Urinary Interleukin-8 Is a Biomarker of Stress in Emergency Physicians,Especially with Advancing Age — The JOBSTRESS* Randomized Trial

Background

Emergency physicians are exposed to greater stress during a 24-hour shift (24 hS) than a 14-hour night shift (14 hS), with an impact lasting several days. Interleukin-8 (IL-8) is postulated to be a chronic stress biomarker. However, no studies have tracked IL-8 over several shifts or used it for monitoring short-term residual stress. The IL-8 response to the shifts may also increase with age. Conveniently, IL-8 can be measured non-intrusively from urine.

Methods

We conducted a shifts-randomized trial comparing 17 emergency physicians’ urinary IL-8 levels during a 24 hS, a 14 hS, and a control day (clerical work on return from leave). Mean levels of IL-8 were compared using a Wilcoxon matched-pairs test. Independent associations of key factors including shifts, stress, and age with IL-8 levels were further assessed in a multivariable generalized estimating equations model.

Results

Mean urinary IL-8 levels almost doubled during and after a 24 hS compared with a 14 hS or a control day. Furthermore, IL-8 levels failed to return to control values at the end of the third day after the shift despite a rest day following the 24 hS. In the multivariable model, engaging in a 24 hS, self-reported stress, and age were independently associated with higher IL-8 levels. A 24 hS significantly increased IL-8 levels by 1.9 ng (p = .007). Similarly, for every unit increase in self-reported stress, there was a 0.11 ng increase in IL-8 levels (p = .003); and for every one year advance in age of physicians, IL-8 levels also increased by 0.11 ng (p = .018).

Conclusion

The 24 hS generated a prolonged response of the immune system. Urinary IL-8 was a strong biomarker of stress under intensive and prolonged demands, both acutely and over time. Because elevated IL-8 levels are associated with cardiovascular disease and negative psychological consequences, we suggest that emergency physicians limit their exposure to 24 hS, especially with advancing age.     

Repeated oral administration of capsaicin increases anxiety-like behaviours with prolonged stress-response in rats

This study was conducted to examine the psycho-emotional effects of repeated oral exposure to capsaicin, the principal active component of chili peppers. Each rat received 1 mL of 0.02% capsaicin into its oral cavity daily, and was subjected to behavioural tests following 10 daily administrations of capsaicin. Stereotypy counts and rostral grooming were significantly increased, and caudal grooming decreased, in capsaicin-treated rats during the ambulatory activity test. In elevated plus maze test, not only the time spent in open arms but also the percent arm entry into open arms was reduced in capsaicin-treated rats compared with control rats. In forced swim test, although swimming duration was decreased, struggling increased in the capsaicin group, immobility duration did not differ between the groups. Repeated oral capsaicin did not affect the basal levels of plasma corticosterone; however, the stress-induced elevation of plasma corticosterone was prolonged in capsaicin treated rats. Oral capsaicin exposure significantly increased c-Fos expression not only in the nucleus tractus of solitarius but also in the paraventricular nucleus. Results suggest that repeated oral exposure to capsaicin increases anxiety-like behaviours in rats, and dysfunction of the hypothalamic-pituitary-adrenal axis may play a role in its pathophysiology.     

Long-term treadmill exercise improves spatial memory of male APPswe/PS1dE9 mice by regulation of BDNF expression and microglia activation

Increasing evidence suggests that physical activity could delay or attenuate the symptoms of Alzheimer''s disease (AD). But the underlying mechanisms are still not fully understood. To investigate the effect of long-term treadmill exercise on the spatial memory of AD mice and the possible role of β-amyloid, brain-derived neurotrophic factor (BDNF) and microglia in the effect, male APPswe/PS1dE9 AD mice aged 4 months were subjected to treadmill exercise for 5 months with 6 sessions per week and gradually increased load. A Morris water maze was used to evaluate the spatial memory. Expression levels of β-amyloid, BDNF and Iba-1 (a microglia marker) in brain tissue were detected by immunohistochemistry. Sedentary AD mice and wildtype C57BL/6J mice served as controls. The results showed that 5-month treadmill exercise significantly decreased the escape latencies (P < 0.01 on the 4th day) and improved the spatial memory of the AD mice in the water maze test. Meanwhile, treadmill exercise significantly increased the number of BDNF-positive cells and decreased the ratios of activated microglia in both the cerebral cortex and the hippocampus. However, treadmill exercise did not significantly alleviate the accumulation of β-amyloid in either the cerebral cortex or the hippocampus of the AD mice (P > 0.05). The study suggested that long-term treadmill exercise could improve the spatial memory of the male APPswe/PS1dE9 AD mice. The increase in BDNF-positive cells and decrease in activated microglia might underpin the beneficial effect.     

Neurogenic potential of the vestibular nuclei and behavioural recovery time course in the adult cat are governed by the nature of the vestibular damage

Functional and reactive neurogenesis and astrogenesis are observed in deafferented vestibular nuclei after unilateral vestibular nerve section in adult cats. The newborn cells survive up to one month and contribute actively to the successful recovery of posturo-locomotor functions. This study investigates whether the nature of vestibular deafferentation has an incidence on the neurogenic potential of the vestibular nuclei, and on the time course of behavioural recovery. Three animal models that mimic different vestibular pathologies were used: unilateral and permanent suppression of vestibular input by unilateral vestibular neurectomy (UVN), or by unilateral labyrinthectomy (UL, the mechanical destruction of peripheral vestibular receptors), or unilateral and reversible blockade of vestibular nerve input using tetrodotoxin (TTX). Neurogenesis and astrogenesis were revealed in the vestibular nuclei using bromodeoxyuridine (BrdU) as a newborn cell marker, while glial fibrillary acidic protein (GFAP) and glutamate decarboxylase 67 (GAD67) were used to identify astrocytes and GABAergic neurons, respectively. Spontaneous nystagmus and posturo-locomotor tests (static and dynamic balance performance) were carried out to quantify the behavioural recovery process. Results showed that the nature of vestibular loss determined the cellular plastic events occurring in the vestibular nuclei and affected the time course of behavioural recovery. Interestingly, the deafferented vestibular nuclei express neurogenic potential after acute and total vestibular loss only (UVN), while non-structural plastic processes are involved when the vestibular deafferentation is less drastic (UL, TTX). This is the first experimental evidence that the vestibular complex in the brainstem can become neurogenic under specific injury. These new data are of interest for understanding the factors favouring the expression of functional neurogenesis in adult mammals in a brain repair perspective, and are of clinical relevance in vestibular pathology.     

Influence of colloid, preservation medium and trimetazidine on renal medulla injury

In organ transplantation, preservation injury is an important factor which could influence short-term and long-term graft outcome. The renal medulla is particularly sensitive to oxidant stress and ischemia-reperfusion injury (IRI). Using an autotransplant pig kidney model, we investigated renal function and medullary damage determined between day 1 and week 2 after 24- or 48-h cold storage in different preservation solutions: University of Wisconsin solution (UW), Hopital Edouard Herriot solution (a high Na+ version of UW), ECPEG (high Na+ preservation solution with PEG) and ICPEG (a high K+ version of ECPEG) with or without trimetazidine (TMZ). TMZ improved renal preservation and increased renal function when added in each preservation solution (particularly HEH and ECPEG). Medullary damage led to the early appearance of trimethylamine-N-oxide (TMAO) followed by 1H-NMR in urine and plasma. TMZ and ECPEG is the most efficient association to reduce medullary damage. This study clarifies the role of colloid and polarity solution and the role of mitochondrial protection by TMZ.     

Efficient selection of branch-specific models of sequence evolution

The analysis of extant sequences shows that molecular evolution has been heterogeneous through time and among lineages. However, for a given sequence alignment, it is often difficult to uncover what factors caused this heterogeneity. In fact, identifying and characterizing heterogeneous patterns of molecular evolution along a phylogenetic tree is very challenging, for lack of appropriate methods. Users either have to a priori define groups of branches along which they believe molecular evolution has been similar or have to allow each branch to have its own pattern of molecular evolution. The first approach assumes prior knowledge that is seldom available, and the second requires estimating an unreasonably large number of parameters. Here we propose a convenient and reliable approach where branches get clustered by their pattern of molecular evolution alone, with no need for prior knowledge about the data set under study. Model selection is achieved in a statistical framework and therefore avoids overparameterization. We rely on substitution mapping for efficiency and present two clustering approaches, depending on whether or not we expect neighbouring branches to share more similar patterns of sequence evolution than distant branches. We validate our method on simulations and test it on four previously published data sets. We find that our method correctly groups branches sharing similar equilibrium GC contents in a data set of ribosomal RNAs and recovers expected footprints of selection through dN/dS. Importantly, it also uncovers a new pattern of relaxed selection in a phylogeny of Mantellid frogs, which we are able to correlate to life-history traits. This shows that our programs should be very useful to study patterns of molecular evolution and reveal new correlations between sequence and species evolution. Our programs can run on DNA, RNA, codon, or amino acid sequences with a large set of possible models of substitutions and are available at http://biopp.univ-montp2.fr/forge/testnh.     

NMR metabolomic of frontal cortex extracts: First study comparing two neurodegenerative diseases,Alzheimer disease and amyotrophic lateral sclerosis

ObjectiveThis study was designed to assess the brain metabolites’ variability between two neurodegenerative diseases in frontal cortex samples obtained post-mortem. NMR metabolomics was used for the first time in this context.Materials and methods¹H NMR metabolomic was applied to tissue extracts from patients with Alzheimer disease (ALZ) and patients with amyotrophic lateral sclerosis (ALS) to investigate qualitative and quantitative variations of brain metabolites.ResultsThe Alzheimer disease metabolic signature was characterized by a high concentration of alanine, acetate, glutamate and glutamine, and low concentrations of lactate and creatine, while the ALS metabolic signature appears to be marked by high concentrations of lactate, N-acetyl aspartate, creatine, choline and myo-inositol. Moreover, in vitro ¹H NMR could detect metabolites such as 3-hydroxybutyrate, alanine, succinate and aspartate that cannot be detected with in vivo NMR.DiscussionThe neurodegenerative diseases exhibit diverging metabolic pathways. Some of the metabolites responsible for the discrimination between the two diseases were detected before in vivo. However, this in vitro metabolomic investigation demonstrates the involvement of metabolites not detected with in vivo studies.ConclusionUpon these findings, in vitro metabolomics appears to be an efficient tool to investigate the fundamentals of the metabolic pathway modulations in these neurodegenerative diseases to help the interpretation of clinical data obtained with in vivo NMR spectroscopy.     

Detecting Site-Specific Biochemical Constraints Through Substitution Mapping

The neutral theory of molecular evolution states that most mutations are deleterious or neutral. It results that the evolutionary rate of a given position in an alignment is a function of the level of constraint acting on this position. Inferring evolutionary rates from a set of aligned sequences is hence a powerful method to detect functionally and/or structurally important positions in a protein. Some positions, however, may be constrained while having a high substitution rate, providing these substitutions do not affect the biochemical property under constraint. Here, I introduce a new evolutionary rate measure accounting for the evolution of specific biochemical properties (e.g., volume, polarity, and charge). I then present a new statistical method based on the comparison of two rate measures: a site is said to be constrained for property X if it shows an unexpectedly high conservation of X knowing its total evolutionary rate. Compared to single-rate methods, the two-rate method offers several advantages: it (i) allows assessment of the significance of the constraint, (ii) provides information on the type of constraint acting on each position, and (iii) detects positions that are not proposed by previous methods. I apply this method to a 200-sequence data set of triosephosphate isomerase and report significant cases of positions constrained for polarity, volume, or charge. The three-dimensional localization of these positions shows that they are of potential interest to the molecular evolutionist and to the biochemist.     

Lakeside cemeteries in the Sahara: 5000 years of holocene population and environmental change

Background

Approximately two hundred human burials were discovered on the edge of a paleolake in Niger that provide a uniquely preserved record of human occupation in the Sahara during the Holocene (∼8000 B.C.E. to the present). Called Gobero, this suite of closely spaced sites chronicles the rapid pace of biosocial change in the southern Sahara in response to severe climatic fluctuation.

Methodology/Principal Findings

Two main occupational phases are identified that correspond with humid intervals in the early and mid-Holocene, based on 78 direct AMS radiocarbon dates on human remains, fauna and artifacts, as well as 9 OSL dates on paleodune sand. The older occupants have craniofacial dimensions that demonstrate similarities with mid-Holocene occupants of the southern Sahara and Late Pleistocene to early Holocene inhabitants of the Maghreb. Their hyperflexed burials compose the earliest cemetery in the Sahara dating to ∼7500 B.C.E. These early occupants abandon the area under arid conditions and, when humid conditions return ∼4600 B.C.E., are replaced by a more gracile people with elaborated grave goods including animal bone and ivory ornaments.

Conclusions/Significance

The principal significance of Gobero lies in its extraordinary human, faunal, and archaeological record, from which we conclude the following:

1. The early Holocene occupants at Gobero (7700–6200 B.C.E.) were largely sedentary hunter-fisher-gatherers with lakeside funerary sites that include the earliest recorded cemetery in the Sahara.
2. Principal components analysis of craniometric variables closely allies the early Holocene occupants at Gobero with a skeletally robust, trans-Saharan assemblage of Late Pleistocene to mid-Holocene human populations from the Maghreb and southern Sahara.
3. Gobero was abandoned during a period of severe aridification possibly as long as one millennium (6200–5200 B.C.E).
4. More gracile humans arrived in the mid-Holocene (5200–2500 B.C.E.) employing a diversified subsistence economy based on clams, fish, and savanna vertebrates as well as some cattle husbandry.
5. Population replacement after a harsh arid hiatus is the most likely explanation for the occupational sequence at Gobero.
6. We are just beginning to understand the anatomical and cultural diversity that existed within the Sahara during the Holocene.