The death receptor antagonist FAIM promotes neurite outgrowth by a mechanism that depends on ERK and NF-κB signaling

Fas apoptosis inhibitory molecule (FAIM) is a protein identified as an antagonist of Fas-induced cell death. We show that FAIM overexpression fails to rescue neurons from trophic factor deprivation, but exerts a marked neurite growth–promoting action in different neuronal systems. Whereas FAIM overexpression greatly enhanced neurite outgrowth from PC12 cells and sympathetic neurons grown with nerve growth factor (NGF), reduction of endogenous FAIM levels by RNAi decreased neurite outgrowth in these cells. FAIM overexpression promoted NF-κB activation, and blocking this activation by using a super-repressor IκBα or by carrying out experiments using cortical neurons from mice that lack the p65 NF-κB subunit prevented FAIM-induced neurite outgrowth. The effect of FAIM on neurite outgrowth was also blocked by inhibition of the Ras–ERK pathway. Finally, we show that FAIM interacts with both Trk and p75 neurotrophin receptor NGF receptors in a ligand-dependent manner. These results reveal a new function of FAIM in promoting neurite outgrowth by a mechanism involving activation of the Ras–ERK pathway and NF-κB.

The impact of a register on the management of neonatal cooling in Switzerland.

BACKGROUND: Therapeutic hypothermia following hypoxic ischaemic encephalopathy in term infants was introduced into Switzerland in 2005. Initial documentation of perinatal and resuscitation details was poor and neuromonitoring insufficient. In 2011, a National Asphyxia and Cooling Register was introduced. AIMS: To compare management of cooled infants before and after introduction of the register concerning documentation, neuromonitoring, cooling methods and evaluation of temperature variability between cooling methods. STUDY DESIGN: Data of cooled infants before the register was in place (first time period: 2005-2010) and afterwards (second time period: 2011-2012) was collected with a case report form. RESULTS: 150 infants were cooled during the first time period and 97 during the second time period. Most infants were cooled passively or passively with gel packs during both time periods (82% in 2005-2010 vs 70% in 2011-2012), however more infants were cooled actively during the second time period (18% versus 30%). Overall there was a significant reduction in temperature variability (p < 0.001) comparing the two time periods. A significantly higher proportion of temperature measurements within target temperature range (72% versus 77%, p < 0.001), fewer temperature measurements above (24% versus 7%, p < 0.001) and more temperatures below target range (4% versus 16%, p < 0.001) were recorded during the second time period. Neuromonitoring improved after introduction of the cooling register. CONCLUSION: Management of infants with HIE improved since introducing the register. Temperature variability was reduced, more temperature measurements in the target range and fewer temperature measurements above target range were observed. Neuromonitoring has improved, however imaging should be performed more often.

"Voyage through death/to life upon these shores": the living dead of the Middle Passage

While historical studies of the Atlantic slave trade have amply demonstrated the magnitude of slave mortality during the Middle Passage, only recently have they started to examine how the captives might have endured and coped with this traumatic experience. Although it constitutes a major topos in African diasporic culture, the Middle Passage has only occasionally been represented directly and in details in novels and in films. This article examines three recent narratives of the Middle Passage, Fred D'Aguiar's novel Feeding the Ghosts (1998), Guy Deslauriers's film Passage du milieu (2000), and Stephanie Smallwood's historical study Saltwater Slavery: A Middle Passage from Africa to American Diaspora (2007). Beyond their individual poetic, aesthetic, and scholarly qualities, what is most striking about these three texts is that they all use the figure of the living dead in order to explore the captives' experience of the transatlantic journey. If the ghastly quality of the living dead powerfully captures the life-threatening material and physical conditions the captives endured on the voyage, its dual, liminal character also allows D'Aguiar, Deslauriers, and Smallwood to represent the metaphysical, psychological, social, and cultural journey they were forced to undertake. Through their use of the trope of the living dead, these three texts show that if death is indeed a central aspect of the experience of the Middle Passage, it impacts the captives in ways that go well beyond the issue of mortality.

European cancer mortality predictions for the year 2015 : does lung cancer have the highest death rate in EU women?

BACKGROUND: Cancer mortality statistics for 2015 were projected from the most recent available data for the European Union (EU) and its six more populous countries. Prostate cancer was analysed in detail. PATIENTS AND METHODS: Population and death certification data from stomach, colorectum, pancreas, lung, breast, uterus, prostate, leukaemias and total cancers were obtained from the World Health Organisation database and Eurostat. Figures were derived for the EU, France, Germany, Italy, Poland, Spain and the UK. Projected 2015 numbers of deaths by age group were obtained by linear regression on estimated numbers of deaths over the most recent time period identified by a joinpoint regression model. RESULTS: A total of 1 359 100 cancer deaths are predicted in the EU in 2015 (766 200 men and 592 900 women), corresponding to standardised death rates of 138.4/100 000 men and 83.9/100 000 women, falling 7.5% and 6%, respectively, since 2009. In men, predicted rates for the three major cancers (lung, colorectum and prostate) are lower than in 2009, falling 9%, 5% and 12%. Prostate cancer showed predicted falls of 14%, 17% and 9% in the 35-64, 65-74 and 75+ age groups. In women, breast and colorectal cancers had favourable trends (-10% and -8%), but predicted lung cancer rates rise 9% to 14.24/100 000 becoming the cancer with the highest rate, reaching and possibly overtaking breast cancer rates-though the total number of deaths remain higher for breast (90 800) than lung (87 500). Pancreatic cancer has a negative outlook in both sexes, rising 4% in men and 5% in women between 2009 and 2015. CONCLUSIONS: Cancer mortality predictions for 2015 confirm the overall favourable cancer mortality trend in the EU, translating to an overall 26% fall in men since its peak in 1988, and 21% in women, and the avoidance of over 325 000 deaths in 2015 compared with the peak rate.

When gas analysis assists with postmortem imaging to diagnose causes of death.

Postmortem imaging consists in the non-invasive examination of bodies using medical imaging techniques. However, gas volume quantification and the interpretation of the gas collection results from cadavers remain difficult. We used whole-body postmortem multi-detector computed tomography (MDCT) followed by a full autopsy or external examination to detect the gaseous volumes in bodies. Gases were sampled from cardiac cavities, and the sample compositions were analyzed by headspace gas chromatography-mass spectrometry/thermal conductivity detection (HS-GC-MS/TCD). Three categories were defined according to the presumed origin of the gas: alteration/putrefaction, high-magnitude vital gas embolism (e.g., from scuba diving accident) and gas embolism of lower magnitude (e.g., following a traumatic injury). Cadaveric alteration gas was diagnosed even if only one gas from among hydrogen, hydrogen sulfide or methane was detected. In alteration cases, the carbon dioxide/nitrogen ratio was often >0.2, except in the case of advanced alteration, when methane presence was the best indicator. In the gas embolism cases (vital or not), hydrogen, hydrogen sulfide and methane were absent. Moreover, with high-magnitude vital gas embolisms, carbon dioxide content was >20%, and the carbon dioxide/nitrogen ratio was >0.2. With gas embolisms of lower magnitude (gas presence consecutive to a traumatic injury), carbon dioxide content was <20% and the carbon dioxide/nitrogen ratio was often <0.2. We found that gas analysis provided useful assistance to the postmortem imaging diagnosis of causes of death. Based on the quantifications of gaseous cardiac samples, reliable indicators were determined to document causes of death. MDCT examination of the body must be performed as quickly as possible, as does gas sampling, to avoid generating any artifactual alteration gases. Because of cardiac gas composition analysis, it is possible to distinguish alteration gases and gas embolisms of different magnitudes.

Humeral development from neonatal period to skeletal maturity—application in age and sex assessment

The goal of the present study is to examine cross-sectional information on the growth of the humerus based on the analysis of four measurements, namely, diaphyseal length, transversal diameter of the proximal (metaphyseal) end of the shaft, epicondylar breadth and vertical diameter of the head. This analysis was performed in 181 individuals (90 ♂ and 91 ♀) ranging from birth to 25 years of age and belonging to three documented Western European skeletal collections (Coimbra, Lisbon and St. Bride). After testing the homogeneity of the sample, the existence of sexual differences (Student"s t- and Mann-Whitney U-test) and the growth of the variables (polynomial regression) were evaluated. The results showed the presence of sexual differences in epicondylar breadth above 20 years of age and vertical diameter of the head from 15 years of age, thus indicating that these two variables may be of use in determining sex from that age onward. The growth pattern of the variables showed a continuous increase and followed first- and second-degree polynomials. However, growth of the transversal diameter of the proximal end of the shaft followed a fourth-degree polynomial. Strong correlation coefficients were identified between humeral size and age for each of the four metric variables. These results indicate that any of the humeral measurements studied herein is likely to serve as a useful means of estimating sub-adult age in forensic samples.

Cardiovascular mechanisms of death in severe COPD exacerbation: time to think and act beyond guidelines.

Three important studies on acute exacerbations of chronic obstructive pulmonary disease (ECOPD)have been published in Thorax. Two of them, by Chang et al1(see page 764) and Hoiset et al2 (see page 775), show the importance of the cardiac biomarkers troponin T and NT-BNP (Nterminal pro-B-type natriuretic peptide) as strong predictors of the increased risk of death of patients hospitalised because of ECOPD.1 2.....

Incidence and outcomes of symptomatic neonatal arterial ischemic stroke.

BACKGROUND AND OBJECTIVES: Neonatal arterial ischemic stroke (NAIS) is associated with considerable lifetime burdens such as cerebral palsy, epilepsy, and cognitive impairment. Prospective epidemiologic studies that include outcome assessments are scarce. This study aimed to provide information on the epidemiology, clinical manifestations, infarct characteristics, associated clinical variables, treatment strategies, and outcomes of NAIS in a prospective, population-based cohort of Swiss children. METHODS: This prospective study evaluated the epidemiology, clinical manifestations, vascular territories, associated clinical variables, and treatment of all full-term neonates diagnosed with NAIS and born in Switzerland between 2000 and 2010. Follow-up was performed 2 years (mean 23.3 months, SD 4.3 months) after birth. RESULTS: One hundred neonates (67 boys) had a diagnosis of NAIS. The NAIS incidence in Switzerland during this time was 13 (95% confidence interval [CI], 11-17) per 100 000 live births. Seizures were the most common symptom (95%). Eighty-one percent had unilateral (80% left-sided) and 19% had bilateral lesions. Risk factors included maternal risk conditions (32%), birth complications (68%), and neonatal comorbidities (54%). Antithrombotic and antiplatelet therapy use was low (17%). No serious side effects were reported. Two years after birth, 39% were diagnosed with cerebral palsy and 31% had delayed mental performance. CONCLUSIONS: NAIS in Switzerland shows a similar incidence as other population-based studies. About one-third of patients developed cerebral palsy or showed delayed mental performance 2 years after birth, and children with normal mental performance may still develop deficits later in life.

Sudden cardiac death in forensic medicine - Swiss recommendations for a multidisciplinary approach.

Sudden cardiac death (SCD) is by definition unexpected and cardiac in nature. The investigation is almost invariably performed by a forensic pathologist. Under these circumstances the role of the forensic pathologist is twofold: (1.) to determine rapidly and efficiently the cause and manner of death and (2.) to initiate a multidisciplinary process in order to prevent further deaths in existing family members. If the death is determined to be due to "natural" causes the district attorney in charge often refuses further examinations. However, additional examinations, i.e. extensive histopathological investigations and/or molecular genetic analyses, are necessary in many cases to clarify the cause of death. The Swiss Society of Legal Medicine created a multidisciplinary working group together with clinical and molecular geneticists and cardiologists in the hope of harmonising the approach to investigate SCD. The aim of this paper is to close the gap between the Swiss recommendations for routine forensic post-mortem cardiac examination and clinical recommendations for genetic testing of inherited cardiac diseases; this is in order to optimise the diagnostic procedures and preventive measures for living family members. The key points of the recommendations are (1.) the forensic autopsy procedure for all SCD victims under 40 years of age, (2.) the collection and storage of adequate samples for genetic testing, (3.) communication with the families, and (4.) a multidisciplinary approach including cardiogenetic counselling.

NADPH oxidase NOX4 mediates stellate cell activation and hepatocyte cell death during liver fibrosis development.

A role for the NADPH oxidases NOX1 and NOX2 in liver fibrosis has been proposed, but the implication of NOX4 is poorly understood yet. The aim of this work was to study the functional role of NOX4 in different cell populations implicated in liver fibrosis: hepatic stellate cells (HSC), myofibroblats (MFBs) and hepatocytes. Two different mice models that develop spontaneous fibrosis (Mdr2−/−/p19ARF−/−, Stat3Δhc/Mdr2−/−) and a model of experimental induced fibrosis (CCl4) were used. In addition, gene expression in biopsies from chronic hepatitis C virus (HCV) patients or non-fibrotic liver samples was analyzed. Results have indicated that NOX4 expression was increased in the livers of all animal models, concomitantly with fibrosis development and TGF-β pathway activation. In vitro TGF-β-treated HSC increased NOX4 expression correlating with transdifferentiation to MFBs. Knockdown experiments revealed that NOX4 downstream TGF-β is necessary for HSC activation as well as for the maintenance of the MFB phenotype. NOX4 was not necessary for TGF-β-induced epithelial-mesenchymal transition (EMT), but was required for TGF-β-induced apoptosis in hepatocytes. Finally, NOX4 expression was elevated in patients with hepatitis C virus (HCV)-derived fibrosis, increasing along the fibrosis degree. In summary, fibrosis progression both in vitro and in vivo (animal models and patients) is accompanied by increased NOX4 expression, which mediates acquisition and maintenance of the MFB phenotype, as well as TGF-β-induced death of hepatocytes.

Geometric stopping of a random walk and its applications to valuing equity-linked death benefits

We study discrete-time models in which death benefits can depend on a stock price index, the logarithm of which is modeled as a random walk. Examples of such benefit payments include put and call options, barrier options, and lookback options. Because the distribution of the curtate-future-lifetime can be approximated by a linear combination of geometric distributions, it suffices to consider curtate-future-lifetimes with a geometric distribution. In binomial and trinomial tree models, closed-form expressions for the expectations of the discounted benefit payment are obtained for a series of options. They are based on results concerning geometric stopping of a random walk, in particular also on a version of the Wiener-Hopf factorization.

Early life host-microbe interactions : implications for the development of asthma

Plus de 300 millions de personnes dans le monde souffrent de l'asthme. L'asthme est une maladie inflammatoire chronique des voies respiratoires caractérisée par des symptômes variables et récurrents, une obstruction bronchique réversible et des bronchospasmes. Les symptômes communs incluent une respiration sifflante, de la toux, une oppression thoracique et de la dyspnée. Normalement, la maladie commence à se manifester pendant l'enfance. Pourtant, facteurs génétiques héréditaires et événements environnementaux survenant au cours de la petite enfance sont responsables de sa manifestation, indiquant que le développement de la maladie est lié à des événements qui se produisent bien avant son déclenchement. L'infection respiratoire virale aiguë constitue un de ces facteurs environnementaux jouant un rôle prépondérant. Un des virus les plus communs est le virus respiratoire syncytial (VRS), qui infecte presque tous les enfants avant l'âge de 2 ans. Ce virus, s'il infecte des tout-petits, peut en effet provoquer une bronchiolite aiguë, un phénomène qui a été épidémiologiquement lié à l'apparition d'asthme plus tard dans la vie. Dans le premier chapitre de cette thèse, nous avons étudié, chez la souris, comment une infection avec le VRS influe sur l'asthme allergique. Nous avons constaté que seule l'infection des souris à l'état de nouveau-né prédispose à un asthme allergique plus sévère chez l'adulte. En effet, si des souris adultes étaient infectées, elles étaient protégées contre l'apparition des symptômes asthmatiques. Cela nous a mené à investiguer les mécanismes immunitaires spécifiques durant cette courte période du début de la vie. Deux événements se produisent en parallèle au cours de la petite enfance: (1) Le système immunitaire, qui est encore immature immédiatement après la naissance, commence à se développer pour être en mesure de jouer son rôle protecteur contre les agents infectieux. (2) Le corps, y compris les poumons, est colonisé par des bactéries commensales, qui vivent en symbiose avec leur hôte humain. Chez l'adulte, ces bactéries sont connues pour influencer notre système immunitaire, l'éduquant à générer des réponses immunitaires adéquates et efficaces. Dans la deuxième partie de cette thèse, nous avons voulu déterminer si ces bactéries symbiotiques étaient impliquées dans l'éducation du système immunitaire du nouveau-né et quelles conséquences cela pourrait avoir sur les réponses immunitaires engendrées par ce dernier. Pour étudier l'effet de ces bactéries symbiotiques, nous avons utilisé des souris stériles, en d'autres termes des souris qui n'hébergent pas ces bactéries symbiotiques. En comparant ces souris stériles à des souris qui abritent une flore microbienne normale, nous avons constaté que les bactéries symbiotiques sont vitales pour la bonne éducation du système immunitaire du nouveau-né. Nous avons démontré que le contact direct des cellules immunitaires avec la flore microbienne dans les poumons modifie le phénotype de ces cellules immunitaires, ce qui change probablement leur réaction au cours de réponses immunitaires. Nous avons donc vérifié si l'éducation immunitaire induite par cette microflore est importante pour prévenir les maladies pulmonaires telles que l'asthme allergique, affections qui sont causées par une réaction excessive du système immunitaire envers des agents inoffensifs. En effet, nous avons observé que le processus de maturation du système immunitaire néonatal, lequel a été déclenché et façonné par la flore microbienne, est important pour éviter une réaction asthmatique exagérée chez la souris adulte. Ce phénomène est dû aux lymphocytes T régulateurs. Ces cellules, dont la présence est induite dans les poumons, ont des capacités immunosuppressives et atténuent donc les réponses immunitaires pour prévenir une inflammation excessive. En conclusion, nous avons montré dans cette thèse que la colonisation par des bactéries symbiotiques tôt dans la vie est un événement décisif pour la maturation du système immunitaire et pour prévenir le développement de l'asthme. Dans l'avenir, il serait intéressant de découvrir quelles bactéries sont présentes dans les poumons du nouveau-né et lesquelles sont directement impliquées dans ce processus de maturation immunitaire. Une prochaine étape serait alors de favoriser la présence de ces bactéries au début de la vie au moyen d'un traitement avec des agents pré- ou probiotiques, ce qui pourrait éventuellement contribuer à une prévention précoce du développement de l'asthme. -- L'asthme est une maladie chronique inflammatoire des voies respiratoires affectant près de 300 millions d'individus dans le monde. Bien que les traits caractéristiques du phénotype asthmatique s'établissent généralement pendant l'enfance, la prédisposition au développement de la maladie est intimement liée à des événements survenant durant la petite enfance, comme le sont par exemple les infections virales respiratoires aiguës. Les mécanismes par lesquels ces événements provoquent un dysfonctionnement immunitaire et, par conséquent, conduisent au développement de l'asthme n'ont pas encore été entièrement décelés. La dysbiose du microbiote des voies respiratoires a été récemment associes au phénotype asthmatique, touisTcis, la cuûoboiatioî! d un lien cause à effet entre la dysbiose microbienne et l'apparition des symptômes asthmatiques reste à être démontrée. Dans cette thèse, nous avons étudié le rôle que joue la colonisation microbienne des voies respiratoires au cours de la petite enfance dans la maturation du système immunitaire ainsi que dans la protection contre l'inflammation pulmonaire de type allergique. Nous avons de surcroît développé un modèle expérimental pour comprendre comment les infections virales respiratoires interfèrent avec ce processus. Dans la première partie de cette thèse, nous avons évalué l'effet d'infections causées par le virus respiratoire syncytial (VRS) sur le développement de l'asthme. En accord avec des études épidémiologiques, nous avons constaté qu'une infection au VRS lors de la période néonatale exacerbait les réponses pulmonaires allergiques ultérieures. Par contraste, une infection à l'âge adulte avait un effet protecteur. Nous avons ainsi démontré que l'influence d'une infection à VRS sur l'issue et la sévérité de l'asthme respiratoire était strictement dépendante de l'âge. Ces résultats nous ont conduit à émettre l'hypothèse que des différences dans le phénotype homéostatique des cellules immunitaires pourraient être responsables de ces disparités liées à l'âge. Par conséquent, dans la deuxième partie de cette thèse, nous avons suivi et caractérisé le processus de maturation des cellules immunitaires dans les poumons du nouveau-né en condition d'homéostasie. Nous avons découvert que leur phénotype change de façon dynamique pendant le développement néonatal et que la colonisation par des microbes était déterminante pour la maturation des cellules immunitaires dans les poumons. Dans la dernière partie de cette thèse, nous avons démontré comment le microbiote pulmonaire éduque le développement immunitaire durant la période néonatale l'orientant de manière à induire une tolérance face aux aéroallergènes. Nous avons découvert que la colonisation microbienne des voies respiratoires provoque une expression transitoire de PD-L1 sur les cellules dendritiques (CD) pulmonaires du type CD11b+ dans les deux premières semaines de la vie. Cet événement engendre par la suite la génération de lymphocytes T régulateurs (TREG) dans les poumons, lesquels sont responsables de la protection contre une réponse inflammatoire allergique exagérée chez la souris adulte. Par conséquent, nous proposons un rôle pivot de la maturation immunitaire induite par le microbiote pulmonaire dans l'établissement de la tolérance aux aéroallergènes. En conclusion, les résultats présentés dans cette thèse fournissent de nouveaux indices révélant comment des événements se produisant lors de la petite enfance peuvent façonner les réponses du système immunitaire dirigées contre les allergènes et soulignent le rôle central joué par le microbiote pulmonaire dans l'édification d'une réponse immunitaire équilibrée. En résumé, notre travail met en évidence le microbiote pulmonaire comme étant une cible potentielle pour la prévention de certaines maladies respiratoires. -- Asthma is a chronic inflammatory disorder of the respiratory tract and affects approximately 300 million individuals world-wide. Although the asthmatic phenotype commonly establishes during childhood, predisposition towards disease development has been linked to events in early infancy, such as severe respiratory viral infections. However, the mechanisms by which these events cause immune dysfunction and, therefore, lead to the development of asthma have yet to be fully deciphered. Dysbiosis of the airway microbiota has recently been associated with the asthmatic phenotype; however, conclusive evidence for a causal link between microbial dysbiosis in the ail ways and asthma development is still missing. In this thesis we investigated the role of early-life microbial airway colonization in immune maturation and the protection against allergic airway inflammation and established an experimental model to address how respiratory viral infections interfere in this process. In the first part of this thesis we evaluated the effect of Respiratory syncytial virus (RSV) infections on the development of asthma. In concurrence with epidemiological studies, we found that neonatal infection exacerbated subsequent allergic airway inflammation. In contrast, adult infection was protective in the same context. Thus, we could demonstrate that the influence of RSV infection on subsequent allergic airway responses was strictly age-dependent. These findings led us to the hypothesis that differences in the homeostatic phenotype of immune cells could be responsible for the age-related disparities seen within the context of RSV. Therefore, in a second part of this thesis, we followed the process of homeostatic immune cell maturation in the neonatal lung. Immune cell phenotypes changed dynamically during neonatal development. We discovered that the colonization with microbes was central to the maturation of immune cells in the lung. In the last part of this thesis, we demonstrated how microbiota-driven immune development during the neonatal period induces tolerance against aeroallergens. We discovered that microbial colonization led to a transient programmed death-ligand (PD-L) 1 expression on CD11b+ pulmonary dendritic cells (DCs) during the first two weeks of life. This in turn induced regulatory T (TREG) cells in the lung, which were responsible for the protection against exaggerated allergic airway inflammation in adult mice. Thus, we propose a key role for microbiota-driven immune maturation in the establishment of tolerance towards aeroallergens. In conclusion, the results presented in this thesis provide new insights into how early-life events shape pulmonary immune responses towards allergens and suggest the airway microbiota as a key player in establishing a balanced immune response. Overall, our work highlights the airway microbiota as potential target for disease prevention.