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ABSTRACTPractical implementations of cryptosystems often suffer from critical information leakage through side-channels (such as their power consumption or their electromagnetic emanations). For public-key cryptography on embedded systems, the core operation is usually group exponentiation – or scalar multiplication on elliptic curves – which is a sequence of group operations derived from the private-key that may reveal secret bits to an attacker (on an unprotected implementation). We present lattice-based polynomial-time (heuristic) algorithms that recover the signer’s secret in popular pairing-based signatures when used to sign several messages under the assumption that blocks of consecutive bits of the corresponding exponents are known by the attacker. Our techniques rely upon Coppersmith's method and apply to many signatures in the so-called exponent-inversionframework in the standard security model (i.e. Boneh-Boyen, Gentry and Pontcheval-Sanders signatures) as well as in the random oracle model (i.e. Sakai-Kasahara signatures).

Le choc hémorragique est une situation à haut risque de morbimortalité. Le pronostic du patient dépend de la rapidité de prise en charge du choc et de la vitesse de correction des troubles de l’hémostase. Il est donc important d’en faire rapidement le diagnostic; celui-ci est essentiellement clinique, facile en cas de saignement extériorisé. Sa reconnaissance peut cependant être difficile chez l’enfant du fait de ses particularités physiopathologiques, particulièrement en cas d’hémorragie interne. La prise en charge associe hémostase de la lésion hémorragique et réanimation hémodynamique pour maintenir une oxygénation cellulaire satisfaisante. L’efficacité du traitement s’apprécie d’abord sur les paramètres hémodynamiques classiques: fréquence cardiaque, pression artérielle moyenne, perfusion cutanée, conscience et diurèse horaire, notamment. Néanmoins, les signes cliniques peuvent être insuffisants pour évaluer le statut hémodynamique, et la mesure de la pression artérielle non invasive peut être imprécise; il est souvent nécessaire de monitorer la pression artérielle invasive dans les cas les plus sévères. Le concept du damage control resuscitation, initialement décrit chez l’adulte, peut être appliqué à l’enfant en tenant compte de ses particularités anatomophysiologiques. Le principe repose sur une réanimation ciblant la triade létale (coagulopathie–acidose–hypothermie) associée à un geste d’hémostase rapide permettant une stabilisation physiologique. Le traitement définitif de la lésion est réalisé une fois le patient stabilisé ou quand tous les patients ont été traités en cas d’afflux de victimes. Le principe du damage controls’applique dès la prise en charge initiale, sur les lieux mêmes d’un accident ou à domicile et se poursuit après l’admission à l’hôpital. Hemorrhagic shock is a situation with a high risk of morbidity and mortality. The recovery widely depends on early and effective treatment. Diagnosis mainly relies upon physical examination and is usually easy in the case of external bleeding. However, diagnosis may be difficult in children because of some pathophysiological particularities, especially in the case of internal hemorrhage. The management of treatment includes the combination of hemostasis of the hemorrhagic lesion and hemodynamic resuscitation to maintain adequate tissue oxygenation. The effectiveness of treatment is first assessed on conventional hemodynamic parameters, including mean arterial pressure, which is the driving perfusion pressure for organs, as well as hourly urine output. Nevertheless, clinical signs may be insufficient to assess precisely the hemodynamic status, while noninvasive blood pressure measurement may be inaccurate. Therefore, it is often necessary to monitor blood pressure invasively, especially in the most severe cases. The concept of damage control resuscitation was first described in adults but can also be applied to children with uncontrolled bleeding; however, some anatomo-physiological particularities of children need to be taken into account. The concept prioritizes short-term physiological recovery and is mainly based on resuscitative maneuvers targeting the lethal triad (coagulopathy, acidosis, and hypothermia), in association with damage control surgery. Definitive repair of all injuries is performed once the patient is stabilized or when all patients have received primary care in case of multiple casualties. The damage control concept starts at the scene of an accident or at home and continues during transport and on admission to the hospital.

Las malformaciones arteriovenosas (MAV) son anomalías congénitas que consisten en una conexión anormal entre arterias y venas cerebrales a través de neovasos. El 3-20% de las MAV se revelan en la infancia por una hemorragia cerebral, convulsiones o cefaleas, o en pruebas de imagen efectuadas por otro motivo en un paciente asintomático. Las malformaciones aneurismáticas de la vena de Galeno (MAVG) representan más del 80% de las MAV en niños menores de 2 años. Pueden tener consecuencias hemodinámicas sistémicas y cerebrales que varían en función de la importancia de la derivación arteriovenosa. El diagnóstico se efectúa en el recién nacido o el lactante de pocos meses, o en el período intrauterino. Las MAVG requieren un tratamiento multidisciplinario, que depende de la edad en el momento del diagnóstico y de la repercusión de la malformación. Las fístulas arteriovenosas piales se desarrollan sobre todo durante la infancia y la edad adulta, rara vez en el período intrauterino. También pueden tener consecuencias hemodinámicas sistémicas y cerebrales. A diferencia de las MAVG, el tratamiento endovascular debe efectuarse tan pronto como se establezca el diagnóstico. Las malformaciones de los senos durales rara vez tienen repercusiones sistémicas y dan lugar a manifestaciones clínicas relacionadas con un defecto del drenaje venoso cerebral. El diagnóstico es prenatal en alrededor del 25% de los casos. El tratamiento endovascular se lleva a cabo en torno a los 4-5 meses de edad o antes si existen factores de mal pronóstico. Las MAV parenquimatosas se diagnostican en menos del 20% de los casos en la infancia. Pueden revelarse por convulsiones o cefaleas, pero la hemorragia cerebral por ruptura es la primera manifestación. La ruptura de una MAV asociada a un coma es una urgencia medicoquirúrgica absoluta.

Mucopolysaccharidosis type I-H (MPS I-H) is a rare lysosomal storage disorder caused by α-L-Iduronidase deficiency. Early haematopoietic stem cell transplantation (HSCT) is the sole available therapeutic option to preserve neurocognitive functions. We report long-term follow-up (median 9 years, interquartile range 8–16.5) for 51 MPS I-H patients who underwent HSCT between 1986 and 2018 in France. 4 patients died from complications of HSCT and one from disease progression. Complete chimerism and normal α-L-Iduronidase activity were obtained in 84% and 71% of patients respectively. No difference of outcomes was observed between bone marrow and cord blood stem cell sources. All patients acquired independent walking and 91% and 78% acquired intelligible language or reading and writing. Intelligence Quotient evaluation (n= 23) showed that 69% had IQ ≥ 70 at last follow-up. 58% of patients had normal or remedial schooling and 62% of the 13 adults had good socio-professional insertion. Skeletal dysplasia as well as vision and hearing impairments progressed despite HSCT, with significant disability. These results provide a long-term assessment of HSCT efficacy in MPS I-H and could be useful in the evaluation of novel promising treatments such as gene therapy.

Small interfering RNA (siRNA) holds promise for treating rheumatoid arthritis by inhibiting major cytokines such as tumor necrosis factor-α (TNF-α). We developed original cationic amphiphilic phosphorus dendrons to produce dendriplexes associated with TNF-α siRNA. The dendrons were made of 10 pyrrolidinium end groups and a C17 aliphatic chain. The dendriplexes demonstrated the ability to protect siRNA from nuclease degradation and to promote macrophage uptake. Moreover, they led to potent inhibition of TNF-α expression in the lipopolysaccharide-activated mouse macrophage cell line RAW264.7 in vitro model. A significant anti-inflammatory effect in the murine collagen-induced arthritis model was observed through arthritis scoring and histological observations. These results open up essential perspectives in using this original amphiphilic dendron to reduce the disease burden and improve outcomes in chronic inflammatory diseases.

Multilayers based on quantum materials (complex oxides, topological insulators, transition-metal dichalcogenides, etc.) have enabled the design of devices that could revolutionize microelectronics and optoelectronics. However, heterostructures incorporating quantum materials from different families remain scarce, while they would immensely broaden the range of possible applications. Here we demonstrate the large-scale integration of compounds from two highly multifunctional families: perovskite oxides and transition-metal dichalcogenides (TMDs). We couple BiFeO3, a room-temperature multiferroic oxide, and WSe2, a semiconducting two-dimensional material with potential for photovoltaics and photonics. WSe2is grown by molecular beam epitaxy and transferred on a centimeter-scale onto BiFeO3films. Using angle-resolved photoemission spectroscopy, we visualize the electronic structure of 1 to 3 monolayers of WSe2and evidence a giant energy shift as large as 0.75 eV induced by the ferroelectric polarization direction in the underlying BiFeO3. Such a strong shift opens new perspectives in the efficient manipulation of TMD properties by proximity effects.

Le sepsis est la principale cause mondiale de morbi-mortalité. L’application de protocoles de diagnostic et de prise en charge du choc septique pédiatrique a permis d’améliorer le pronostic de ces patients. Depuis plusieurs décennies, les sociétés savantes (Sepsis Surviving Campaign – SSC et American College of Critical Care Medecine – ACCM) ont publié des recommandations pour aider à la reconnaissance rapide d’un sepsis chez l’enfant et permettre ainsi une prise en charge appropriée précoce. En pédiatrie, les données cliniques et biologiques utilisées pour définir le sepsis et les dysfonctions d’organes dépendent des variations physiologiques liées à l’âge. Le socle de réanimation du choc septique pédiatrique, dans le cadre de la Golden Hour, repose sur le remplissage vasculaire après l’obtention rapide d’un abord vasculaire (voie veineuse périphérique ou intra-osseuse), le dosage du lactate, les catécholamines, l’antibiothérapie empirique à large spectre (idéalement après prélèvement microbiologique), l’oxygénothérapie et le traitement de la porte d’entrée infectieuse. La réanimation est guidée par un monitorage multimodal : clinique, hémodynamique avancé des macro et microcirculations et biologiques (marqueurs du sepsis et de la perfusion tissulaire, microbiologique). La prise en charge de chaque patient doit être personnalisée et adaptée à sa situation physiopathologique qui peut varier rapidement dans le temps.

IntroductionThis study aims to define the phenotypic and molecular spectrum of the two clinical forms of β-galactosidase (β-GAL) deficiency, GM1-gangliosidosis and mucopolysaccharidosis IVB (Morquio disease type B, MPSIVB).MethodsClinical and genetic data of 52 probands, 47 patients with GM1-gangliosidosis and 5 patients with MPSIVB were analysed.ResultsThe clinical presentations in patients with GM1-gangliosidosis are consistent with a phenotypic continuum ranging from a severe antenatal form with hydrops fetalis to an adult form with an extrapyramidal syndrome. Molecular studies evidenced 47 variants located throughout the sequence of the GLB1gene, in all exons except 7, 11 and 12. Eighteen novel variants (15 substitutions and 3 deletions) were identified. Several variants were linked specifically to early-onset GM1-gangliosidosis, late-onset GM1-gangliosidosis or MPSIVB phenotypes. This integrative molecular and clinical stratification suggests a variant-driven patient assignment to a given clinical and severity group.ConclusionThis study reports one of the largest series of b-GAL deficiency with an integrative patient stratification combining molecular and clinical features. This work contributes to expand the community knowledge regarding the molecular and clinical landscapes of b-GAL deficiency for a better patient management.

Primary bone cancers commonly involve surgery to remove the malignant tumor, complemented with a postoperative treatment to prevent cancer resurgence. Studies on magnetic hyperthermia, used as a single treatment or in synergy with chemo- or radiotherapy, have shown remarkable success in the past few decades. Multifunctional biomaterials with bone healing ability coupled with hyperthermia property could thus be of great interest to repair critical bone defects resulting from tumor resection. For this purpose, we designed superparamagnetic and bioactive nanoparticles (NPs) based on iron oxide cores (γ-Fe2O3) encapsulated in a bioactive glass (SiO2–CaO) shell. Nanometric heterostructures (122 ± 12 nm) were obtained through a two-step process: co-precipitation of 16 nm sized iron oxide NPs, followed by the growth of a bioactive glass shell viaa modified Stöber method. Their bioactivity was confirmed by hydroxyapatite growth in simulated body fluid, and cytotoxicity assays showed they induced no significant death of human mesenchymal stem cells after 7 days. Calorimetric measurements were carried out under a wide range of alternating magnetic field amplitudes and frequencies, considering clinically relevant parameters, and some were made in viscous medium (agar) to mimic the implantation conditions. The experimental specific loss power was predictable with respect to the Linear Response Theory, and showed a maximal value of 767 ± 77 W gFe−1(769 kHz, 23.9 kA m−1in water). An interesting value of 166 ± 24 W gFe−1was obtained under clinically relevant conditions (157 kHz, 23.9 kA m−1) for the heterostructures immobilized in agar. The good biocompatibility, bioactivity and heating ability suggest that these γ-Fe2O3@SiO2–CaO NPs are a promising biomaterial to be used as it is or included in a scaffold to heal bone defects resulting from bone tumor resection.

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency?>?0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency?=?0.01) variant BP associations (P?

Retinoblastoma is a malignant tumor of the retina in infants. Conventional therapies are associated to severe side effects and some of them induce secondary tumors. Photodynamic therapy (PDT) thus appears as a promising alternative as it is nonmutagenic and generates minimal side effects. The effectiveness of PDT requires the accumulation of a photosensitizer (PS) in the tumor. However, most porphyrins are hydrophobic and aggregate in aqueous medium. Their incorporation into a nanocarrier may improve their delivery to the cell cytoplasm. In this work, we designed biodegradable liponanoparticles (LNPs) consisting of a poly(d,l)-lactide (PDLLA) nanoparticle coated with a phospholipid (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine/1,2-dioleoyl-3-trimethylammonium-propane) bilayer. An anticancer drug, beta-lapachone (β-Lap) and a PS, m-THPC, were co-encapsulated for combined chemo- and PDT because it has been suggested that they may have a synergistic effect based on the activation of β-Lap by PDT-induced over-expression of the enzyme NQO1. Using dynamic light scattering measurements, cryogenic transmission electron microscopy, and fluorescence confocal microscopy, we selected the appropriate conditions for the encapsulation of the compounds. LNPs were internalized in retinoblastoma cells within few hours. No obvious synergistic effect related to the activation of β-Lap by PDT was observed. Conversely, the LNPs were cytotoxic at lower doses of the two encapsulated compounds as compared to the single therapies. Analysis of the combinatorial treatment showed that PDT and chemotherapy had an additive effect on the viability of retinoblastoma cells.

Dans un contexte d’une consommation importante des psychotropes chez la personne âgée (PA), un état des lieux et une analyse des prescriptions ont été réalisés en ville par une équipe mobile de gériatrie (EMG). L’objectif était d’identifier les problèmes liés à la thérapeutique (PLT) et les prescriptions potentiellement inappropriées (PPI) de psychotropes.

High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.

From around 2750 to 2500 bc, Bell Beaker pottery became widespread across western and central Europe, before it disappeared between 2200 and 1800 bc. The forces that propelled its expansion are a matter of long-standing debate, and there is support for both cultural diffusion and migration having a role in this process. Here we present genome-wide data from 400 Neolithic, Copper Age and Bronze Age Europeans, including 226 individuals associated with Beaker-complex artefacts. We detected limited genetic affinity between Beaker-complex-associated individuals from Iberia and central Europe, and thus exclude migration as an important mechanism of spread between these two regions. However, migration had a key role in the further dissemination of the Beaker complex. We document this phenomenon most clearly in Britain, where the spread of the Beaker complex introduced high levels of steppe-related ancestry and was associated with the replacement of approximately 90% of Britain’s gene pool within a few hundred years, continuing the east-to-west expansion that had brought steppe-related ancestry into central and northern Europe over the previous centuries.

Van der Waals heterojunctions composed of graphene and transition metal dichalcogenides have gain much attention because of the possibility to control and tailor band structure, promising applications in two-dimensional optoelectronics and electronics. In this report, we characterized the van der Waals heterojunction MoSe2/few-layer graphene with a high-quality interface using cutting-edge surface techniques scaling from atomic to microscopic range. These surface analyses gave us a complete picture of the atomic structure and electronic properties of the heterojunction. In particular, we found two important results: the commensurability between the MoSe2and few-layer graphene lattices and a band-gap opening in the few-layer graphene. The band gap is as large as 250 meV, and we ascribed it to an interface charge transfer that results in an electronic depletion in the few-layer graphene. This conclusion is well supported by electron spectroscopy data and density functional theory calculations. The commensurability between the MoSe2and graphene lattices as well as the band-gap opening clearly show that the interlayer interaction goes beyond the simple van der Waals interaction. Hence, stacking two-dimensional materials in van der Waals heterojunctions enables us to tailor the atomic and electronic properties of individual layers. It also permits the introduction of a band gap in few-layer graphene by interface charge transfer.

Les donneurs pédiatriques d’organes sont rares et principalement la conséquence de mort encéphalique (ME) de causes non naturelles. Ces circonstances, plus souvent traumatiques accidentelles ou non, orientent potentiellement les décès dans un processus d’obstacle médicolégal (OML), compliquant les démarches de coordination de prélèvement d’organes (PMO). Pour espérer faire participer ces jeunes défunts au pool des donneurs potentiels d’organe, les soignants doivent faire preuve d’une coopération étroite avec les équipes médicojudiciaires, en préservant notamment les preuves utiles à la recherche de la vérité. Ils doivent aussi apporter au médecin légiste (ML) le maximum d’informations médicales sur les lésions observées cliniquement ou radiologiquement en pré- et peropératoire du PMO. En réponse, les procureurs seront souvent plus attentifs envers ces médecins réanimateurs et ces professionnels de la coordination de prélèvement d’organes (CPO), qui les sollicitent pour une autorisation officielle de PMO. Ils pourront suggérer dès que possible un « accord de principe » si l’enquête judiciaire le permet et si le ML requis ne s’y oppose pas. Ultérieurement, si la démarche évolue favorablement vers un accord parental, une « autorisation officielle » pourra être fournie à la CPO qui en fera la demande. Cette collaboration étroite entre les professionnels de santé et les équipes médicojudiciaires, a contribué à mettre en place tous ces principes permettant un recensement supérieur des enfants en ME, avec un meilleur taux de prélèvement parmi la cohorte présentée de 22 enfants de moins de 3 ans identifiés par la CPO.

Despite a similar health insurance coverage and access to contraception, Martinique F.W.I. has a higher rate of abortion than continental France (25.6 versus 15.3 per thousand respectively). The reasons are still largely unknown. A different contraceptive pattern, a lower use of emergency contraception in Martinique may be involved. We sought to explore the contraceptive pattern, to evaluate the use of emergency contraception and the reasons leading to an unwanted pregnancy among women seeking for an abortion.

Les donneurs pédiatriques d’organes sont rares et principalement la conséquence de mort encéphalique (ME) de causes non naturelles. Ces circonstances, plus souvent traumatiques accidentelles ou non, orientent les décès dans un processus d’obstacle médicolégal compliquant les démarches de coordination de prélèvement multiorgane (PMO). Pour espérer faire participer ces jeunes défunts au pool de donneurs potentiels d’organes, les soignants doivent faire preuve d’une coopération étroite avec les équipes judiciaires, avec en priorité la préservation des preuves utiles à la recherche de la vérité. Ils doivent notamment apporter le maximum d’informations médicales sur les lésions observées cliniquement ou radiologiquement en pré- et peropératoire. En réponse, les procureurs seront souvent plus attentifs envers ces médecins réanimateurs et les professionnels de la coordination de prélèvement d’organes (CPO) qui les sollicitent pour une autorisation officielle de PMO. Ils pourront suggérer dès que possible un « accord de principe » si l’enquête judiciaire le permet. Ultérieurement, si la démarche évolue favorablement avec un accord parental, une « autorisation officielle » pourra être fournie à la CPO qui en fera la demande. Cette collaboration entre les professionnels de santé et ceux de la justice a contribué à mettre en place tous ces principes permettant un meilleur recensement avec un taux de prélèvement supérieur, parmi cette cohorte de 22 enfants de moins de trois ans en ME identifiés par la CPO. Pediatric organ donors are rare and mainly due to unnatural brain death. These traumatic circumstances issued from accidental or nonaccidental events can lead to forensic reservations, which complicate the donation process. In the aim to recruit these young potential donors, health care professionals have to prove a close collaboration with the judiciary team, by not interfering in the research of the exact cause of death. They must make available any medical and radiological date before and during operative period. In response, prosecutors will be more attentive to these intensive care doctors and the Organ Donation Service Teams (ODST) who solicit them for an authorization of a Multiple Organ Procurement. If the judiciary investigation permits it, the prosecutors can initially give an agreement in principle. Later, if the donation process develops favorably with a parental agreement, an official judiciary authorization can be given to the ODST who claim it. This close collaboration and mutual respect between the health care workers and the judiciary team has contributed to facilitate recruitment of potential donors with an increased organ procurement in this cohort of 22 brain dead children under 3 years old, identified by the ODST.

Le choc hémorragique est une situation à haut risque de morbimortalité. Le pronostic du patient dépend de la rapidité de prise en charge du choc et de la vitesse de correction des troubles de l’hémostase. Il est donc important d’en faire rapidement le diagnostic; celui-ci est essentiellement clinique, facile en cas de saignement extériorisé. Sa reconnaissance peut cependant être difficile chez l’enfant du fait de ses particularités physiopathologiques, particulièrement en cas d’hémorragie interne. La prise en charge associe hémostase de la lésion hémorragique et réanimation hémodynamique pour maintenir une oxygénation cellulaire satisfaisante. L’efficacité du traitement s’apprécie d’abord sur les paramètres hémodynamiques classiques: fréquence cardiaque, pression artérielle moyenne, perfusion cutanée, conscience et diurèse horaire, notamment. Néanmoins, les signes cliniques peuvent être insuffisants pour évaluer le statut hémodynamique, et la mesure de la pression artérielle non invasive peut être imprécise; il est souvent nécessaire de monitorer la pression artérielle invasive dans les cas les plus sévères. Le concept du damage control resuscitation, initialement décrit chez l’adulte, peut être appliqué à l’enfant en tenant compte de ses particularités anatomophysiologiques. Le principe repose sur une réanimation ciblant la triade létale (coagulopathie–acidose–hypothermie) associée à un geste d’hémostase rapide permettant une stabilisation physiologique. Le traitement définitif de la lésion est réalisé une fois le patient stabilisé ou quand tous les patients ont été traités en cas d’afflux de victimes. Le principe du damage controls’applique dès la prise en charge initiale, sur les lieux mêmes d’un accident ou à domicile et se poursuit après l’admission à l’hôpital. Hemorrhagic shock is a situation with a high risk of morbidity and mortality. The recovery widely depends on early and effective treatment. Diagnosis mainly relies upon physical examination and is usually easy in the case of external bleeding. However, diagnosis may be difficult in children because of some pathophysiological particularities, especially in the case of internal hemorrhage. The management of treatment includes the combination of hemostasis of the hemorrhagic lesion and hemodynamic resuscitation to maintain adequate tissue oxygenation. The effectiveness of treatment is first assessed on conventional hemodynamic parameters, including mean arterial pressure, which is the driving perfusion pressure for organs, as well as hourly urine output. Nevertheless, clinical signs may be insufficient to assess precisely the hemodynamic status, while noninvasive blood pressure measurement may be inaccurate. Therefore, it is often necessary to monitor blood pressure invasively, especially in the most severe cases. The concept of damage control resuscitation was first described in adults but can also be applied to children with uncontrolled bleeding; however, some anatomo-physiological particularities of children need to be taken into account. The concept prioritizes short-term physiological recovery and is mainly based on resuscitative maneuvers targeting the lethal triad (coagulopathy, acidosis, and hypothermia), in association with damage control surgery. Definitive repair of all injuries is performed once the patient is stabilized or when all patients have received primary care in case of multiple casualties. The damage control concept starts at the scene of an accident or at home and continues during transport and on admission to the hospital.

L’activité de prélèvement et de greffe d’organes pédiatriques représente moins de 5 % de l’activité nationale. Chez les enfants de moins de deux ans, le prélèvement est particulièrement rare et exigeant, mais strictement indispensable. De nombreux obstacles tenant notamment à des contextes étiologiques traumatiques, à l’opposition parentale et à la rareté des petits receveurs compatibles, rendent ces prélèvements d’organes rares et compliqués. L’évolution des précédentes recommandations sur la mort encéphalique (ME) pédiatrique posent des problèmes pratiques non encore résolus, qui peuvent impacter négativement sur le recensement des donneurs potentiels. Le Doppler transcrânien (DTC), qui permet de suivre plus facilement en pédiatrie que chez l’adulte les altérations de la circulation cérébrale et l’évolution vers la ME, peut mettre en confiance les équipes de réanimation pédiatrique concernées par ce diagnostic médico-légal. En préconisant une évaluation clinique et DTC répétée, les nouvelles recommandations de l’Agence de la biomédecine valorisent le diagnostic clinique de ME et permettent de simplifier la confirmation paraclinique, soit par angioscanner cérébral soit par deux électro-encéphalogrammes avec un délai raccourci à 4heures quel que soit l’âge.

High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to 192,763 individuals and used ∼155,063 samples for independent replication. We identified 30 new blood pressure– or hypertension-associated genetic regions in the general population, including 3 rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5 mm Hg/allele) than common variants. Multiple rare nonsense and missense variant associations were found in A2ML1, and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention.

L’objectif, de cet article de synthèse, est de décliner le concept de damage control(DC) à la pédiatrie, de la phase initiale préhospitalière à la phase hospitalière, en insistant sur les implications des spécificités physiopathologiques sur la prise en charge. Type d’article : mise au point. Source des données : recherche dans la base de données Medline des articles et des revues générales de langue française et anglaise, et documents personnels. Dans les grands principes, le damage control ground zero, le damage control ressuscitationet le damage controlchirurgical appliqués à la pédiatrie, utilisent les mêmes concepts et techniques que chez l’adulte, malgré une littérature peu documentée. L’optimisation de la prise en charge du choc hémorragique, et singulièrement la lutte contre la coagulopathie, reste au centre des préoccupations. Les particularités pédiatriques se caractérisent par des objectifs, en particulier hémodynamiques, différents, et impliquent de disposer de matériel adapté à l’âge et au poids de l’enfant. L’extension du paradigme de DC concerne tous les enfants présentant un choc hémorragique avec un saignement non contrôlé. Les spécificités de cette prise en charge ne doivent pas modifier les grands principes de celle des enfants polytraumatisés et plus particulièrement des enfants traumatisés crâniens graves. Un contexte émotionnel particulièrement difficile impose également une organisation spécifique pour l’accueil des parents et des familles.

La surveillance de l’évolution de la résistance aux antibiotiques et des sérotypes des souches de Streptococcus pneumoniaeen France repose sur un réseau alliant les observatoires du pneumocoque, le Centre national de référence du pneumocoque et l’Institut de veille sanitaire.

En pédiatrie comme chez l’adulte, le choix du soluté de remplissage vasculaire fait l’objet de nombreuses controverses : différences d’efficacité volémique entre colloïdes et cristalloïdes, effets secondaires des solutés, place des hydroxyéthylamidons (HEA) et des solutions balancées, indications de plus en plus réduites de l’albumine y compris en néonatalogie. Cet article propose une mise au point concernant ces différentes controverses afin d’aider le lecteur à guider le choix du soluté de remplissage vasculaire en fonction de la situation clinique.

ABSTRACTMolecular typing of Mycoplasma pneumoniaeis an important tool for identifying grouped cases and investigating outbreaks. In the present study, we developed a new genotyping method based on single nucleotide polymorphisms (SNPs) selected from the whole-genome sequencing of eight M. pneumoniaestrains, using the SNaPshot minisequencing assay. Eight SNPs, localized in housekeeping genes, predicted lipoproteins, and adhesin P1 genes were selected for genotyping. These SNPs were evaluated on 140 M. pneumoniaeclinical isolates previously genotyped by multilocus variable-number tandem-repeat analysis (MLVA-5) and adhesin P1 typing. This method was also adapted for direct use with clinical samples and evaluated on 51 clinical specimens. The analysis of the clinical isolates using the SNP typing method showed nine distinct SNP types with a Hunter and Gaston diversity index (HGDI) of 0.836, which is higher than the HGDI of 0.583 retrieved for the MLVA-4 typing method, where the nonstable Mpn1 marker was removed. A strong correlation with the P1 adhesin gene typing results was observed. The congruence was poor between MLVA-5 and SNP typing, indicating distinct genotyping schemes. Combining the results increased the discriminatory power. This new typing method based on SNPs and the SNaPshot technology is a method for rapid M. pneumoniaetyping directly from clinical specimens, which does not require any sequencing step. This method is based on stable markers and provides information distinct from but complementary to MLVA typing. The combined use of SNPs and MLVA typing provides powerful discrimination of strains.

ABSTRACTOrganisms of the Burkholderia cepaciacomplex are especially important pathogens in cystic fibrosis (CF), with a propensity for patient-to-patient spread and long-term respiratory colonization. B. cenocepaciaand Burkholderia multivoransaccount for the majority of infections in CF, and major epidemic clones have been recognized throughout the world. The aim of the present study was to develop and evaluate a multilocus variable-number tandem-repeat (VNTR) analysis (MLVA) scheme for B. cenocepacia. Potential VNTR loci were identified upon analysis of the annotated genome sequences of B. cenocepaciastrains AU1054, J2315, and MCO-3, and 10 of them were selected on the basis of polymorphisms and size. A collection of 100 B. cenocepaciastrains, including epidemiologically related and unrelated strains, as well as representatives of the major epidemic lineages, was used to evaluate typeability, epidemiological concordance, and the discriminatory power of MLVA-10 compared with those of pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). Longitudinal stability was assessed by testing 39 successive isolates from 14 patients. Typeability ranged from 0.91 to 1, except for that of one marker, which was not amplified in 53% of the B. cenocepaciaIIIA strains. The MLVA types were shown to be stable in chronically colonized patients and within outbreak-related strains, with excellent epidemiological concordance. Epidemic and/or globally distributed lineages (epidemic Edinburgh-Toronto electrophoretic type 12 [ET-12], sequence type 32 [ST-32], ST-122, ST-234, and ST-241) were successfully identified. Conversely, the discriminatory power of MLVA was lower than that of PFGE or MLST, although PFGE variations within the epidemic lineages sometimes masked their genetic relatedness. In conclusion, MLVA represents a promising cost-effective first-line tool in B. cenocepaciasurveillance.

The general language and opensource Python, coupled with its scientific libraries, offers an interesting alternative to Matlab, Java, and C++ for the development of scientific applications. In this context, authors present the main features of the language, associated tools, architecture and the diversity of its scientific environment. Three applications related to control education are presented: programming from a web browser (for system identification and PID tuning) and embedded computing (for motors control).

The success of related diversification is not a given. Although synergies between a firm's businesses may exist, problems can arise in the sharing of key resources and capabilities as the firm attempts to exploit the synergies. To achieve success in related diversification, firms often leverage their organizational slack, or resources and capabilities that are in excess of the level demanded by their normal operations. However, sharing is difficult when firms have insufficient organizational slack, and this can lead to an overstretching of shared resources. Through case study methodology, this paper investigates how one technological SME managed its limited organizational slack while engaged in related diversification. Particular attention is given to the mechanisms that contribute to diversification failure. Consideration is also given to how the capability life-cycle may affect capability sharing in related diversification efforts.

ABSTRACTThe objective of this study was to determine the genetic diversity of multidrug-resistant (MDR) Pseudomonas aeruginosastrains isolated over a period of 12 months in two French hospitals and to test their susceptibility to bacteriophages. A total of 47 MDR isolates recovered from hospitalized patients were genotyped using multiple-locus variable number of tandem repeats analysis. The genotypes were distributed into five clones (including 19, 5, 5, 3, and 3 isolates, respectively) and 12 singletons. Comparison to 77 MDR strains from three other countries, and MLST analysis of selected isolates showed the predominance of international MDR clones. The larger clone, CC235, contained 59 isolates displaying different antibiotic resistance mechanisms, including the presence of the GES1, VIM-2, VIM-4, and IMP-1 β-lactamases. Three newly isolated P. aeruginosabacteriophages were found to lyse 42 of the 44 analyzed strains, distributed into the different clonal complexes. This pilot study suggests that systematic genotyping of P. aeruginosaMDR strains could improve our epidemiological understanding of transmission at both the local (hospital) and the national level and that phage therapy could be an alternative or a complementary treatment to antibiotics for treating MDR-infected patients.

ABSTRACTUsing high-resolution melting (HRM) analysis, we developed a cost-effective method to genotype a set of 13 phylogenetically informative single-nucleotide polymorphisms (SNPs) within the genome of Bacillus anthracis. SNP discrimination assays were performed in monoplex or duplex and applied to 100 B. anthracisisolates collected in France from 1953 to 2009 and a few reference strains. HRM provided a reliable and cheap alternative to subtype B. anthracisinto one of the 12 major sublineages or subgroups. All strains could be correctly positioned on the canonical SNP (canSNP) phylogenetic tree, except the divergent Pasteur vaccine strain ATCC 4229. We detected the cooccurrence of three canSNP subgroups in France. The dominant B.Br.CNEVA sublineage was found to be prevalent in the Alps, the Pyrenees, the Auvergne region, and the Saône-et-Loire department. Strains affiliated with the A.Br.008/009 subgroup were observed throughout most of the country. The minor A.Br.001/002 subgroup was restricted to northeastern France. Multiple-locus variable-number tandem-repeat analysis using 24 markers further resolved French strains into 60 unique profiles and identified some regional patterns. Diversity found within the A.Br.008/009 and B.Br.CNEVA subgroups suggests that these represent old, ecologically established clades in France. Phylogenetic relationships with strains from other parts of the world are discussed.

ABSTRACTClostridium botulinumis a taxonomic designation that encompasses a broad variety of spore-forming, Gram-positive bacteria producing the botulinum neurotoxin (BoNT). C. botulinumis the etiologic agent of botulism, a rare but severe neuroparalytic disease. Fine-resolution genetic characterization of C. botulinumisolates of any BoNT type is relevant for both epidemiological studies and forensic microbiology. A 10-locus multiple-locus variable-number tandem-repeat analysis (MLVA) was previously applied to isolates of C. botulinumtype A. The present study includes five additional loci designed to better address proteolytic B and F serotypes. We investigated 79 C. botulinumgroup I strains isolated from human and food samples in several European countries, including types A (28), B (36), AB (4), and F (11) strains, and 5 nontoxic Clostridium sporogenes. Additional data were deduced from in silicoanalysis of 10 available fully sequenced genomes. This 15-locus MLVA (MLVA-15) scheme identified 86 distinct genotypes that clustered consistently with the results of amplified fragment length polymorphism (AFLP) and MLVA genotyping in previous reports. An MLVA-7 scheme, a subset of the MLVA-15, performed on a lab-on-a-chip device using a nonfluorescent subset of primers, is also proposed as a first-line assay. The phylogenetic grouping obtained with the MLVA-7 does not differ significantly from that generated by the MLVA-15. To our knowledge, this report is the first to analyze genetic variability among all of the C. botulinumgroup I serotypes by MLVA. Our data provide new insights into the genetic variability of group I C. botulinumisolates worldwide and demonstrate that this group is genetically highly diverse.

Clostridium botulinum is a taxonomic designation that encompasses a broad variety of spore-forming, Gram-positive bacteria producing the botulinum neurotoxin (BoNT). C. botulinum is the etiologic agent of botulism, a rare but severe neuroparalytic disease. Fine-resolution genetic characterization of C. botulinum isolates of any BoNT type is relevant for both epidemiological studies and forensic microbiology. A 10-locus multiple-locus variable-number tandem-repeat analysis (MLVA) was previously applied to isolates of C. botulinum type A. The present study includes five additional loci designed to better address proteolytic B and F serotypes. We investigated 79 C. botulinum group I strains isolated from human and food samples in several European countries, including types A (28), B (36), AB (4), and F (11) strains, and 5 nontoxic Clostridium sporogenes. Additional data were deduced from in silico analysis of 10 available fully sequenced genomes. This 15-locus MLVA (MLVA-15) scheme identified 86 distinct genotypes that clustered consistently with the results of amplified fragment length polymorphism (AFLP) and MLVA genotyping in previous reports. An MLVA-7 scheme, a subset of the MLVA-15, performed on a lab-on-a-chip device using a nonfluorescent subset of primers, is also proposed as a first-line assay. The phylogenetic grouping obtained with the MLVA-7 does not differ significantly from that generated by the MLVA-15. To our knowledge, this report is the first to analyze genetic variability among all of the C. botulinum group I serotypes by MLVA. Our data provide new insights into the genetic variability of group I C. botulinum isolates worldwide and demonstrate that this group is genetically highly diverse.

ABSTRACTA multiple-locus variable-number tandem-repeat analysis (MLVA) was applied to investigate the epidemiological relationship and genetic diversity among 162 human Brucellaisolates collected from all geographic regions of Turkey in an 8-year period (2001 to 2008). The isolates were genotyped by using an MLVA assay developed in Orsay, France (MLVA-16Orsay) including eight minisatellite (panel 1) and eight microsatellite (panel 2, subdivided into 2A and 2B) markers. Panels 1 and 2A distinguish 14 genotypes; two of these represented 85% of the strains. Panel 2B displayed a very high discriminatory power. Three loci from panel 2B had diversity index values higher than 0.74. MLVA-16Orsayyielded 105 genotypes; 73 were represented by a unique isolate, and 32 included two to eight isolates. The isolates from different patients within the same outbreak or from the same patient before first-line therapy and after relapse showed identical genotypes. A number of MLVA genotypes appeared to be partially restricted to some geographic areas and displayed no annual variation, possibly reflecting persistence of genotypes in certain areas for a time span of at least a decade. This study, representing the first molecular typing results of human Brucellaisolates from Turkey, indicated that Turkish human Brucella melitensisisolates were most closely related to the neighboring countries' isolates included in the East Mediterranean group.

Abstract: Objectives: Web-based studies nowadays raise a major interest as they can improve all steps involved in observational studies. Our objective was to compare the web-based version of the NutriNet-Santé self-administered socio-demographic and economic questionnaire with the traditional paper version. Methods: Both versions of the questionnaire were sent to 170 volunteers and filled in by 147 of them (either paper first, n = 76, or web-based first, n = 71). Agreement between versions was assessed by intraclass correlations (ICC) and kappas. Results: Agreement between both versions was high, with ICC and kappas ranging between 0.81–1.00 and 0.76–1.00, respectively, similarly across groups of administration order, age, gender and self-estimated web knowledge in general. The web-based version was the one preferred by 93.7% of the subjects and enabled to avoid 553 missing values (2.00% of the total entries), 24 inconsistent data (0.09%), 8 aberrant data (0.03%), 472 data entry errors (0.85%) and to save 2,800 € (US $4,072) when sent to 170 subjects. Conclusion: The web-based socio-demographic and economic questionnaire provided information of similar-to-superior quality compared to the traditional paper version, with substantial logistic and cost advantages.

The neuromuscular spindle (NMS) is a proprioceptive myofibrillar component of skeletal muscles that is necessary to maintain normal muscle tone and coordination. Recently, an excess of NMS has been reported as a congenital neuromuscular syndrome with a Noonan phenotype, now linked to Costello syndrome (CS). The vast majority of patients with CS have a de novo heterozygous mutation in the HRASgene involved in the Ras/mitogen-activated protein kinase (MAPK) pathway. CS has many features in common with Noonan and cardiofaciocutaneous syndromes, also linked to activating mutations (but in other genes) of the Ras/MAPK pathway. This makes the orientation of molecular screening difficult. The observation of excess NMS in a 26-weeks'-gestation stillborn prompted us to screen the HRASgene for mutation. The identification of a HRASmutation made it possible to establish a diagnosis of CS. We conclude that the excess of NMS is the most reliable sign for the diagnosis of CS. Our findings also show the instrumental role of histological study of the skeletal muscles in the context of polyhydramnios and fetal hydrops.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease associated with potentially debilitating joint inflammation, as well as altered skeletal bone metabolism and co-morbid conditions. Early diagnosis and aggressive treatment to control disease activity offers the highest likelihood of preserving function and preventing disability. Joint inflammation is characterized by synovitis, osteitis, and/or peri-articular osteopenia, often accompanied by development of subchondral bone erosions, as well as progressive joint space narrowing. Biochemical markers of joint cartilage and bone degradation may enable timely detection and assessment of ongoing joint damage, and their use in facilitating treatment strategies is under investigation. Early detection of joint damage may be assisted by the characterization of biochemical markers that identify patients whose joint damage is progressing rapidly and who are thus most in need of aggressive treatment, and that, alone or in combination, identify those individuals who are likely to respond best to a potential treatment, both in terms of limiting joint damage and relieving symptoms. The aims of this review are to describe currently available biochemical markers of joint metabolism in relation to the pathobiology of joint damage and systemic bone loss in RA; to assess the limitations of, and need for additional, novel biochemical markers in RA and other rheumatic diseases, and the strategies used for assay development; and to examine the feasibility of advancement of personalized health care using biochemical markers to select therapeutic agents to which a patient is most likely to respond.

ABSTRACTAcinetobacter baumanniiis an important opportunistic pathogen responsible for nosocomial outbreaks, mostly occurring in intensive care units. Due to the multiplicity of infection sources, reliable molecular fingerprinting techniques are needed to establish epidemiological correlations among A. baumanniiisolates. Multiple-locus variable-number tandem-repeat analysis (MLVA) has proven to be a fast, reliable, and cost-effective typing method for several bacterial species. In this study, an MLVA assay compatible with simple PCR- and agarose gel-based electrophoresis steps as well as with high-throughput automated methods was developed for A. baumanniityping. Preliminarily, 10 potential polymorphic variable-number tandem repeats (VNTRs) were identified upon bioinformatic screening of six annotated genome sequences of A. baumannii. A collection of 7 reference strains plus 18 well-characterized isolates, including unique types and representatives of the three international A. baumanniilineages, was then evaluated in a two-center study aimed at validating the MLVA assay and comparing it with other genotyping assays, namely, macrorestriction analysis with pulsed-field gel electrophoresis (PFGE) and PCR-based sequence group (SG) profiling. The results showed that MLVA can discriminate between isolates with identical PFGE types and SG profiles. A panel of eight VNTR markers was selected, all showing the ability to be amplified and good amounts of polymorphism in the majority of strains. Independently generated MLVA profiles, composed of an ordered string of allele numbers corresponding to the number of repeats at each VNTR locus, were concordant between centers. Typeability, reproducibility, stability, discriminatory power, and epidemiological concordance were excellent. A database containing information and MLVA profiles for several A. baumanniistrains is available from http://mlva.u-psud.fr/.

Background Few studies have examined the association between global diet, assessed through dietary patterns, and arterial structure and function. The aim of this study was to investigate the relationship between carotid-femoral pulsewave velocity (PWV), common carotid-arteries intima-media thickness (CCA-IMT) and plaques with dietary patterns measured 7.5 years earlier.Design A prospective cohort study between diet and markers of structure and function of large arteries.Methods Dietary patterns (linear combination of food consumption) were identified using principal component analysis among 1026 middle-aged participants in the SUpplémentation en VItamines et Minéraux AntioXydants (SU.VI.MAX) vascular substudy. Dietary data were based on repeated 24-h dietary records (at least three records during 2 years) obtained at inclusion. Carotid-femoral PWV was used to assess aortic stiffness. Carotid ultrasound examination included measurements of CCA-IMT and carotid plaques.Results Four dietary patterns were identified. In multivariate models, a significant positive association was observed between PWV and a dietary pattern positively correlated with meat and alcohol consumption and negatively correlated with fibers, vitamins B9 and C, β-carotene and calcium consumption. Adjusted PWV mean across tertiles of this pattern score was 11.15,11.26 and 11.58m/s in the first, second and third tertiles, respectively (Pfor trend = 0.03). Others dietary patterns were not associated with PWV and we detected no association between dietary patterns and IMT or plaques.Conclusion This study suggests that a nutritionally poor dietary pattern, characterized by a high meat and alcohol consumption and low micronutrients intake, is related to an increased stiffening of large arteries.

Abstract: Oral dosage forms with controlled release exhibit various advantages over their immediate release counterparts, but they must be built adequately by dispersing the drug through the well-defined polymer matrix. This study is concerned with diffusion-controlled dosage forms to resolve the problems that appear: in vitro tests generally used for determining the kinetics of drug release do not take into account the nature of the drug. On the contrary, the plasma drug profiles obtained through in vivo tests strongly depend on the nature of the drug, through their typical pharmacokinetic parameters. Moreover, the effect of the stirring rate is difficult to evaluate. Following the demand from the FDA concerned with the in vitro/in vivo correlation, a numerical model was built so as to evaluate the plasma drug profile obtained with any drug delivered from a diffusion-controlled release dosage form. The results are expressed by connecting the half-life times of the drugs obtained either with bolus injection or with the dosage forms, for various values of the parameters of interest: the diffusivity of the matrix polymer and the size of the dosage form. Thus, these diagrams make it possible to promptly determine the characteristics of the dosage forms able to give the desired plasma drug profile for any drug. Of course, for each drug being defined by its pharmacokinetic parameters, the polymer matrix should be selected as a function of its diffusivity. Finally, the evaluation of the plasma drug profile is of effective help to determine quantitatively the effect of the intervariability of the patients as well as the effect of the patient’s noncompliance.

ABSTRACTWe describe an improved multiple-locus variable-number tandem-repeat (VNTR) analysis (MLVA) scheme for genotyping Staphylococcus aureus. We compare its performance to those of multilocus sequence typing (MLST) and spatyping in a survey of 309 strains. This collection includes 87 epidemic methicillin-resistant S. aureus(MRSA) strains of the Harmony collection, 75 clinical strains representing the major MLST clonal complexes (CCs) (50 methicillin-sensitive S. aureus[MSSA] and 25 MRSA), 135 nasal carriage strains (133 MSSA and 2 MRSA), and 13 published S. aureusgenome sequences. The results show excellent concordance between the techniques' results and demonstrate that the discriminatory power of MLVA is higher than those of both MLST and spatyping. Two hundred forty-two genotypes are discriminated with 14 VNTR loci (diversity index, 0.9965; 95% confidence interval, 0.9947 to 0.9984). Using a cutoff value of 45%, 21 clusters are observed, corresponding to the CCs previously defined by MLST. The variability of the different tandem repeats allows epidemiological studies, as well as follow-up of the evolution of CCs and the identification of potential ancestors. The 14 loci can conveniently be analyzed in two steps, based upon a first-line simplified assay comprising a subset of 10 loci (panel 1) and a second subset of 4 loci (panel 2) that provides higher resolution when needed. In conclusion, the MLVA scheme proposed here, in combination with available on-line genotyping databases (including http://mlva.u-psud.fr/), multiplexing, and automatic sizing, can provide a basis for almost-real-time large-scale population monitoring of S. aureus.

When two sheets of EPDM with different percent peroxide as curing agent, 2% for the one and 10% for the other, are firmly pressed and cured together at a convenient temperature, a transfer of the curing agent has been proved to take place through the interface between these two sheets. The following two facts are observed. On the one hand, when this cured bi-layer system is immersed in toluene, a large swelling is observed but the two layers are not separated, in spite of the different rate and extent of swelling for each EPDM taken separately. On the other hand, the hardness does not vary discontinuously at the interface between the two sheets, but on the contrary it varies continuously through the thickness of the two layer system. This variation of the hardness through the thickness gives an idea of the gradient of peroxide concentration which has been developed during the stage of heating before the onset of cure. The kinetics of absorption of toluene is controlled by diffusion, and the two parameters, with the diffusivity and the capacity of absorption at equilibrium, are evaluated for the two-layer system by using the values measured on the two EPDM components with different percentages of peroxide taken separately. Modelling of the process of absorption and evaporation has been possible from these values for the bi-layer system, explaining the torsion of the bi-layer sheet during the stage of absorption and its stability. An application of this matter transfer during the cure process opens a way for re-treading a truck tyre with a new rubber band.

ABSTRACTBrucellosis remains an important anthropozoonosis worldwide. Brucellaspecies are genetically homogeneous, and thus, the typing of Brucellaspecies for epidemiological purposes by conventional molecular typing methods has remained elusive. Although many methods could segregate isolates into the phylogenetically recognized taxa, limited within-species genetic diversity has been identified. Recently, multilocus variable-number tandem-repeat analysis (MLVA) was found to have a high degree of resolution when it was applied to collections of Brucellaisolates from geographically widespread locations, and an assay comprising 16 such loci (MLVA-16) was proposed. This scheme includes eight minisatellite loci (panel 1) and eight microsatellites (panel 2, which is subdivided into panels 2A and 2B). The utility of MLVA-16 for the subtyping of human Brucellaisolates from geographically restricted regions needs to be further evaluated, and genotyping databases with worldwide coverage must be progressively established. In the present study, MLVA-16 was applied to the typing of 42 human Brucellaisolates obtained from 41 patients recovered from 2002 to 2006 at a tertiary-care center in Lebanon. All isolates were identified as Brucella melitensisby MLVA-16 and were found to be closely related to B. melitensisisolates from neighboring countries in the Middle East when their genotypes were queried against those in the web-based Brucella2007 MLVA database (http://mlva.u-psud.fr/). Panel 2B, which comprised the most variable loci, displayed a very high discriminatory power, while panels 1 and 2A showed limited diversity. The most frequent genotype comprised seven isolates obtained over 7 weeks in 2002, demonstrating an outbreak from a common source. Two isolates obtained from one patient 5 months apart comprised another genotype, indicating relapsing disease. These findings confirm that MLVA-16 has a good discriminatory power for species determination, typing of B. melitensisisolates, and inferring their geographical origin. Abbreviated panel 2B could be used as a short-term epidemiological tool in a small region of endemicity.

ABSTRACTThe Shigellagenus has historically been separated into four species, based on biochemical assays. The classification within each species relies on serotyping. Recently, genome sequencing and DNA assays, in particular the multilocus sequence typing (MLST) approach, greatly improved the current knowledge of the origin and phylogenetic evolution of Shigellaspp. The Shigellaand Escherichiagenera are now considered to belong to a unique genomospecies. Multilocus variable-number tandem-repeat (VNTR) analysis (MLVA) provides valuable polymorphic markers for genotyping and performing phylogenetic analyses of highly homogeneous bacterial pathogens. Here, we assess the capability of MLVA for Shigellatyping. Thirty-two potentially polymorphic VNTRs were selected by analyzing in silico five Shigellagenomic sequences and subsequently evaluated. Eventually, a panel of 15 VNTRs was selected (i.e., MLVA15 analysis). MLVA15 analysis of 78 strains or genome sequences of Shigellaspp. and 11 strains or genome sequences of Escherichia colidistinguished 83 genotypes. Shigellapopulation cluster analysis gave consistent results compared to MLST. MLVA15 analysis showed capabilities for E. colityping, providing classification among pathogenic and nonpathogenic E. colistrains included in the study. The resulting data can be queried on our genotyping webpage (http://mlva.u-psud.fr). The MLVA15 assay is rapid, highly discriminatory, and reproducible for Shigellaand Escherichiastrains, suggesting that it could significantly contribute to epidemiological trace-back analysis of Shigellainfections and pathogenic Escherichiaoutbreaks. Typing was performed on strains obtained mostly from collections. Further studies should include strains of much more diverse origins, including all pathogenic E. colitypes.

The ESH2003 report (J Hypertens2003, 21:1011–1053) has classified brachial blood pressure into six groups reflecting the consistently increasing cardiovascular risk caused by high blood pressure. Chronically treated hypertensive individuals with well-controlled blood pressure retain higher cardiovascular risk than normotensive untreated individuals. Differences between these groups in arterial stiffness, pressure wave reflections and central blood pressure, which are all predictors of cardiovascular risk independently of peripheral blood pressure, have never been studied.