Modélisation mathématique et simulation numérique de la polymérisation de l’hémoglobine drépanocytaire

La drépanocytose, ou anémie falciforme, présente une variabilité interindividuelle considérable, conditionnée par de multiples facteurs, dynamiques et interactifs, depuis le niveau moléculaire jusqu’au niveau du patient. L’hémoglobine drépanocytaire, ou hémoglobine S (HbS, tétramère a2bS 2), est un mutant de l’hémoglobine A (a2b2) : elle possède à sa surface une valine (hydrophobe) substituant un acide glutamique natif (négativement chargé). Cette mutation entraîne l’agrégation de l’HbS désoxygénée en polymères, ainsi que l’altération des propriétés de l’érythrocyte -dont sa rhéologie et ses interactions avec les différentes cellules vasculaires. C’est pourquoi la polymérisation de l’HbS constitue un facteur étiologique clef, sinon le primum movens, de la drépanocytose, et une hypothèse thérapeutique (étayée par l’observation) postule que la réduction des fibres intra-érythrocytaires de HbS pourrait améliorer le statut clinique des patients en abaissant la fréquence et la sévérité des crises vasoocclusives. Dans l’optique de mieux comprendre et de mieux gérer la variabilité individuelle drépanocytaire, il apparaît donc indispensable de disposer, en premier lieu, d’une description réaliste de la polymérisation de l’HbS. L’objectif de ce travail de thèse est la mise en place et la validation d’un modèle mathématique de la polymérisation de l’HbS désoxygénée, en tant que processus cinétiquethermodynamique, sous l’influence de la concentration et de la température –les deux facteurs modulateurs les plus importants. A partir d’un modèle existant, mais linéaire et incomplet (Ferrone et al., 1985), nous avons procédé à son implémentation, à sa correction et à sa mise à jour, ainsi qu’à l’évaluation quantitative de ses performances dynamiques, par intégration complète et simulation numérique (Simulink©). Ceci nous a permis de réaliser un diagnostic et d’effectuer un certain nombre de raffinements, concernant en particulier (i) la voie de nucléation hétérogène (formation de néo-fibres sur les fibres préexistantes), (ii) la non-idéalité de la solution protéique de HbS, induite par le volume exclus des fibres polymères (coefficients d’activité calculé à partir de la « théorie des particules convexes »), ainsi que (iii) la structuration spatiale des polymères en domaines. Le modèle développé dans ce travail servira de base pour une description (i) de l’influence dynamique de l’oxygénation et des hémoglobines non-polymérisantes sur la polymérisation de HbS, puis (ii) des polymères de HbS sur les propriétés membranaires et rhéologiques de l’érythrocyte drépanocytaire.Sickle cell disease pathology exhibits a strong interindividual variability, which depends upon multiple, dynamic and interacting factors, from the molecular to the patient level. Sickle hemoglobin, hemoglobin S (HbS, a2bS 2 tetramer), is a mutant of HbA (a2b2), with a surface valine (hydrophobic) substituting a native glutamic acid (negatively charged). Such a mutation endows deoxygenated HbS with the propensity to agregate into polymers, altering erythrocyte properties –including its rheology and its interactions with vascular and circulatory cells. Thus HbS polymerization is a key etiological factor of sickle cell disease, if not the primum movens. Indeed, one therapeutical hypothesis (supported by observation) postulates that the reduction of intra-erythrocytic HbS fibers could improve patients clinical status by lowering the frequency and the severity of vasooclusive crisis. In order to better understand and manage sickle cell disease variability, it is essential to have a realistic description of HbS polymerization. This work aims at developing and validating a mathematical model of deoxygenated HbS polymerization, as a kinetic and thermodynamic process under the influence of concentration and temperature –the two most important modulators. Building on an existing, but linearized and uncomplete (Ferrone et al., 1985) model, we have implemented, corrected and updated, and quantitatively evaluated its dynamical performances: this was done by full numerical integration using Simulink©. This allowed us to make several improvements, related in particular to : (i) the heterogeneous nucleation pathway (seeding and formation of new fibers from pre-existing ones), (ii) the non-ideality of the HbS protein solution, caused by polymer fibers excluded volume (activity coefficients were calculated with the CPT, Convex Particle Theory), and (iii) the spatial organization of polymers into domains. The model developped in this work will ground the description of the dynamic influence (i) oxygenation and non-polymerizing hemoglobins, (ii) HbS polymers interactions with membrane and consequences upon rheological properties of sickle cell erythrocyte

Modélisation mathématique et simulation numérique de la polymérisation de l'hémoglobine drépanocytaire

La drépanocytose, ou anémie falciforme, présente une variabilité interindividuelle considérable, conditionnée par de multiples facteurs, dynamiques et interactifs, depuis le niveau moléculaire jusqu au niveau du patient. L hémoglobine drépanocytaire, ou hémoglobine S (HbS, tétramère a2bS 2), est un mutant de l hémoglobine A (a2b2) : elle possède à sa surface une valine (hydrophobe) substituant un acide glutamique natif (négativement chargé). Cette mutation entraîne l agrégation de l HbS désoxygénée en polymères, ainsi que l altération des propriétés de l érythrocyte -dont sa rhéologie et ses interactions avec les différentes cellules vasculaires. C est pourquoi la polymérisation de l HbS constitue un facteur étiologique clef, sinon le primum movens, de la drépanocytose, et une hypothèse thérapeutique (étayée par l observation) postule que la réduction des fibres intra-érythrocytaires de HbS pourrait améliorer le statut clinique des patients en abaissant la fréquence et la sévérité des crises vasoocclusives. Dans l optique de mieux comprendre et de mieux gérer la variabilité individuelle drépanocytaire, il apparaît donc indispensable de disposer, en premier lieu, d une description réaliste de la polymérisation de l HbS. L objectif de ce travail de thèse est la mise en place et la validation d un modèle mathématique de la polymérisation de l HbS désoxygénée, en tant que processus cinétiquethermodynamique, sous l influence de la concentration et de la température les deux facteurs modulateurs les plus importants. A partir d un modèle existant, mais linéaire et incomplet (Ferrone et al., 1985), nous avons procédé à son implémentation, à sa correction et à sa mise à jour, ainsi qu à l évaluation quantitative de ses performances dynamiques, par intégration complète et simulation numérique (Simulink ). Ceci nous a permis de réaliser un diagnostic et d effectuer un certain nombre de raffinements, concernant en particulier (i) la voie de nucléation hétérogène (formation de néo-fibres sur les fibres préexistantes), (ii) la non-idéalité de la solution protéique de HbS, induite par le volume exclus des fibres polymères (coefficients d activité calculé à partir de la théorie des particules convexes ), ainsi que (iii) la structuration spatiale des polymères en domaines. Le modèle développé dans ce travail servira de base pour une description (i) de l influence dynamique de l oxygénation et des hémoglobines non-polymérisantes sur la polymérisation de HbS, puis (ii) des polymères de HbS sur les propriétés membranaires et rhéologiques de l érythrocyte drépanocytaire.Sickle cell disease pathology exhibits a strong interindividual variability, which depends upon multiple, dynamic and interacting factors, from the molecular to the patient level. Sickle hemoglobin, hemoglobin S (HbS, a2bS 2 tetramer), is a mutant of HbA (a2b2), with a surface valine (hydrophobic) substituting a native glutamic acid (negatively charged). Such a mutation endows deoxygenated HbS with the propensity to agregate into polymers, altering erythrocyte properties including its rheology and its interactions with vascular and circulatory cells. Thus HbS polymerization is a key etiological factor of sickle cell disease, if not the primum movens. Indeed, one therapeutical hypothesis (supported by observation) postulates that the reduction of intra-erythrocytic HbS fibers could improve patients clinical status by lowering the frequency and the severity of vasooclusive crisis. In order to better understand and manage sickle cell disease variability, it is essential to have a realistic description of HbS polymerization. This work aims at developing and validating a mathematical model of deoxygenated HbS polymerization, as a kinetic and thermodynamic process under the influence of concentration and temperature the two most important modulators. Building on an existing, but linearized and uncomplete (Ferrone et al., 1985) model, we have implemented, corrected and updated, and quantitatively evaluated its dynamical performances: this was done by full numerical integration using Simulink . This allowed us to make several improvements, related in particular to : (i) the heterogeneous nucleation pathway (seeding and formation of new fibers from pre-existing ones), (ii) the non-ideality of the HbS protein solution, caused by polymer fibers excluded volume (activity coefficients were calculated with the CPT, Convex Particle Theory), and (iii) the spatial organization of polymers into domains. The model developped in this work will ground the description of the dynamic influence (i) oxygenation and non-polymerizing hemoglobins, (ii) HbS polymers interactions with membrane and consequences upon rheological properties of sickle cell erythrocyte.PARIS-EST-Université (770839901) / SudocPARIS12-Bib. électronique (940280011) / SudocSudocFranceF

Osteopathic medicine for fibromyalgia: a sham-controlled randomized clinical trial

International audienceBackground: Patients with fibromyalgia (FM) frequently resort to osteopathic or chiropractic treatment, despite very weak supporting evidence. We aimed to assess the efficacy of osteopathic manipulation in FM in a properly controlled and powered randomized clinical trial.Methods: Patients were randomized to osteopathic or sham treatment. Treatment was administered by experienced physical medicine physicians, and consisted of six sessions per patient, over 6 weeks. Treatment credibility and expectancy were repeatedly evaluated. Patients completed standardized questionnaires at baseline, during treatment, and at 6, 12, 24, and 52 weeks after randomization. The primary outcome was pain intensity (100-mm visual analog scale) during the treatment period. Secondary outcomes included fatigue, functioning, and health-related quality of life. We performed primarily intention-to-treat analyses adjusted for credibility, using multiple imputation for missing data.Results: In total, 101 patients (94% women) were included. Osteopathic treatment did not significantly decrease pain relative to sham treatment (mean difference during treatment: -2.2 mm; 95% confidence interval, -9.1 to 4.6 mm). No significant differences were observed for secondary outcomes. No serious adverse events were observed, despite a likely rebound in pain and altered functioning at week 12 in patients treated by osteopathy. Patient expectancy was predictive of pain during treatment, with a decrease of 12.9 mm (4.4-21.5 mm) per 10 points on the 0-30 scale. Treatment credibility and expectancy were also predictive of several secondary outcomes.Conclusion: Osteopathy conferred no benefit over sham treatment for pain, fatigue, functioning, and quality of life in patients with FM. These findings do not support the use of osteopathy to treat these patients. More attention should be paid to the expectancy of patients in FM management

Mechanisms of chronic pain in inflammatory rheumatism: the role of descending modulation

International audiencePersistent pain despite satisfactory disease treatment is frequent in rheumatoid arthritis (RA) and spondyloarthritis (Spa) and may result from specific changes in central pain processing. We assessed these mechanisms further by systematically comparing thermal pain thresholds and conditioned pain modulation (CPM) between patients with active RA or Spa and healthy controls. We included 50 patients with RA and 50 patients with Spa and 100 age-matched and sex-matched controls. Heat and cold pain thresholds (HPT-CPT) were measured on the dominant forearm, and CPM was assessed by applying conditioning stimuli (immersion in a cold-water bath) to one foot and the nondominant hand in 2 successive randomized sequences. Descending pain modulation was assessed as the difference in HPTs (in °C) before and after conditioning. Larger HPT differences (ie, a larger CPM effect) reflected more efficient descending inhibition. Potential associations between changes in CPM and clinical data, including disease activity, pain intensity, and psychological and functional variables, were systematically assessed. Heat pain threshold and cold pain threshold were similar in patients and controls. The mean CPM effect was significantly weaker in patients than that in controls for conditioning applied to either the foot (0.25°C ±2.57 vs 2.79°C ±2.31; P < 0.001) or the nondominant hand (0.57°C ±2.74 vs 2.68°C ±2.12; P < 0.001). The smaller CPM effect in patients was correlated with average pain intensity, but not with disease activity or other clinical characteristics, suggesting a significant pathophysiological role for changes in endogenous pain modulation in the mechanisms of chronic pain associated with inflammatory rheumatism

Changes in heat pain, pressure pain and sleepiness without or with napping after sleep restriction.

<p>We assessed the effects of napping, by comparing the different sleep restriction conditions (“sleep restriction” session and “sleep restriction + nap” session), using normalized delta scores for each sleep restriction condition relative to the corresponding baseline. Changes are shown for heat pain (A), pressure pain (B) and sleepiness (C). Sleep restriction increased sleepiness and decreased pain tolerance, whereas napping reversed the increase in pain sensitivity but did not decrease sleepiness (due to sleep inertia). Mean ± SEM; * indicates significant differences between conditions.</p

Experimental design.

<p>The experimental design included two three-day sessions, during which continuous ambulatory polysomnography (PSG) recordings were taken for each volunteer. The volunteers were randomly allocated to two groups, one of which started with the “sleep restriction” session, the other group beginning with the “sleep restriction + nap” session. In the “sleep restriction” session, the volunteers were allowed to sleep for only two hours during one night (in bed from 02:00 to 04:00), the previous night of 8 hours of sleep being used as the baseline (in bed from 00:00 to 08:00). The night after sleep deprivation, the volunteers were allowed to sleep from 20:00 until spontaneous awakening, for recovery. In the “sleep restriction + nap” session, the volunteers repeated the protocol described for the sleep restriction only session, but were allowed to take 30-minute naps at 09:30 and 15:30 on the day following the night of sleep restriction. Subjective sleepiness was assessed and QST was carried out each day, at 10:00 and 16:00.</p

Patient Reported Outcome Measures in Chronic Neuropathic Pain Clinical Trials – A Systematic Literature Review

International audienceIn neuropathic pain clinical trials, the patient's perspective is often insufficiently reflected focusing mainly on pain intensity. Comparability of outcome assessment is limited due to heterogenous patient reported outcome measures (PROMs). The MEDLINE, CENTRAL, and Embase databases and reference lists of published meta-analyses were searched. Randomized controlled studies assessing treatment efficacy of drugs for chronic neuropathic pain were included. PROMs were assigned to recommended IMMPACT/NeuPSIG domains: pain intensity, pain other aspects, physical functioning, emotional functioning, global improvement and satisfaction, adverse events, participant disposition. Domains and PROMs were compared regarding the publication year and methodological quality of the studies. Within the 251 included studies 200 PROMs were used with 27 being recommended by IMMPACT/NeuPSIG. The number of domains was higher in high/moderate quality studies. The (sub-) domains ‘physical functioning’, ‘global improvement and satisfaction’, and ‘neuropathic pain quality’ were assessed more frequently in high/moderate quality studies and those published after 2011. Recent studies and those of better quality more often used the recommended PROMs. Although neuropathic assessment via PROMs has improved, there is still a high heterogeneity. A standardized core set of outcome domains and should be defined to improve neuropathic pain treatment and to achieve better comparability of clinical trials. Perspective: This systematic literature review assesses the use of patient reported outcome measures (PROMs) in chronic neuropathic pain. The results show that there is still a high heterogeneity, highlighting the need for a standardized core set of outcome domains and PROMs to improve comparability of clinical trials and neuropathic pain treatment

Quality of life and impact of pain in women treated with aromatase inhibitors for breast cancer. A multicenter cohort study.

Women with hormone-dependent breast cancer are treated with aromatase inhibitors (AI) to slow disease progression by decreasing estrogen levels. However, AI have adverse effects, including pain, with potentially serious impact on quality of life (QOL) and treatment compliance. We evaluated quality of life during the first year of AI treatment, focusing particularly on the impact of pain. In a multicenter cohort study of 135 women with early-stage breast cancer, free of pain at the initiation of AI treatment, quality of life (by the EORTC QLQ-BR23), somatic and psychic symptoms, psychological characters, temperament and coping strategies were assessed at baseline and at each follow-up visit (1, 3, 6 and 12 months). The impact of treatment-induced pain on quality of life during follow-up was determined with repeated-measures regression models. These models were constructed to assess the effects of pain and pain type on quality of life during follow-up, taking into account predictors associated with quality of life at baseline. Prior ganglion resection, taxane treatment and chemotherapy, a high amplification score on the pain catastrophizing scale, and a high harm avoidance score on the personality questionnaire were associated with a significantly lower baseline QOL. Fifty-seven percent of women developed pain of five different types: upper or lower limb joint pain, diffuse pain, neuropathic pain, tendon pain and mixed pain. A significant decrease in QOL was noted in the women with pain, particularly for body image, sexual functioning and future perspectives. Moreover, the impact of pain on QOL depended on the type of pain experienced. In conclusion, women treated with aromatase inhibitors display changes in quality of life and the degree of change in quality of life depends mostly on the type of pain experienced. Oncologists and patients should be aware of painful adverse effects of AI and encouraged to provide or receive earlier and more appropriate management of these effects

Quality of life follow up during the 12 months of AI treatment (EORTC QLQ-BR23 questionnaire).

<p>Mean scores of scales are shown: Body image (BRBI), Sexual functioning (BRSEF), Sexual enjoyment (BRSEE), Future perspective (BRFU); Systemic therapy side effects (BRST), Breast symptoms (BRBS), Arm symptoms (BRAS), Upset by hair loss (BRHL).</p

Flow Chart of the study.

<p>Flow Chart of the study.</p