Omega-3 Fatty Acids from Fish Oil Lower Anxiety, Improve Cognitive Functions and Reduce Spontaneous Locomotor Activity in a Non-Human Primate

Omega-3 (ω3) polyunsaturated fatty acids (PUFA) are major components of brain cells membranes. ω3 PUFA-deficient rodents exhibit severe cognitive impairments (learning, memory) that have been linked to alteration of brain glucose utilization or to changes in neurotransmission processes. ω3 PUFA supplementation has been shown to lower anxiety and to improve several cognitive parameters in rodents, while very few data are available in primates. In humans, little is known about the association between anxiety and ω3 fatty acids supplementation and data are divergent about their impact on cognitive functions. Therefore, the development of nutritional studies in non-human primates is needed to disclose whether a long-term supplementation with long-chain ω3 PUFA has an impact on behavioural and cognitive parameters, differently or not from rodents. We address the hypothesis that ω3 PUFA supplementation could lower anxiety and improve cognitive performances of the Grey Mouse Lemur (Microcebus murinus), a nocturnal Malagasy prosimian primate. Adult male mouse lemurs were fed for 5 months on a control diet or on a diet supplemented with long-chain ω3 PUFA (n = 6 per group). Behavioural, cognitive and motor performances were measured using an open field test to evaluate anxiety, a circular platform test to evaluate reference spatial memory, a spontaneous locomotor activity monitoring and a sensory-motor test. ω3-supplemented animals exhibited lower anxiety level compared to control animals, what was accompanied by better performances in a reference spatial memory task (80% of successful trials vs 35% in controls, p<0.05), while the spontaneous locomotor activity was reduced by 31% in ω3-supplemented animals (p<0.001), a parameter that can be linked with lowered anxiety. The long-term dietary ω3 PUFA supplementation positively impacts on anxiety and cognitive performances in the adult mouse lemur. The supplementation of human food with ω3 fatty acids may represent a valuable dietary strategy to improve behavioural and cognitive functions

ECMO for COVID-19 patients in Europe and Israel

Since March 15th, 2020, 177 centres from Europe and Israel have joined the study, routinely reporting on the ECMO support they provide to COVID-19 patients. The mean annual number of cases treated with ECMO in the participating centres before the pandemic (2019) was 55. The number of COVID-19 patients has increased rapidly each week reaching 1531 treated patients as of September 14th. The greatest number of cases has been reported from France (n = 385), UK (n = 193), Germany (n = 176), Spain (n = 166), and Italy (n = 136) .The mean age of treated patients was 52.6 years (range 16–80), 79% were male. The ECMO configuration used was VV in 91% of cases, VA in 5% and other in 4%. The mean PaO2 before ECMO implantation was 65 mmHg. The mean duration of ECMO support thus far has been 18 days and the mean ICU length of stay of these patients was 33 days. As of the 14th September, overall 841 patients have been weaned from ECMO support, 601 died during ECMO support, 71 died after withdrawal of ECMO, 79 are still receiving ECMO support and for 10 patients status n.a. . Our preliminary data suggest that patients placed on ECMO with severe refractory respiratory or cardiac failure secondary to COVID-19 have a reasonable (55%) chance of survival. Further extensive data analysis is expected to provide invaluable information on the demographics, severity of illness, indications and different ECMO management strategies in these patients

Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.

RATIONALE: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. OBJECTIVES: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 <80 or PaCO2 ≥60 mmHg). We controlled for confounding using a multivariable Cox model based on predefined variables. MAIN RESULTS: 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability at Day-7 from the onset of eligibility criteria (87% vs 83%, risk difference: 4%, 95% CI 0;9%) which decreased during follow-up (survival at Day-90: 63% vs 65%, risk difference: -2%, 95% CI -10;5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand, and when initiated within the first 4 days of MV and in profoundly hypoxemic patients. CONCLUSIONS: In an emulated trial based on a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and in regions with ECMO capacities specifically organized to handle high demand. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock

Multiple facets of membrane lipids and the diversity of their action mode with special emphasis on the central nervous system

This issue of Reproduction Nutrition Development was scheduled along with 8 papers on the metabolism of polyunsaturated fatty acids (PUFAs) and their physiological roles within the central nervous system. Topics focused on PUFAs from the n-3 series, especially on docosahexaenoic acid (DHA) which is particularly abundant in the cell membranes of brain and retina. Reviews and original articles emphasize the impact of n-3 PUFAs on the physical properties of membranes, the neuroprotective mechanisms via Ca2+ signalling in astrocytes, the n-3 status of infants suffering of Attention Deficit Hyperactivity Disorder (ADHD) and the mental development of neonates in relation with maternal feeding. The DHA metabolism in humans and its endogenous production from alpha-linolenic acid is reviewed. Besides, it is described and discussed how the generation of PUFA-derived mediators is modulated by the retinoic acid-receptor signalling via activation of cognate phospholipase activities. The sensitivity and recovering of neurons to oxidative stress is also addressed in this volume, through the description of a model of iron-induced injury in the rat brain. The diversity of these 8 articles illustrates the multiple roles of PUFAs within the central nervous system

Bilan du 7

The 7th congress was organized by the International Society For the Study of Fatty Acids and Lipids (ISSFAL) in Cairns (Australia) from 23 to 28 July 2006. It joined more than 400 delegates from 35 countries. The meeting included a plenary program, with 25 conferences and selected short communications, and 32 concurrent sessions in which around 300 free communications were presented (oral + posters). The primary themes explored several areas of research on lipids, fatty acids, metabolism and cerebral functions (3 sessions and 4 plenary conferences) with respect to maternal and infant health (3 sessions), ageing (1 session) and Alzheimer disease (1 session), omega-3 fatty acids and mental health (1 session), PUFA metabolism (3 sessions), the impact of dietary omega-3 and trans fatty acids on several pathologies such as obesity (1 session), cardiovascular disease and the metabolic syndrome (4 sessions and 3 plenary conferences), diabetes (1 session), cancer (1 session) and osteoporosis (1 session). Lastly, several concurrent sessions focused on methodological aspects for implementing new dietary sources of fatty acids (4 sessions)

La teneur en acides gras polyinsaturés du lait maternel : un marqueur biologique fiable du niveau de consommation des populations

Polyunsaturated fatty acids (PUFA) are nutritionally important constituents of breast milk to support normal growth, immune function and central nervous system development of newborn infants. Both linoleic acid (18:2 n-6; LA) and alpha-linolenic acid (18:3 n-3 ; ALA), the essential fatty acids, precursors of n-6 and n-3 long-chain PUFA. LA and LNA contents in human milk reflect differences in dietary fats consumed by the mothers, including those consumed during several months (long term impact). The composition of breast milk from this point of view is a reliable biological marker of the level of habitual consumption of PUFAs in different populations. An increase of LA content for the 1950-1990 period, without any change of LNA content, has been reported in breast milk of women living in western countries, reflecting changes in LA intake by the mother

Place des lipides dans l’alimentation du nourrisson

The rapid growth of the neonate requires a high intake of both energy and lipids. Fatty acids may play an important role in the brain development and in the etiology of several disorders in children and adults. Most of infant formulas currently marketed have a fatty acid profile globally mimicking that of the ‘‘gold reference’’, the human milk. However several issues remain to be improved to optimizing their lipid status: Structure of the fat globule. Fat globules of human milk differ from those of infant formulas by their larger size and the presence of a phospholipid membrane. Recent experimental data in animal models of infant nutrition suggest that this specificity of natural milk may prevent the development of the metabolic syndrome. In addition, palmitic acid is mainly esterified in the sn-2 position of triglycerides in human milk, versus in the sn-1 and sn-3 positions in infant formulas. This sn-2 esterification may favor the intestinal absorption of other fatty acids and then their tissue bioavailability ; PUFA metabolism. The exclusive use of vegetable oils in infant formulas has increased the content of both polyunsaturated fatty acid precursors (linoleic and a-linolenic acids). However, several studies have led to the observation that high PUFA contents in formulas may reduce the incorporation of docosahexaenoic acid in tissues ; N-6 PUFA intake and obesity. In western countries, the increasing incidence of obesity has coincided with the gradual increase of n-6 PUFA from food and, incidentally, from an n-6/n-3 imbalance. Animal studies have recently shown that high linoleic acid intake and high ratio of linoleic to a-linolenic acids during the perinatal period activate the adipose tissue growth in the young and adult. To date, two observational studies confirm the existence of a link between the n-6/n-3 ratio in cord or the n-6 content in maternal plasma and adiposity in 3-7 years old infants

Analysis of the 2nd symposium “Anomalies of fatty acids, ageing and degenerating pathologies”

The second symposium on anomalies of fatty acids, ageing and degenerating pathologies for the French-speaking community was held during January 2002 in Paris (France) and reunited more than 200 participants, including a majority of medical practitioners. It was organised around 8 conferences treating the following subjects: a general presentation of the metabolism of fatty acids and their biological functions (in particular polyunsaturated fatty acids or PUFA), the exploration of PUFA in man during situations of nutritional and pathological disequilibrium, and the importance of PUFA in the aetiology and prevention of pathophysiologies such as cardiovascular, autoimmune and inflammatory diseases, diabetes and obesity, cancer and certain neuropsychiatric affections such as depression. Indeed, even though edible fatty acids present a common energetic function, by $\beta$-oxidation, and a structural function, as a constituent of membrane lipids, some of them have a more specific role as an essential nutrient. These are essential fatty acids including the two families of polyunsaturated fatty acids (n-6 and n-3 PUFA). Their metabolism leads to the synthesis of derivatives found in cellular membranes (structural role) and oxygenated molecules, the eicosanoids, whose main action is of the same type as that of hormones. These derivatives and oxygenated molecules also regulate different metabolic pathways by modulating the expression of target genes via activation of specific transcription factors. Due to their quality and their quantity in food, the PUFA may interfere with the incidence of a large number of pathologies whose causes are varied (cardiovascular and inflammatory diseases, cancers, neuropathologies, …). The particular interest in nutrition of PUFA of the n-3 series (or $\omega$3) and in particular of long-chain derivatives mainly found in high quantity in fish oils (eicosapentaenoic acid and docosahexaenoic acid) is now widely confirmed for cardiovascular and inflammatory physiology and formed the subject of increasing investigations for prevention of certain pathologies of the central nervous system. In this paper, we are first going to recall the generalities of metabolism and functional properties of PUFA. Secondly, we will list the pathologies whose frequency and symptoms are susceptible to be corrected by the dietary intake of PUFA, notably by reaching the nutritional equilibrium between the family of linoleic acid (n-6 or $\omega$6) and that of $\alpha$-linolenic acid (n-3 or $\omega$3)