Outcome and Prognostic Factors of COVID-19 Infection in Swiss Cancer Patients: Final Results of SAKK 80/20 (CaSA).

PURPOSE These are the final results of a national registry on cancer patients with COVID-19 in Switzerland. METHODS We collected data on symptomatic COVID-19-infected cancer patients from 23 Swiss sites over a one-year period starting on 1 March 2020. The main objective was to assess the outcome (i.e., mortality, rate of hospitalization, ICU admission) of COVID-19 infection in cancer patients; the main secondary objective was to define prognostic factors. RESULTS From 455 patients included, 205 patients (45%) had non-curative disease, 241 patients (53%) were hospitalized for COVID-19, 213 (47%) required oxygen, 43 (9%) invasive ventilation and 62 (14%) were admitted to the ICU. Death from COVID-19 infection occurred in 98 patients, resulting in a mortality rate of 21.5%. Age ≥65 years versus <65 years (OR 3.14, p = 0.003), non-curative versus curative disease (OR 2.42, p = 0.012), ICU admission (OR 4.45, p < 0.001) and oxygen requirement (OR 20.28, p < 0.001) were independently associated with increased mortality. CONCLUSIONS We confirmed high COVID-19 severity and mortality in real-world cancer patients during the first and second wave of the pandemic in a country with a decentralized, high-quality, universal-access health care system. COVID-19-associated mortality was particularly high for those of older age in a non-curative disease setting, requiring oxygen or ICU care

Subklinische Hypothyreose: Risiken, aktuelle Empfehlungen und randomisierte Studie in der Schweiz

Quintessenz: • Die subklinische Hypothyreose ist definiert durch erhöhte TSH und normwertige ThyroxinSpiegel; sie kommt bei älteren Patienten häufig vor (10–15%). • Daten aus Beobachtungsstudien zeigen einen möglichen Zusammenhang zwischen der subklinischen Hypothyreose und verschiedenen Krankheitsbildern wie kardiovaskulären Erkrankungen, Muskelbeschwerden sowie depressiven oder kognitiven Störungen. • Die Indikation zur Thyroxin Substitution bei subklinischer Hypothyreose ist derzeit noch nicht klar, was sich in grossen Unterschieden bezüglich Therapie zwischen verschiedenen Ländern niederschlägt. Es zeigt sich jedoch eine Zunahme der ThyroxinVerschreibungen. • Die Teilnahme an der randomisierten TRUST Studie ist die derzeit beste «Behandlungsoption» für ältere Patienten mit subklinischer Hypothyreose

Catch-Up Growth Following Fetal Growth Restriction Promotes Rapid Restoration of Fat Mass but Without Metabolic Consequences at One Year of Age

BACKGROUND: Fetal growth restriction (FGR) followed by rapid weight gain during early life has been suggested to be the initial sequence promoting central adiposity and insulin resistance. However, the link between fetal and early postnatal growth and the associated anthropometric and metabolic changes have been poorly studied. METHODOLOGY/PRINCIPAL FINDINGS: Over the first year of post-natal life, changes in body mass index, skinfold thickness and hormonal concentrations were prospectively monitored in 94 infants in whom the fetal growth velocity had previously been measured using a repeated standardized procedure of ultrasound fetal measurements. 45 infants, thinner at birth, had experienced previous FGR (FGR+) regardless of birth weight. Growth pattern in the first four months of life was characterized by greater change in BMI z-score in FGR+ (+1.26+/-1.2 vs +0.58 +/-1.17 SD in FGR-) resulting in the restoration of BMI and of fat mass to values similar to FGR-, independently of caloric intakes. Growth velocity after 4 months was similar and BMI z-score and fat mass remained similar at 12 months of age. At both time-points, fetal growth velocity was an independent predictor of fat mass in FGR+. At one year, fasting insulin levels were not different but leptin was significantly higher in the FGR+ (4.43+/-1.41 vs 2.63+/-1 ng/ml in FGR-). CONCLUSION: Early catch-up growth is related to the fetal growth pattern itself, irrespective of birth weight, and is associated with higher insulin sensitivity and lower leptin levels after birth. Catch-up growth promotes the restoration of body size and fat stores without detrimental consequences at one year of age on body composition or metabolic profile. The higher leptin concentration at one year may reflect a positive energy balance in children who previously faced fetal growth restriction

A Fear-Inducing Odor Alters PER2 and c-Fos Expression in Brain Regions Involved in Fear Memory

Evidence demonstrates that rodents learn to associate a foot shock with time of day, indicating the formation of a fear related time-stamp memory, even in the absence of a functioning SCN. In addition, mice acquire and retain fear memory better during the early day compared to the early night. This type of memory may be regulated by circadian pacemakers outside of the SCN. As a first step in testing the hypothesis that clock genes are involved in the formation of a time-stamp fear memory, we exposed one group of mice to fox feces derived odor (TMT) at ZT 0 and one group at ZT 12 for 4 successive days. A separate group with no exposure to TMT was also included as a control. Animals were sacrificed one day after the last exposure to TMT, and PER2 and c-Fos protein were quantified in the SCN, amygdala, hippocampus, and piriform cortex. Exposure to TMT had a strong effect at ZT 0, decreasing PER2 expression at this time point in most regions except the SCN, and reversing the normal rhythm of PER2 expression in the amygdala and piriform cortex. These changes were accompanied by increased c-Fos expression at ZT0. In contrast, exposure to TMT at ZT 12 abolished the rhythm of PER2 expression in the amygdala. In addition, increased c-Fos expression at ZT 12 was only detected in the central nucleus of the amygdala in the TMT12 group. TMT exposure at either time point did not affect PER2 or c-Fos in the SCN, indicating that under a light-dark cycle, the SCN rhythm is stable in the presence of repeated exposure to a fear-inducing stimulus. Taken together, these results indicate that entrainment to a fear-inducing stimulus leads to changes in PER2 and c-Fos expression that are detected 24 hours following the last exposure to TMT, indicating entrainment of endogenous oscillators in these regions. The observed effects on PER2 expression and c-Fos were stronger during the early day than during the early night, possibly to prepare appropriate systems at ZT 0 to respond to a fear-inducing stimulus

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

Etude de l'expression de l'homéoprotéine Engrailed dans l'hippocampe et de ses effets sur la complexité dendritique

Engrailed (En) est un facteur de transcription important pour la mise en place de la segmentation de l embryon et du plan d organisation antéro-postérieur. Comme d autres membres de la famille des homéoprotéines, Engrailed peut aussi agir comme une molécule de signalisation extracellulaire, internalisable grâce à son domaine pénétratine et stimulant dans la cellule cible la transcription ou la traduction des ARNm. De cette façon, Engrailed guide les axones en modifiant la traduction dans le cône de croissance axonal et l infusion cérébrale d Engrailed protège les neurones dopaminergiques dans un modèle de la maladie de Parkinson en augmentant la traduction de protéines mitochondriales. Des troubles cognitifs et un déficit des interactions sociales ont été observés chez les souris En1+/- et les souris En2-/-. Une augmentation de l expression d En2 a aussi été observée chez des patients atteints de troubles du spectre autistique. Néanmoins, le lien entre les modifications de l expression d Engrailed et l autisme ne sont pas compris. L objectif de cette thèse a été d étendre notre connaissance des fonctions d Engrailed dans une région télencéphalique où elle est a priori peu exprimée (l hippocampe). Nos résultats confirment l expression d En1 et En2 dans l hippocampe mature et décrivent les variations de l expression de ces gènes au cours du développement de cette structure. En1 et En2 présentent des patrons d expression différents pendant la première semaine postnatale et chez l adulte suggérant que des variations du dosage génique d Engrailed sont liées à certaines phases du développement, en particulier au début de la synaptogenèse. Nous avons également découvert que dans les cultures de cellules d hippocampe Engrailed est exprimé dans les neurones et que son expression est plus forte dans les neurones GABA-ergiques, notamment dans leurs prolongements dendritiques et axonaux. Nous avons constaté qu un excès d Engrailed (décrit dans certains cas de TSA) augmente la complexité dendritique ainsi que la densité des épines dendritiques plastiques mais sans augmenter parallèlement la formation de synapses matures excitatrices. Nous avons observé des variations de densité des épines dendritiques chez les souris En2-/- et les souris En1+/-, ce qui confirme l implication d Engrailed dans leur formation ou leur stabilisation. Si dans nos conditions expérimentales l excès d Engrailed ne modifie pas la densité des synapses, un mutant d Engrailed qui présente une interaction réduite avec eIF4E est moins efficace qu Engrailed pour augmenter la densité des épines et diminue la densité des boutons présynaptiques et le synaptic matching. Ces résultats indiquent que l interaction avec eIF4E régule au moins en partie les effets d Engrailed sur la spinogenèse et suggèrent également une implication d Engrailed dans la formation ou la stabilisation des boutons présynaptiques. Le rôle clef d eIF4E dans la traduction permet de postuler que certains effets d Engrailed observés dans notre étude pourraient dépendre de la synthèse protéique. Nos résultats montrent à cet égard qu Engrailed augmente la synthèse protéique dans les neurones d hippocampe. Cette traduction est différente de celle induite par la LTP chimique (LTPc) car insensible à l action des oligomères synthétiques d AbO, responsables sous leur forme naturelle de synaptopathies dans le contexte de la maladie d Alzheimer. Engrailed permet également de restaurer la traduction défaillante de neurones issus de souris TG2576, modèles de la maladie d Alzheimer. Dans leur ensemble, nos résultats identifient Engrailed comme un nouvel acteur de la plasticité dendritique. Ils révèlent qu un excès d Engrailed au cours de la synaptogenèse modifie les caractéristiques des dendrites, une situation susceptible d altérer les caractéristiques fonctionnelles du réseau dendritique dans une situation de surexpression pathologique de la protéine. (...)Engrailed (En) is an important transcription factor in embryo s segmentation and anterior-posterior axis establishment during early embryogenesis. As several homeoproteins, Engrailed can act as an extracellular signalling molecule which can be internalized by target cells thanks to its penetratin domain and act through transcriptional and/or translation dependent mechanisms. Engrailed has for instance, translation-dependent effects on axonal guidance and cerebral infusion of Engrailed protects dopaminergic neurons in a Parkinson disease model by increasing mitochondrial protein translation. Also, cognitive defects were observed in En1+/+ and En2-/- and En2 expression is increased in ASD patients. This work consisted in extending the knowledge of Engrailed expression and functions. We explored the links with a telencephalic structure where it is a priori fewly expressed (hippocampus). Our results confirm En1 and En2 expression in the mature hippocampus and describe their respective expression along the development of this structure. En1 and En2 have different expression patterns during the first post-natal week as well as in the adulthood suggesting a genetic dosage of Engrailed during the development, specifically with the beginning of synaptogenesis. We also reveal that Engrailed, expressed in hippocampal neurons, is more expressed in GABA-ergic neurons, notably in their dendritic and axonal neurites. We observe that an excess of Engrailed (described in some ASD cases) increases dendritic complexity as well as plastic dendritic spine density, without affecting mature excitatory synapses. We show that En2-/- and heterozygote En1 mice have variations in dendritic spine density, which confirms that Engrailed is involved either in their formation or stabilization. Even though our experiments show no modification of synapse density with an excess of Engrailed, a mutant showing a decreased eIF4E interaction and less efficient than wild type Engrailed to increase dendritic spine density, decreases presynaptic button density and synaptic matching. Those results indicate that eIF4E interaction with Engrailed is, at least in part, responsible for its effects on spinogenesis and suggest a role of Engrailed in presynaptic button formation/stabilization. Key-role of eIF4E in translation allow to hypothesize that some of Engrailed effects we report could be translation dependent. In this sense, our results show that Engrailed is able to increase proteic synthesis in hippocampal neurons. This translation is different from the one induced by chemical LTP (LTPc): it is not altered by synthetic AbO, which are the main toxic agent when produced at abnormally high levels in Alzheimer disease. Engrailed is also able to restore defaulting translation in neurons from Alzheimer disease mice model (TG2576). As a whole, our results identify Engrailed as a novel actor in dendritic plasticity. They reveal that an excess of Engrailed during synaptogenesis can modify dendrite characteristics. This can lead to dendritic network dysfunction in a context of pathologic surexpression of Engrailed. Our observations open to new perspectives contributing to a better understanding of the relationship between Engrailed and ASD. Finally, this work lays the foundation to potentially fruitful links between Engrailed and AbOligomers signalling pathways, where modulation of protein synthesis could be a therapeutic lever in physiopathologic conditions.PARIS5-Bibliotheque electronique (751069902) / SudocSudocFranceF

Double In Situ Hybridization Reveals Overlapping Neuronal Populations Expressing the Low Molecular Weight GTPases Rab3a and Rab3b in Rat Brain

International audienceThe ras-related Rab3 gene subfamily codes for small GTP-binding proteins which control a late step of exocytosis during which vesicles become docked to the plasma membrane. Rab3a and Rab3b are the most abundant Rab3 isoforms expressed in the CNS of mammals. We have shown previously that the Rab3a protein was selectively distributed and expressed in various regions of the rat brain. Here we have determined the pattern of expression of Rab3b mRNA in the brain and compared it with that of Rab3a mRNA. In addition, we examined the co-expression of these two Rab within individual neurons. In general the Rab3b transcript was detected in many regions which also express Rab3a mRNA but at a lower level than Rab3a, except in the olfactory bulb and in the pituitary where the Rab3b hybridization signal was similar and higher respectively. Double in situ hybridization revealed that Rab3a and Rab3b mRNAs were co-localized in most neurons, in all brain areas examined. However, in each of these areas, subsets of neurons appeared to preferentially express either Rab3b or Rab3a, or some neurons did not express either Rab3 homologue at detectable levels. These data support the view of a functional specialization of Rab3a and Rab3b in the control of exocytosis in neuronal and neuroendocrine cells