Episodes of violence suffered by migrants transiting through Libya: a cross-sectional study in "Médecins du Monde's" reception and healthcare centre in Seine-Saint-Denis, France.

INTRODUCTION: The Central Mediterranean Route, passing through Libya, is one of the most dangerous for migrants. Episodes of violence have been documented but have not been accurately quantified. The objective of the study was to estimate the prevalence of episodes of violence suffered in Libya by migrants consulting the Médecins du Monde reception and healthcare centre in Seine-Saint-Denis (Ile-de-France). METHODOLOGY: A monocentric cross-sectional study was conducted from February to May 2019 including migrants over the age of 18 years who had passed through Libya and arrived in Europe from 2017. The presence of emotional distress was considered as exclusion criterion. The proportion, frequency and factors associated to physical, deprivation and sexual violence in Libya were estimated through a bespoke questionnaire, as well as healthcare access in Libya and psychosocial support needs. RESULTS: Ninety eight people were recruited and 72 were interviewed (17 refused to participate and 9 were excluded). 76.4% were men, with a mean age of 31.9 years, 76.4% had low educational level, 66.7% came from Ivory Coast and 59.7% had left their country for security reasons. The median length of stay in Libya was 180 days. The overall proportion of participants having suffered from violence was 96.4% among men and 88.2% among women. The prevalence of physical, deprivation and sexual violence for men and women were 94.2, 81.7 and 18% and 80.0, 86.7 and 53.3%, respectively. Access to healthcare in Libya was 2.8 and 63.9% of participants were oriented to psychosocial support after the interview. CONCLUSIONS: The vast majority of migrants reported having been victims of violence during their transit through Libya. Women were at particular risk of sexual violence. Access to health care in Libya was almost non-existent. Psychosocial support for this population is urgent.

Key role of endothelium in the eNOS-dependent cardioprotection with exercise training.

Modulation of endothelial nitric oxide synthase (eNOS) activation is recognized as a main trigger of the cardioprotective effects of exercise training on heart vulnerability to ischemia-reperfusion (IR). However, this enzyme is expressed both in coronary endothelial cells and cardiomyocytes and the contribution of each one to such cardioprotection has never been challenged. The aim of this study was to investigate the role of eNOS from the cardiomyocytes vs. the endothelium in the exercise cardioprotection. Male Wistar rats were assigned to a chronic aerobic training (Ex) (vs. sedentary group; Sed) and we investigated the role of eNOS in the effects of exercise on sensitivity to IR or anoxia-reoxygenation (A/R) at whole heart, isolated cardiomyocytes and left coronary artery (LCA) levels. We observed that exercise increased eNOS activation (Ser1177 phosphorylation) and protein S-nitrosylation in whole heart but not at cardiomyocyte level, suggesting the specific target of endothelial cells by exercise. Consistently, in isolated cardiomyocytes submitted to the A/R procedure, exercise reduced cell death and improved cells contractility, but independently of the eNOS pathway. Next, to evaluate the contribution of endothelial cells in exercise cardioprotection, LCA were isolated before and after an IR procedure performed on Langendorff hearts. Exercise improved basal relaxation sensitivity to acetylcholine and markedly reduced the alteration of endothelium-dependent coronary relaxation induced by IR. Furthermore, inactivation of coronary endothelial cells activity just before IR, obtained with a bolus of Triton X-100, totally suppressed cardioprotective effects of exercise on both left ventricular functional recovery after IR and infarct size, whereas no effect of Triton X-100 was observed in Sed group. In conclusion, these results show that coronary endothelial cells rather than cardiomyocytes play a key role in the eNOS-dependent cardioprotection of exercise.

Structural and dynamic requirements for optimal activity of the essential bacterial enzyme dihydrodipicolinate synthase.

Dihydrodipicolinate synthase (DHDPS) is an essential enzyme involved in the lysine biosynthesis pathway. DHDPS from E. coli is a homotetramer consisting of a 'dimer of dimers', with the catalytic residues found at the tight-dimer interface. Crystallographic and biophysical evidence suggest that the dimers associate to stabilise the active site configuration, and mutation of a central dimer-dimer interface residue destabilises the tetramer, thus increasing the flexibility and reducing catalytic efficiency and substrate specificity. This has led to the hypothesis that the tetramer evolved to optimise the dynamics within the tight-dimer. In order to gain insights into DHDPS flexibility and its relationship to quaternary structure and function, we performed comparative Molecular Dynamics simulation studies of native tetrameric and dimeric forms of DHDPS from E. coli and also the native dimeric form from methicillin-resistant Staphylococcus aureus (MRSA). These reveal a striking contrast between the dynamics of tetrameric and dimeric forms. Whereas the E. coli DHDPS tetramer is relatively rigid, both the E. coli and MRSA DHDPS dimers display high flexibility, resulting in monomer reorientation within the dimer and increased flexibility at the tight-dimer interface. The mutant E. coli DHDPS dimer exhibits disorder within its active site with deformation of critical catalytic residues and removal of key hydrogen bonds that render it inactive, whereas the similarly flexible MRSA DHDPS dimer maintains its catalytic geometry and is thus fully functional. Our data support the hypothesis that in both bacterial species optimal activity is achieved by fine tuning protein dynamics in different ways: E. coli DHDPS buttresses together two dimers, whereas MRSA dampens the motion using an extended tight-dimer interface.

Carbon monoxide exposure in the urban environment: an insidious foe for the heart?

Since Claude Bernard first demonstrated in the 19th century that carbon monoxide (CO) poisoning occurs through hemoglobin binding, CO has proven to be more than simply a toxic gas, and to possess complex biological properties. In this review, we highlight the dual nature of CO in cardiovascular function, from endogenous and therapeutic properties to harmful aspects. Focussing on exposure to low environmental CO levels, the most common but least studied form of exposure, we summarize the pathophysiological effects of CO in vivo and in vitro, from cardiac disorders to phenotypic remodelling of cardiomyocytes, based on clinical observations and experimental studies. While acute exposure to low CO levels is considered beneficial and cardioprotective, prolonged exposure appears deleterious, mainly due to alterations in redox status, ion homeostasis, intracellular Ca(2+) handling, and sympathovagal balance. We emphasize that, despite its fascinating therapeutic potential at low levels, regular exposure to CO may have significant consequences on cardiovascular health and must be considered a cardiovascular risk factor.

Carbon monoxide pollution impairs myocardial perfusion reserve: implication of coronary endothelial dysfunction.

Chronic exposure to simulated urban CO pollution is reported to be associated with cardiac dysfunction. Despite the potential implication of myocardial perfusion alteration in the pathophysiology of CO pollution, the underlying mechanisms remain today still unknown. Therefore, the aim of this work was to evaluate the effects of prolonged exposure to simulated urban CO pollution on the regulation of myocardial perfusion. Cardiac hemodynamics and myocardial perfusion were assessed under basal conditions and during the infusion of a ß-Adrenergic agonist. The effects of CO exposure on capillary density, coronary endothelium-dependent vasodilatation, eNOS expression and eNOS uncoupling were also evaluated. Our main results were that prolonged CO exposure was associated with a blunted myocardial perfusion response to a physiological stress responsible for an altered contractile reserve. The impairment of myocardial perfusion reserve was not accounted for a reduced capillary density but rather by an alteration in coronary endothelium-dependent vasorelaxation (-45% of maximal relaxation to ACh). In addition, though chronic CO exposure did not change eNOS expression, it significantly increased eNOS uncoupling. Therefore, the present work underlines the fact that chronic CO exposure, at levels found in urban air pollution, is associated with reduced myocardial perfusion reserve. This phenomenon is explained at the coronary-vessel level by deleterious effects of CO exposure on the endothelium NO-dependent vasorelaxation via eNOS uncoupling.

Moderate exercise prevents impaired Ca2+ handling in heart of CO-exposed rat: implication for sensitivity to ischemia-reperfusion.

Sustained urban carbon monoxide (CO) exposure exacerbates heart vulnerability to ischemia-reperfusion via deleterious effects on the antioxidant status and Ca(2+) homeostasis of cardiomyocytes. The aim of this work was to evaluate whether moderate exercise training prevents these effects. Wistar rats were randomly assigned to a control group and to CO groups, living during 4 wk in simulated urban CO pollution (30-100 parts/million, 12 h/day) with (CO-Ex) or sedentary without exercise (CO-Sed). The exercise procedure began 4 wk before CO exposure and was maintained twice a week in standard filtered air during CO exposure. On one set of rats, myocardial ischemia (30 min) and reperfusion (120 min) were performed on isolated perfused rat hearts. On another set of rats, myocardial antioxidant status and Ca(2+) handling were evaluated following environmental exposure. As a result, exercise training prevented CO-induced myocardial phenotypical changes. Indeed, exercise induced myocardial antioxidant status recovery in CO-exposed rats, which is accompanied by a normalization of sarco(endo)plasmic reticulum Ca(2+)-ATPase 2a expression and then of Ca(2+) handling. Importantly, in CO-exposed rats, the normalization of cardiomyocyte phenotype with moderate exercise was associated with a restored sensitivity of the myocardium to ischemia-reperfusion. Indeed, CO-Ex rats presented a lower infarct size and a significant decrease of reperfusion arrhythmias compared with their sedentary counterparts. To conclude, moderate exercise, by preventing CO-induced Ca(2+) handling and myocardial antioxidant status alterations, reduces heart vulnerability to ischemia-reperfusion.

Simulated urban carbon monoxide air pollution exacerbates rat heart ischemia-reperfusion injury.

Myocardial damages due to ischemia-reperfusion (I/R) are recognized to be the result of a complex interplay between genetic and environmental factors. Epidemiological studies suggested that, among environmental factors, carbon monoxide (CO) urban pollution can be linked to cardiac diseases and mortality. The aim of this work was to evaluate the impact of exposure to CO pollution on cardiac sensitivity to I/R. Regional myocardial I/R was performed on isolated perfused hearts from rats exposed for 4 wk to air enriched with CO (30-100 ppm). Functional variables, reperfusion ventricular arrhythmias (VA) and cellular damages (infarct size, lactate dehydrogenase release) were assessed. Sarcomere length shortening and Ca(2+) handling were evaluated in intact isolated cardiomyocytes during a cellular anoxia-reoxygenation protocol. The major results show that prolonged CO exposure worsens myocardial I/R injuries, resulting in increased severity of postischemic VA, impaired recovery of myocardial function, and increased infarct size (60 +/- 5 vs. 33 +/- 2% of ischemic zone). The aggravating effects of CO exposure on I/R could be explained by a reduced myocardial enzymatic antioxidant status (superoxide dismutase -45%; glutathione peroxidase -49%) associated with impaired intracellular Ca(2+) handling. In conclusion, our results are consistent with the idea that chronic CO pollution dramatically increases the severity of myocardial I/R injuries.

Alteration of endothelium-mediated vasodilator response in the rat hindlimb vasculature consecutive to chronic hypoxic stress: NO and EDHF involvement.

The previously documented impairment of hindlimb blood flow consecutive to chronic hypoxia might be related to endothelial vasomotor dysfunction. The aim of this study was to assess in-vivo the effect of chronic hypoxic stress on endothelium-mediated vasodilator response of hindlimb vascular bed, especially as regards to endothelium-derived hyperpolarizing factor (EDHF) and nitric oxide (NO) pathway contribution. Dark Agouti rats were randomly assigned to live at barometric pressure approximately 760 mmHg (N rats) or approximately 550 mmHg (CH rats). Under anesthesia, catheters were placed in the carotid artery for arterial pressure measurement, and in the saphenous vein and iliac artery for drug delivery. Hindlimb blood flow (HBF) was measured by transit-time ultrasound flowmetry, at baseline and during endothelium-dependent vasodilator response induced by intra-arterial injection of acetylcholine (0.75 ng and 7.5 ng) with and without specific blockers of NOS (L-NAME) and EDHF (Charybdotoxin+Apamin). HBF and hindlimb vascular conductance changes in response to ACh infusion were significantly lower in CH than in N rats. The mechanisms responsible for this blunted response involved impairment in both NO pathway and EDHF. The chronic hypoxia-induced alteration of NO pathway was mainly related to the bioavailability of its substrate l-Arginine, since the infusion of l-Arginine restored the endothelial response to ACh in CH rats to the level of N rats. These results demonstrate that the impairment in endothelium-mediated vasodilator response of the hindlimb vascular tree induced by chronic hypoxic stress involves both NO and EDHF.

Paradoxical effects of endurance training and chronic hypoxia on myofibrillar ATPase activity.

This study aimed to determine the changes in soleus myofibrillar ATPase (m-ATPase) activity and myosin heavy chain (MHC) isoform expression after endurance training and/or chronic hypoxic exposure. Dark Agouti rats were randomly divided into four groups: control, normoxic sedentary (N; n = 14), normoxic endurance trained (NT; n = 14), hypoxic sedentary (H; n = 10), and hypoxic endurance trained (HT; n = 14). Rats lived and trained in normoxia at 760 mmHg (N and NT) or hypobaric hypoxia at 550 mmHg (approximately 2,800 m) (H and HT). m-ATPase activity was measured by rapid flow quench technique; myosin subunits were analyzed with mono- and two-dimensional gel electrophoresis. Endurance training significantly increased m-ATPase (P < 0.01), although an increase in MHC-I content occurred (P < 0.01). In spite of slow-to-fast transitions in MHC isoform distribution in chronic hypoxia (P < 0.05) no increase in m-ATPase was observed. The rate constants of m-ATPase were 0.0350 +/- 0.0023 s(-1) and 0.047 +/- 0.0050 s(-1) for N and NT and 0.033 +/- 0.0021 s(-1) and 0.038 +/- 0.0032 s(-1) for H and HT. Thus, dissociation between variations in m-ATPase and changes in MHC isoform expression was observed. Changes in fraction of active myosin heads, in myosin light chain isoform (MLC) distribution or in MLC phosphorylation, could not explain the variations in m-ATPase. Myosin posttranslational modifications or changes in other myofibrillar proteins may therefore be responsible for the observed variations in m-ATPase activity.

Aortic vasoconstriction related to smooth muscle cells ET-A and ET-B receptors is not involved in hypoxia-induced sustained systemic arterial hypertension in rats.

OBJECTIVES: We report in the present study the role of endothelin (ET-1) and ET-1 receptors in the sustained hypoxia-induced systemic hypertension. METHODS: Wistar rats were randomly assigned to live continuously in hypobaric hypoxia (CH rats) or normoxia (N rats). At the end of hypoxic stress exposure (5 weeks at 450 mm Hg), measurements of mean systemic arterial pressure were done. The effects of ET-1 in the presence or not of the endothelium and/or of specific ET-A inhibitors (BQ-123) or ET-B inhibitors (BQ-788), have been investigated in an isolated model of rat thoracic aorta. Finally, plasmatic ET-1 concentrations have been determined by assay procedure. RESULTS: Following five weeks of chronic hypoxic stress, CH rats presented a significant increase of mean systemic arterial pressure (N: 129.1+/-6.8 mm Hg vs CH: 152.5+/-3.4 mm Hg; P<0.05). Despite of this hypoxia-induced hypertension, ET-1 plasmatic concentration was not different between N and CH rats. Finally, CH rats presented a reduce response to ET-1 when compared to N rats. This phenomenon seems to be associated to the ET-A vascular smooth muscle cell receptors, since difference between N and CH rats was still present in endothelium denuded aortic rings in the presence or not of the specific ET-B inhibitors (BQ-788). In addition, in the presence of the specific ET-A inhibitor (BQ-123) response to ET-1 was abolished in N and CH rats to the same extent (N:-98%; CH:-99%). CONCLUSION: This work clearly suggests that, following long term exposure to hypoxia, ET-1 and ET-1 receptors are not involved in the persistence of systemic hypertension in a rat model, and that chronic exposure to severe hypoxic stress was associated with a downregulation of the ET-A receptors response to ET-1.

Protection against reactive oxygen species injuries in rat isolated perfused hearts: effect of LPBNAH, a new amphiphilic spin-trap derived from PBN.

Numerous strategies have been designed to protect the myocardium against reactive oxygen species (ROS). The present study was designed to test wether LPBNAH, a new amphiphilic spin-trap derived from PBN is able to protect isolated perfused rat hearts against ROS injuries. Following total glola ischemia (30 min), hearts were reperfused in the presence or not of LPBNAH (10 micromol/l), and left ventricular function was continuously monitored. The addition of LPBNAH led to a significant recovery in left ventricular developped pressure (LVDevP, control: 16.5+/- 7.5, p < 0.05). To conclude, the present results strongly suggest that the modification of previous wellknown molecules in order to facilitate their access to intracellular site of ROS production might be of interest to limit oxidative stresses.

Chronic exercise does not prevent hypoxia-induced increased aortic sensitivity to endothelin in rats.

OBJECTIVES: We report in the present study the effect of regular exercise on vascular reactivity alterations to endothelin (ET-1) following prolonged exposure to hypoxic stress. METHODS: Male Dark Agouti rats were randomly assigned to N (sedentary rats), NCE (normoxic exercised rats), CH (chronic hypoxic sedentary rats) and CHCE (chronic hypoxic exercised rats) groups. The effects of ET-1 in the presence or not of the endothelium and/or of the specific inhibitor, bosentan, have been investigated in an isolated model of rat thoracic aorta. RESULTS: Prolonged exposure to hypoxia induced a significant increase in aortic sensitivity to ET-1 (-log ED50 in CH = 8.15 +/- 0.01 vs in N = 7.98 +/- 0.02, p < 0.05). Despite exercise training reduced the sensitivity to ET-1 in normoxic rats, it has no effects in hypoxic rats (-log ED50 in CH = 8.15 +/- 0.01 vs in CHCE = 8.19 +/- 0.01, NS). Moreover, although the removal of endothelium has no effect in N rats, it leads, in NCE rats, to a significant increase in sensitivity to ET-1 (-log ED50 in endothelium intact rings = 7.89 +/- 0.04 vs in denuded rings = 8.04 +/- 0.02, p < 0.05). The implication of ET-1 receptors on both endothelial and smooth muscle cells is confirmed by the significant reduced sensitivity to ET-1 in the four groups when bosentan is present in organ bath. CONCLUSION: Our study clearly suggests that part of the beneficial effect of chronic exercise could be mediated by enhancing endothelial function associated with endothelin reactivity in peripheric vessels. However, chronic exercise training does not seem to be able to limit the increased vasoconstriction to ET-1 stimulation induced by chronic hypoxia exposure.

Chronic hypoxia exposure depresses aortic endothelium-dependent vasorelaxation in both sedentary and trained rats: involvement of L-arginine.

This study was designed to test the hypothesis that the previously demonstrated training-induced improvement of the endothelium vasodilator function would be blunted under conditions of chronic hypoxia exposure as a result of deleterious effects of hypoxia per se on the nitric oxide pathway. Sea-level-native rats were randomly assigned to N (living in normoxia), NT (living and training 5 days/wk for 5 wk in normoxia), CH (living in hypoxia, 2,800 m), and CHT (living and training 5 days/wk for 5 wk in hypoxia, 2,800 m) groups. Concentration-response curves to acetylcholine (ACh; 10(-9) to 10(-4) M) with or without L-arginine (10(-3) to 10(-5) M) and/or nitro-L-arginine methyl ester (10(-5) M) were assessed on aortic isolated rings. The main finding was that chronic hypoxia severely depressed maximal ACh-responses of aortic rings in both sedentary and trained groups. However, chronic hypoxia did not interfere with training-induced increases in maximal ACh responses, considering that maximal ACh vasorelaxation was improved in CHT rats to the same extent as in NT rats when both groups were directly compared with their sedentary counterparts. It should be pointed out that the vasodilator response to ACh was restored in CH and CHT rats to the level obtained in N and NT rats, respectively, by an in vitro L-arginine addition. A hypoxia-induced decrease in L-arginine bioavailability resulting from acclimatization at altitude may be involved in this limitation of the NO pathway in CH and CHT rats. These results are of importance for aerobic performance as the specific vascular adaptations to training at altitude could contribute to limit peripheral vasodilatation and subsequently blood flow during exercise.

Cardiac remodeling and functional adaptations consecutive to altitude training in rats: implications for sea level aerobic performance.

This study questioned the effect of living and training at moderate altitude on cardiac morphological and functional adaptations and tested the incidences of potential specific adaptations compared with aerobic sea level training on maximal left ventricular performance. Sea level-native rats were randomly assigned to N (living in normoxia), NT (living and training 5 days/wk for 5 wk in normoxia), CH (living in hypoxia, 2,800 m), and CHT (living and training 5 days/wk for 5 wk in hypoxia, 2,800 m) groups. Cardiac adaptations were evaluated throughout the study period by Doppler echocardiography. Maximal stroke volume (LV(SVmax)) was measured during volume overloading before and after the study period. Finally, at the end of the study period, passive pressure-volume relationships on isolated heart and cardiac weighing were obtained. Altitude training resulted in a specific left ventricular (LV) remodeling compared with NT, characterized by an increase in wall thicknesses without any alteration in internal dimensions. These morphological adaptations associated with hypoxia-induced alterations in pulmonary outflow and preload conditions led to a decrease in LV filling and subsequently no improvement in LV performance during resting physiological conditions in CHT compared with NT. Such a lack of improvement was confirmed during volume overloading that simulated maximal effort (LV(SVmax) pretest: NT = 0.58 +/- 0.05, CHT = 0.57 +/- 0.08 ml; posttest: NT = 0.72 +/- 0.06, CHT = 0.58 +/- 0.07 ml; NT vs. CHT in posttest session, P < 0.05). Maximal aerobic velocities increased to the same extent in NT and CHT rats despite marked polycythemia in the latter. The lack of LV(SVmax) improvement resulting from altitude training-induced cardiac morphological and functional adaptations could be responsible for this phenomenon.

External fixation and arthrodesis.

Arthrodesis of joint is widely employed in case of infected nonunion especially after failed total knee replacement. Instead of the conventional methods of immobilization including plaster cast or internal fixation we think that the use of the external fixation is highly satisfactory, providing an excellent method of immobilization and allowing an early weight-bearing gait. In our series of more than 200 applications the Hoffmann external fixation has proved to be indicated most in arthrodesis of the knee, but has also been used in arthrodesis of the hip and in arthrodesis of the lower and upper extremities.

[Intramedullary locking nailing. Experimental study. Surgical technic. Results]. / Enclouage centro-médullaire claveté. Etude expérimentale - Technigue operatoire - Résultats.

The authors describe a new type of intramedullary nail used mainly in the femur and or tibia. This nail can be locked by the provision of holes into which screws can be driven transversely. The technique of insertion is described and the use of ancillary devices. The advantages are that weight-bearing can be commenced early even in comminuted fractures. The method includes open reduction of the fracture and allows some compression of the fracture site. The results of a biomechanical study are given. One hundred and forty six patients have been operated on with only 2 non-unions. The authors consider that their method is superior to plating and can be applied in cases that could not be fixed by conventional nails.