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The ongoing translational and reproducibility crisis dominates preclinical research today as results from animal studies often disappoint when transferred to human clinical studies. This problem is especially relevant in the field of brain diseases and translational neuropsychiatry.
Here, we discuss if the 3R concept could be part of the translational crisis.
The focus has been on the second R, which is to reduce the variation between the experimental animals, so that the number of animals per study can be reduced. However, the risk of obtaining false results has also increased. We, therefore, recommend that researchers use a broader perspective as also suggest by Russell and Burch who founded the 3Rs when considering the 3R concept, which involves the translational aspects described in detail in their 3R book from 1959.
This may together with systematic reviews and well-designed and well-performed animal studies and accurate reporting of the results indeed contribute to solving the translational crisis in preclinical research.
Experimental studies have reported on the anti-inflammatory properties of polyphenols. However, results from epidemiological investigations have been inconsistent, and especially studies using biomarkers for assessment of polyphenol intake have been scant. We aimed to characterize the association between plasma concentrations of 35 polyphenol compounds and low-grade systemic inflammation state as measured by high-sensitivity C-reactive protein (hsCRP). A cross-sectional data analysis was performed based on 315 participants in the European Prospective Investigation into Cancer and Nutrition cohort with available measurements of plasma polyphenols and hsCRP. In logistic regression analysis the odds and 95% confidence intervals (CI-s) of elevated serum hsCRP (>3 mg/L) were calculated within quartiles and per standard deviation (SD) higher level of plasma polyphenol concentrations. In multivariable-adjusted model, the sum of plasma concentrations of all polyphenols measured (per SD) was associated with 29% lower odds of elevated hsCRP (95% CI: 50%-1%). In the class of flavonoids, daidzein was inversely associated with elevated hsCRP (OR= 0.66, 95%CI 0.46-0.96). Among phenolic acids, statistically significant associations were observed for 3,5-dihydroxyphenylpropionic acid (OR=0.58, 95%CI 0.39-0.86), 3,4-dihydroxyphenylpropionic acid (OR= 0.63, 95% CI 0.46-0.87), ferulic acid (OR= 0.65, 95%CI 0.44-0.96), and caffeic acid (OR= 0.69, 95%CI 0.51-0.93). The odds of elevated hsCRP were significantly reduced for hydroxytyrosol (OR= 0.67, 95%CI 0.48-0.93). This study showed that polyphenol biomarkers are associated with lower odds of elevated hsCRP. Whether diet rich in bioactive polyphenol compounds could be an effective strategy to prevent or modulate deleterious health effects of inflammation should be addressed by further well-powered longitudinal studies.
The USA is the largest consumer of legally, internationally-traded wildlife. A proportion of this trade consists of species listed in the Appendices of CITES, and recorded in the CITES Trade Database. Using this resource, we quantified wildlife entering the USA for 82 of the most frequently recorded wildlife products and a range of taxonomic groups during 1979–2014. We examined trends in legal trade and seizures of illegally traded items over time, and relationships between trade and four national measures of biodiversity. We found that: (1) there is an overall positive relationship between legal imports and seizures; (2) Asia was the main region exporting CITES-listed wildlife products to the USA; (3) bears, crocodilians and other mammals (i.e. other than Ursidae, Felidae, Cetacea, Proboscidea, Primates or Rhinocerotidae) increased in both reported legal trade and seizures over time; (4) legal trade in live specimens was reported to be primarily from captive-produced, artificially-propagated or ranched sources, whereas traded meat was primarily wild sourced; (5) both seizures and legally traded items of felids and elephants decreased over time; and (6) volumes of both legally traded and seized species were correlated with four attributes of exporting countries: species endemism, species richness, number of IUCN threatened species, and country size. The goal of our analysis was to inform CITES decision-making and species conservation efforts.
The recent observations of ferromagnetic order in several two-dimensional (2D) materials have generated an enormous interest in the physical mechanisms underlying 2D magnetism. In the present Prospective Article, we show that Density Functional Theory combined with either classical Monte Carlo simulations or renormalized spin-wave theory can predict Curie temperatures for ferromagnetic insulators that are in quantitative agreement with experiments. The case of materials with in-plane anisotropy is then discussed, and it is argued that finite size effects may lead to observable magnetic order in macroscopic samples even if long range magnetic order is forbidden by the Mermin–Wagner theorem.
Atlantic salmon (Salmo salar) possess enzymes required for the endogenous biosynthesis of n-3 long-chain PUFA (LC-PUFA), EPA and DHA, from α-linolenic acid (ALA). Linoleic acid (LA) competes with ALA for LC-PUFA biosynthesis enzymes leading to the production of n-6 LC-PUFA, including arachidonic acid (ARA). We aimed to quantify the endogenous production of EPA and DHA from ALA in salmon fed from first feeding on diets that contain no EPA and DHA and to determine the influence of dietary LA and ALA:LA ratio on LC-PUFA production. Salmon were fed from first feeding for 22 weeks with three diets formulated with linseed and sunflower oils to provide ALA:LA ratios of approximately 3:1, 1:1 and 1:3. Endogenous production of n-3 LC-PUFA was 5·9, 4·4 and 2·8 mg per g fish and that of n-6 LC-PUFA was 0·2, 0·5 and 1·4 mg per g fish in salmon fed diets with ALA:LA ratios of 3:1, 1:1 and 1:3, respectively. The ratio of n-3:n-6 LC-PUFA production decreased from 27·4 to 2·0, and DHA:EPA ratio increased and EPA:ARA and DHA:ARA ratios decreased, as dietary ALA:LA ratio decreased. In conclusion, with a dietary ALA:LA ratio of 1, salmon fry/parr produced about 28 μg n-3 LC-PUFA per g fish per d, with a DHA:EPA ratio of 3·4. Production of n-3 LC-PUFA exceeded that of n-6 LC-PUFA by almost 9-fold. Reducing the dietary ALA:LA ratio reduced n-3 LC-PUFA production and EPA:ARA and DHA:ARA ratios but increased n-6 LC-PUFA production and DHA:EPA ratio.
Well-stratified Middle Palaeolithic assemblages are extremely rare in Mongolia. Initially investigated between the 1960s and 1990s, three major Middle Palaeolithic sites in the Orkhon Valley of central Mongolia yielded a large quantity of data and generated many research questions that still await answers. Re-investigation of these sites has uncovered chronostratigraphic and cultural sequences that may shed new light on human dispersal routes.
Women suffering from first onset postpartum mental disorders (PPMD) have a highly elevated risk of suicide. The current study aimed to: (1) describe the risk of self-harm among women with PPMD and (2) investigate the extent to which self-harm is associated with later suicide.
We conducted a register-based cohort study linking national Danish registers. This identified women with any recorded first inpatient or outpatient contact to a psychiatric facility within 90 days after giving birth to their first child. The main outcome of interest was defined as the first hospital-registered episode of self-harm. Our cohort consisted of 1 202 292 women representing 24 053 543 person-years at risk.
Among 1554 women with severe first onset PPMD, 64 had a first-ever hospital record of self-harm. Women with PPMD had a hazard ratio (HR) for self-harm of 6.2 (95% CI 4.9–8.0), compared to mothers without mental disorders; but self-harm risk was lower in PPMD women compared to mothers with non-PPMD [HR: 10.1, (95% CI 9.6–10.5)] and childless women with mental disorders [HR: 9.3 (95% CI 8.9–9.7)]. Women with PPMD and records of self-harm had a significantly greater risk for later suicide compared with all other groups of women in the cohort.
Women with PPMD had a high risk of self-harm, although lower than risks observed in other psychiatric patients. However, PPMD women who had self-harmed constituted a vulnerable group at significantly increased risk of later suicide.
Introduction: Although oral rehydration therapy is recommended for children with acute gastroenteritis (AGE) with none to some dehydration, intravenous (IV) rehydration is still commonly administered to these children in high-income countries. IV rehydration is associated with pain, anxiety, and emergency department (ED) revisits in children with AGE. A better understanding of the factors associated with IV rehydration is needed to inform knowledge translation strategies. Methods: This was a planned secondary analysis of the Pediatric Emergency Research Canada (PERC) and Pediatric Emergency Care Applied Research Network (PECARN) randomized, controlled trials of oral probiotics in children with AGE-associated diarrhea. Eligible children were aged 3-48 months and reported > 3 watery stools in a 24-hour period. The primary outcome was administration of IV rehydration at the index ED visit. We used mixed-effects logistic regression model to explore univariable and multivariable relationships between IV rehydration and a priori risk factors. Results: From the parent study sample of 1848 participants, 1846 had data available for analysis: mean (SD) age of 19.1 ± 11.4 months, 45.4% females. 70.2% (1292/1840) vomited within 24 hours of the index ED visit and 34.1% (629/1846) received ondansetron in the ED. 13.0% (240/1846) were administered IV rehydration at the index ED visit, and 3.6% (67/1842) were hospitalized. Multivariable predictors of IV rehydration were Clinical Dehydration Scale (CDS) score [compared to none: mild to moderate (OR: 8.1, CI: 5.5-11.8); severe (OR: 45.9, 95% CI: 20.1-104.7), P < 0.001], ondansetron in the ED (OR: 1.8, CI: 1.2-2.6, P = 0.003), previous healthcare visit for the same illness [compared to no prior visit: prior visit with no IV (OR: 1.9, 95% CI: 1.3-2.9); prior visit with IV (OR: 10.5, 95% CI: 3.2-34.8), P < 0.001], and country [compared to Canada: US (OR: 4.1, CI: 2.3-7.4, P < 0.001]. Significantly more participants returned to the ED with symptoms of AGE within 3 days if IV fluids were administered at the index visit [30/224 (13.4%) versus 88/1453 (6.1%), P < 0.001]. Conclusion: Higher CDS scores, antiemetic use, previous healthcare visits and country were independent predictors of IV rehydration which was also associated with increased ED revisits. Knowledge translation focused on optimizing the use of antiemetics (i.e. for those with dehydration) and reducing the geographic variation in IV rehydration use may improve the ED experience and reduce ED-revisits.
The contents of a pit located in the centre of a large communal structure at Asiab in the central Zagros mountains provides rare evidence for ritual food practices during the Early Neolithic (~9660–9300 cal. bc). This pit contained the skulls of at least 19 wild boars carefully placed inside and subsequently sealed. Antler from red deer and the skull of a brown bear were also concealed within the pit. The boars included both male and female animals varying in age and some of the larger canines were deliberately removed. Such a unique collection of remains is unlikely to be the result of day-to-day activities; instead, this represents a group of ritually interred bones. This new evidence strengthens views that activities reinforcing social cohesion were important as human society was approaching a juncture leading towards agricultural subsistence strategies.
The hunting of marine mammals as a source of subsistence, trade, and commercial revenue has formed an important part of human cultures across the North Atlantic. One important prey species has been the Atlantic walrus (Odobenus rosmarus rosmarus), sought after for meat, skin, blubber, ivory, and bone. Unfortunately, biological studies of current walrus populations and studies across the humanities and social sciences into past use and hunting of walruses, have been poorly integrated. Disciplinary boundaries have left a gap in understanding the reciprocal effects of human-walrus interactions. Emerging interdisciplinary methods offer new opportunities to write the historical ecology of Atlantic walruses. The integration of methods such as ancient DNA, isotopes, past population modelling, zooarchaeological assemblages, and ethnographic interviews can now be used to answer previously intractable questions. For example, how has walrus hunting shaped and been influenced by changes in human settlement and trade, what have been the cumulative impacts on walrus populations, the extent of anthropogenic selective pressures or the effect of changing hunting regimes on particular populations of walruses? New, collaborative research approaches applied to the wealth of Arctic archaeological faunal remains already housed in museum collections offer a unique chance to explore the past dynamics of human-animal interactions.
To Investigate the peripheral inflammatory profile in patients with mild cognitive impairment (MCI) from three subgroups – probable Lewy body disease (probable MCI-LB), possible Lewy body disease, and probable Alzheimer’s disease (probable MCI-AD) – as well as associations with clinical features.
Memory clinics and dementia services.
Patients were classified based on clinical symptoms as probable MCI-LB (n = 38), possible MCI-LB (n = 18), and probable MCI-AD (n = 21). Healthy comparison subjects were recruited (n = 20).
Ten cytokines were analyzed from plasma samples: interferon (IFN)-gamma, interleukin (IL)-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, and tumor necrosis factor (TNF)-alpha. C-reactive protein levels were investigated.
There was a higher level of IL-10, IL-1beta, IL-2, and IL-4 in MCI groups compared to the healthy comparison group (p < 0.0085). In exploratory analyses to understand these findings, the MC-AD group lower IL-1beta (p = 0.04), IL-2 (p = 0.009), and IL-4 (p = 0.012) were associated with increasing duration of memory symptoms, and in the probable MCI-LB group, lower levels of IL-1beta were associated with worsening motor severity (p = 0.002). In the possible MCI-LB, longer duration of memory symptoms was associated with lower levels of IL-1beta (p = 0.003) and IL-4 (p = 0.026).
There is increased peripheral inflammation in patients with MCI compared to healthy comparison subjects regardless of the MCI subtype. These possible associations with clinical features are consistent with other work showing that inflammation is increased in early disease but require replication. Such findings have importance for timing of putative therapeutic strategies aimed at lowering inflammation.
Les relations commerciales entre les habitants du Golfe Persique et ceux de Zanj ou Afrique orientale sont très anciennes: n'oublions pas non plus que Mascat et Zanzibar étaient liés par une union politique de 1690 environ jusqu'à 1861. On a souvent parlé de l'influence arabe sur les peuplades de la côte est d'Afrique; on a beaucoup moins parlé des conséquences de la présence de minorités importantes d'Africains dans les principautés arabes du Golfe.
La musique arabe de Kuwait, de Bahrain et de la Côte des Pirates n'est pas sensiblement influencée par les musiques africaines: la seule exception notable concerne les danses de guerres normalement appelées ardha à Bahrain, ayala sur la Côte des Pirates; les mélodies, les textes et les danses sont indiscutablement d'origine béouine mais l'influence africaine est sensible dans les rhythmes produits par le groupe de joueurs de tambour qui danse entre les deux rangs de chanteurs arabes.