials such as stiff clays or ...argillites under controlled temperature and pore pressure conditions. The main advantage of this device is the short drainage path allowed by the hollow cylinder geometry that is reduced to half the thickness of the sample (10
mm)—four times less than that of standard full cylinder samples of 78
mm height. The reduced drainage path allows a significantly faster resaturation procedure of initially unsaturated samples compared to conventional full cylindrical samples. It also permits the achievement of drained conditions (i.e. negligible excess pore pressure during testing) with a higher loading rate. A numerical simulation of the saturation process demonstrates that the resaturation of the hollow cylinder clay sample can be achieved almost 30 times faster than in standard full samples that are drained at one end, and about seven times faster than in samples drained at both ends. Appropriate loading rates to be used in drained tests on stiff clays and argillites are also discussed based on a numerical simulation of the isotropic compression test. The effect of the deformability of the drainage system on the measured parameters during undrained tests is also analyzed. A correction method is proposed, based on the work of Bishop, by considering the deformability of the porous elements and of the drainage system.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Hidradenitis suppurativa (HS) is a chronic skin disorder of unknown etiology that manifests as recurrent, painful lesions. Cutaneous dysbiosis and unresolved inflammation are hallmarks of active HS, ...but their origin and interplay remain unclear. Our metabolomic profiling of HS skin revealed an abnormal induction of the kynurenine pathway of tryptophan catabolism in dermal fibroblasts, correlating with the release of kynurenine pathway-inducing cytokines by inflammatory cell infiltrates. Notably, overactivation of the kynurenine pathway in lesional skin was associated with local and systemic depletion in tryptophan. Yet the skin microbiota normally degrades host tryptophan into indoles regulating tissue inflammation via engagement of the aryl hydrocarbon receptor (AHR). In HS skin lesions, we detected contextual defects in AHR activation coinciding with impaired production of bacteria-derived AHR agonists and decreased incidence of AHR ligand-producing bacteria in the resident flora. Dysregulation of tryptophan catabolism at the skin-microbiota interface thus provides a mechanism linking the immunological and microbiological features of HS lesions. In addition to revealing metabolic alterations in patients with HS, our study suggests that correcting AHR signaling would help restore immune homeostasis in HS skin.
While medical students are losing interest in lectures in favor of other educational materials, many studies suggest the benefit of active learning, combined with gamified educational tools. The ...authors developed a psychiatric adaptation of the « Hat Game ». It was hypothesised that this game would increase both knowledge and motivation in medical students toward psychiatric semiology. The aim of the study was to assess the benefit of a Psychiatric Hat Game session for learning psychiatric symptoms in third-year medical students. Student performance was also evaluated at 3 months.
This gamified fast-track training consists of two teams and each team has to guess as many psychiatric semiology terms as possible using different techniques (i.e. speech, mime). The study involved a pre- and post-evaluation of knowledge (Multiple Choice Questions) and a satisfaction survey. Baseline, post-immediate, and three-months scores were compared by using Friedman analysis for paired samples. Comparisons of mean scores at two different times were performed by using Wilcoxon test for paired samples.
One hundred and sixty-six students were proposed to take part in the study. Among them 129 completed the whole program (response rate = 77.7%). Mean scores measured at the three points in time were significantly different (p < 0.001, N = 129). Knowledge mean scores were significantly higher after the game than before (+ 28.6%, p < 0.001). Improvement was maintained 3 months after the game (+ 18.9%, p < 0.001). Satisfaction survey items highlighted that students enjoyed and would recommend this type of gamified training.
The Psychiatric Hat Game improved knowledge of psychiatric semiology in medical students. Results suggest that it is a promising and efficient tool to playfully teach medical semiology, with transferable features, utility and acceptability from one medical field to another. This study contributes to the growing body of knowledge advocating for serious games and gamified training in medical education.
Donor lymphocyte infusion (DLI) is used to prevent or treat haematological malignancies relapse after allogeneic stem cell transplantation (allo-SCT). Recombinant human granulocyte colony-stimulated ...factor primed DLI (gDLI) is derived from frozen aliquots of the peripheral blood stem cell collection. We compared the efficacy and safety of gDLI and classical DLI after allo-SCT. We excluded haploidentical allo-SCT. Initial diseases were acute myeloblastic leukaemia (n = 45), myeloma (n = 38), acute lymphoblastic leukaemia (n = 20), non-Hodgkin lymphoma (n = 10), myelodysplasia (n = 8), Hodgkin lymphoma (n = 8), chronic lymphocytic leukaemia (n = 7), chronic myeloid leukaemia (n = 2) and osteomyelofibrosis (n = 1). Indications for DLI were relapse (n = 96) or pre-emptive treatment (n = 43). Sixty-eight patients had classical DLI and 71 had gDLI. The response rate was 38.2%, the 5-year progression-free survival (PFS) rate was 38% (29–48) and the 5-year overall survival (OS) rate was 37% (29–47). Graft versus host disease rate was 46.7% and 10.1% of patients died from toxicity. There were no differences between classical DLI and gDLI in terms of response (p = 0.28), 5-year PFS (p = 0.90), 5-year OS (p. 0.50), GvHD (p = 0.86), treated GvHD (p = 0.81) and cause of mortality (p. 0.14). In conclusion, this study points out no major effectiveness or toxicity of gDLI compared to classical DLI.
•BTG1 inactivation drives lymphomagenesis.•BTG1 inactivation promotes lymphoma dissemination through the BCAR1-RAC1 pathway, which is targetable by dasatinib.
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Understanding the ...functional role of mutated genes in cancer is required to translate the findings of cancer genomics into therapeutic improvement. BTG1 is recurrently mutated in the MCD/C5 subtype of diffuse large B-cell lymphoma (DLBCL), which is associated with extranodal dissemination. Here, we provide evidence that Btg1 knock out accelerates the development of a lethal lymphoproliferative disease driven by Bcl2 overexpression. Furthermore, we show that the scaffolding protein BCAR1 is a BTG1 partner. Moreover, after BTG1 deletion or expression of BTG1 mutations observed in patients with DLBCL, the overactivation of the BCAR1-RAC1 pathway confers increased migration ability in vitro and in vivo. These modifications are targetable with the SRC inhibitor dasatinib, which opens novel therapeutic opportunities in BTG1 mutated DLBCL.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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