Acquired von Willebrand syndrome in patients with monoclonal gammopathy of undetermined significance investigated using a mechanistic approach

BACKGROUND: Acquired von Willebrand syndrome (AVWS) has been reported to occur in association with monoclonal gammopathy, usually of undetermined significance (MGUS). It may present as a type 1 or type 2 von Willebrand factor (VWF) defect depending on the patient’s representation of large VWF multimers. MATERIALS AND METHODS: The mathematical model by Galvanin et al., already employed for studying inherited von Willebrand disease (VWD), was used to explore the pathogenic mechanisms behind MGUS-associated AVWS. RESULTS: The patients studied showed significantly reduced VWF levels and function; an increased VWF propeptide to VWF antigen ratio; and all VWF multimers present but in reduced quantities, with the low-molecular-weight VWF forms being significantly more represented than those of higher molecular weight. Our mathematical model revealed a significantly increased VWF elimination rate constant, with values similar to those of type Vicenza VWD. An even more increased VWF proteolysis rate constant was observed, with values one order of magnitude higher than in type 2A VWD but, in contrast, no loss of large multimers. The model predicted the same elimination rate for high- and low-molecular-weight VWF multimers, but proteolysis of the high-molecular-weight forms also contributes to the pool of low-molecular-weight oligomers, which explains why they were relatively over-represented. DISCUSSION: In MGUS-associated AVWS the increase of both clearance and proteolysis contributes to the circulating levels and multimer pattern of VWF, with a phenotype that appears to be a combination of type Vicenza and type 2A VWD. Hence, the mechanisms behind the onset of AVWS seem to differ from those of inherited VWD

Formação de recursos humanos: estagiários, iniciação científica, mestres, doutores e pós-doutores orientados na Embrapa Instrumentação.

bitstream/item/128894/1/capa-livro-rh-novo-29-05-2015.pdf; bitstream/item/128896/1/Embrapa-RH-16-06-2015.pdf2. ed. rev. ampl

A model‐based protocol for the diagnosis of von Willebrand disease

Von Willebrand disease (VWD) is one of the main inherited coagulation disorders. It is caused by a deficiency and/or a dysfunction of the von Willebrand factor (VWF), a fundamental multimeric glycoprotein involved in the hemostasis process. Correct detection of the disease is not an easy task because the disease manifests itself in many variants and a high intra-subject variability is observed. For these reasons, the diagnostic clinical trials typically rely on a 24-h sampling protocol, which makes the overall test long, stressful, and costly. Using a new pharmacokinetic model derived from Galvanin et al.'s 2014 study, this study aims at i) assessing the theoretical possibility to perform a shorter clinical test and ii) proposing a set of model-based diagnostic methods as a support for the clinical team. A preliminary information analysis is performed in order to understand which sampling instants are more informative for model identification. This allowed us to propose a novel, 8-h diagnostic protocol, which is still able to ensure model identifiability. Three alternative diagnostic methods are then proposed based on this short-length clinical protocol. One of them directly uses the pharmacokinetic model, whereas the other two are based on the use of three indices (two pharmacokinetic indices, namely clearance, total VWF released, and as third index the basal multimer ratio) to formulate the diagnosis problem as a classification one. The classification problem is then solved using K-nearest neighbours and linear discriminant analysis. Results show the theoretical feasibility of a VWD diagnosis based on a shorter protocol

Leucine Supplementation Does Not Improve Muscle Recovery from Resistance Exercise in Young Adults: A Randomized, Double-Blinded, Crossover Study

International Journal of Exercise Science 14(2): 486-497, 2021. This study aimed to investigate the effects of free leucine supplementation on muscle recovery from resistance exercise (RE) in young adults. Fourteen untrained subjects (23.9 ± 3.6 years old) underwent RE sessions (leg press and hack squat: three sets of 8-12 reps at 70% 1RM) supplemented with leucine (LEU: two daily doses of 3g) or a placebo (PLA), separated by a seven-day washout period. Following each occasion, participants were evaluated in three subsequent days (24h, 48h, and 72h) for muscle recovery via a repetition-to-failure test. The following markers were assessed: repetition performance, perceived exertion, lactate, creatine kinase, muscle soreness (DOMS), testosterone, and cortisol. No significant difference was observed between LEU and PLA conditions (p \u3e 0.05). Number of repetitions performed in the repetition-to-failure tests, perceived exertion, cortisol, and testosterone:cortisol ratio did not change over time (p \u3e 0.05). Creatine kinase increased immediately after exercise, at 24h, and 48h, and was attenuated at 72h post-exercise, while testosterone, lactate, and DOMS increased at 24h post-exercise (p \u3c 0.05) and remained elevated up to 72h. All outcomes were similar between LEU and PLA. Results indicate that a 6g daily dose of free leucine supplementation does not improve muscle recovery following lower-limb RE in untrained young adults

The development of parental monitoring during adolescence : A meta-analysis

As adolescents grow up, one of the important developmental tasks is to individuate themselves and to become more autonomous from parents. This requires a realignment of the parent-adolescent communication. The current meta-analytic study aims at identifying developmental changes in parent-adolescent communication, conceptualized within the parental monitoring framework, as entailing parental solicitation, control and knowledge, and adolescent’s disclosure and secrecy. Thirty-one longitudinal studies published between 2000 and 2015 were identified and included in the current meta-analysis. Informants, age at assessment and study duration were tested as moderators. Results showed a low to medium normative decline in parental control (Cohen’s d = −.395, 95% CI [−.541, −.249]), knowledge (d = −.245,95% CI [−.331, −.160] and adolescence disclosure (d = −.147, 95% CI [−.204, −.090]), and an increase in adolescent’s secrecy (d = .194, CI [031, .356]). Parental solicitation decreased based on parents’ (d = −.242, 95% CI[−.376, −.109]) but not on adolescents’ reports (d = .038, 95% CI[−.099, .175]). Another significant moderator was the duration of the study, with studies longer than 2 years being able to detect a more pronounced change in parental control than studies lasting less than 2 years (≤2 years, d = −.139 vs. duration > 2 years, d = −.581). Limitations of the current knowledge and new directions of studies are discussed.Peer reviewe

The effects of poetry-writing SANTEL on erotic body image in remission of cancer in women: a pilot study

International audienceAbstract Aim: Our pilot study aims to describe the effects ofa new specific and structured protocol focused on poetic/erotic writing (named SANTEL) on the (re)sexualization ofbody image in women, who have experienced cancer.Procedure: The protocol consists of four steps: to choose alist of erotic verses focused on the body parts, to fill a semistructuredpoetic text, to write sentences after target phraseson the body; and in the end, to write a free poem. Mrs V.suffered from breast cancer, and one breast was removed.She and her husband participated in this poetic writing protocol,separately. We analyzed the linguistic metaphors ofthe body by QSR Nvivo10 software.Results: Using this protocol, we showed discourse variationsof metaphors before and after the experience of writing.Patient V used “I feel like an alien” as a starting metaphorto describe her cancer experience and after poetic writingsessions, she used other bodily metaphors like “My body isa flower” and “My sensual and white flesh”.Conclusion: This poetic perspective promises a type of“perceptive-literary surgery”, characterized by a sensualinvestment process after remission: a poetic reconstructionof erotic body image.Les effets d'un protocole d'écriture poétique SANTEL sur l'image érotique du corps dans le traitement du cancer féminin : étude pilote The effects of poetry-writing SANTEL on erotic body image in remission of cancer in women: a pilot study A. Santarpia · J. Tellène · M. Carrier Résumé Objectif : Cette étude pilote de type qualitative et exploratoire vise à décrire les effets d'un nouveau protocole d'écriture poético-érotique (nommée SANTEL) sur la rééro-tisation de l'image du corps chez une femme, ayant vécu un cancer. Matériel et méthodes : Il s'agit d'un protocole composé de quatre étapes : une liste des phrases à caractères poétiques et érotiques à choisir, un texte à trous à remplir, des amorces de phrases ciblées sur le corps et en fin un poème libre. Madame V. a subi un cancer du sein nécessitant une ablation complète. Madame V. et son conjoint exécutent le protocole d'écriture séparément. Nous montrons les variations discursives des métaphores utilisées avant et après l'expérience de l'écriture, à travers le logiciel d'analyse qualitative QSR NVivo10. Résultats : Madame V. passera de la métaphore initiale « je me sens une extraterrestre » vers la plus atténuée « Non. Je me dis qu'extraterrestre c'était peut-être un peu énorme ». En plus, elle utilisera de nouvelles métaphores linguistiques du corps pour raconter son image du corps telles que « ce corps de chair blanche » et « une fleur qui s'ouvre délicatement ». Conclusion : Cet exercice spécifique d'écriture promet un type de « chirurgie perceptive-littéraire » dans le processus d'investissement sensuel et affectif après la rémission, une reconstruction perceptive et poétique de l'image érotique du corps. Mots clés Métaphores perceptives · Image du corps · Cancer féminin · Corps érotique · Écriture poétique · Chirurgie perceptive-littéraire · Logiciel QSR NVivo10. Abstract Aim: Our pilot study aims to describe the effects of a new specific and structured protocol focused on poetic/ erotic writing (named SANTEL) on the (re)sexualization of body image in women, who have experienced cancer. Procedure: The protocol consists of four steps: to choose a list of erotic verses focused on the body parts, to fill a semi-structured poetic text, to write sentences after target phrases on the body; and in the end, to write a free poem. Mrs V. suffered from breast cancer, and one breast was removed. She and her husband participated in this poetic writing protocol , separately. We analyzed the linguistic metaphors of the body by QSR Nvivo10 software. Results: Using this protocol, we showed discourse variations of metaphors before and after the experience of writing. Patient V used " I feel like an alien " as a starting metaphor to describe her cancer experience and after poetic writing sessions, she used other bodily metaphors like " My body is a flower " and " My sensual and white flesh ". Conclusion: This poetic perspective promises a type of " perceptive-literary surgery " , characterized by a sensual investment process after remission: a poetic reconstruction of erotic body image. Keywords Bodily metaphors · Body image · Feminine cancer · Erotic body · Poetry writing · Perceptive-literary surgery · QSR Nvivo10 software

Candidate biomarkers from the integration of methylation and gene expression in discordant autistic sibling pairs

While the genetics of autism spectrum disorders (ASD) has been intensively studied, resulting in the identification of over 100 putative risk genes, the epigenetics of ASD has received less attention, and results have been inconsistent across studies. We aimed to investigate the contribution of DNA methylation (DNAm) to the risk of ASD and identify candidate biomarkers arising from the interaction of epigenetic mechanisms with genotype, gene expression, and cellular proportions. We performed DNAm differential analysis using whole blood samples from 75 discordant sibling pairs of the Italian Autism Network collection and estimated their cellular composition. We studied the correlation between DNAm and gene expression accounting for the potential effects of different genotypes on DNAm. We showed that the proportion of NK cells was significantly reduced in ASD siblings suggesting an imbalance in their immune system. We identified differentially methylated regions (DMRs) involved in neurogenesis and synaptic organization. Among candidate loci for ASD, we detected a DMR mapping to CLEC11A (neighboring SHANK1) where DNAm and gene expression were significantly and negatively correlated, independently from genotype effects. As reported in previous studies, we confirmed the involvement of immune functions in the pathophysiology of ASD. Notwithstanding the complexity of the disorder, suitable biomarkers such as CLEC11A and its neighbor SHANK1 can be discovered using integrative analyses even with peripheral tissues

HIF-driven SF3B1 induces KHK-C to enforce fructolysis and heart disease.

Fructose is a major component of dietary sugar and its overconsumption exacerbates key pathological features of metabolic syndrome. The central fructose-metabolising enzyme is ketohexokinase (KHK), which exists in two isoforms: KHK-A and KHK-C, generated through mutually exclusive alternative splicing of KHK pre-mRNAs. KHK-C displays superior affinity for fructose compared with KHK-A and is produced primarily in the liver, thus restricting fructose metabolism almost exclusively to this organ. Here we show that myocardial hypoxia actuates fructose metabolism in human and mouse models of pathological cardiac hypertrophy through hypoxia-inducible factor 1α (HIF1α) activation of SF3B1 and SF3B1-mediated splice switching of KHK-A to KHK-C. Heart-specific depletion of SF3B1 or genetic ablation of Khk, but not Khk-A alone, in mice, suppresses pathological stress-induced fructose metabolism, growth and contractile dysfunction, thus defining signalling components and molecular underpinnings of a fructose metabolism regulatory system crucial for pathological growth

Performance related factors are the main determinants of the von Willebrand factor response to exhaustive physical exercise

Background: Physical stress triggers the endothelium to release von Willebrand Factor (VWF) from the Weibel Palade bodies. Since VWF is a risk factor for arterial thrombosis, it is of great interest to discover determinants of VWF response to physical stress. We aimed to determine the main mediators of the VWF increase by exhaustive physical exercise. Methods: 105 healthy individuals (18-35 years) were included in this study. Each participant performed an incremental exhaustive exercise test on a cycle ergometer. Respiratory gas exchange measurements were obtained while cardiac function was continuously monitored. Blood was collected at baseline and directly after exhaustion. VWF antigen (VWF:Ag) levels, VWF collagen binding (VWF:CB) levels, ADAMTS13 activity and common variations in Syntaxin Binding Protein-5 (STXBP5, rs1039084 and rs9399599), Syntaxin-2 (STX2, rs7978987) and VWF (promoter, rs7965413) were determined. Results: The median VWF:Ag level at baseline was 0.94 IU/mL [IQR 0.8-1.1] and increased with 47% [IQR 25-73] after exhaustive exercise to a median maximum VWF:Ag of 1.38 IU/mL [IQR 1.1-1.8] (p<0.0001). VWF:CB levels and ADAMTS13 activity both also increased after exhaustive exercise (median increase 43% and 12%, both p<0.0001). The strongest determinants of the VWF:Ag level increase are performance related (p<0.0001). We observed a gender difference in VWF:Ag response to exercise (females 1.2 IU/mL; males 1.7 IU/mL, p = 0.001), which was associated by a difference in performance. Genetic variations in STXBP5, STX2 and the VWF promoter were not associated with VWF:Ag levels at baseline nor with the VWF:Ag increase. Conclusions: VWF:Ag levels strongly increase upon exhaustive exercise and this increase is strongly determined by physical fitness level and the intensity of the exercise, while there is no clear effect of genetic variation in STXBP5, STX2 and the VWF promoter

Memorie dai margini della metropoli. Un progetto partecipativo di valorizzazione del patrimonio culturale delle periferie urbane rivolto alle scuole

Scuola Attiva Risorse (ScAR) is a research project of Milan Polytechnic that offers new interpretations of suburban landscapes through a participatory process with schools, fostering innovative strategies for the development of cultural heritage. The text presents a summary of the project and describes a digital structure developed for scholastic activities, combining traditional methodologies and advanced technologies