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Abstract Obstructive sleep apnea (OSA) is characterized by chronic intermittent hypoxemia, which is associated with progressive loss of kidney function, where postprandial fluctuations in renal physiology may further compromise oxygen supply and kidney function. Therefore, we measured biomarkers of acute kidney injury (AKI) following a high‐fat meal with and without intermittent hypoxemia. Eighteen healthy young men (mean age [SD]: 22.7 years [3.1]) and seven middle‐aged to older individuals with OSA (54.4 years [6.4]) consumed a high‐fat meal during normoxia or intermittent hypoxemia (~15 hypoxic cycles per hour, ~85% oxyhemoglobin saturation) for 6 h. We observed no changes in estimated glomerular filtration rate and plasma concentrations of creatinine, neutrophil gelatinase‐associated lipocalin (NGAL), and kidney injury molecule‐1 (KIM‐1) at any measured time points. In both groups, plasma concentrations of interleukin‐18 (IL‐18) increased after 6 h during normoxia only (p = 0.033, ηp2 = 0.122), and plasma concentrations of liver‐type fatty acid‐binding protein (L‐FABP) transiently decreased after 3 h in both conditions (p = 0.008, ηp2 = 0.152). These findings indicate that AKI biomarkers are not acutely elevated during the postprandial state with or without intermittent hypoxemia, suggesting that other mechanisms may play more important roles in the progression of kidney disease in OSA.

Abstract Psychotic disorders are currently diagnosed by examining the patient’s mental state and medical history. Identifying reliable diagnostic, monitoring, predictive, or prognostic biomarkers would be useful in clinical settings and help to understand the pathophysiology of schizophrenia. Here, we performed an untargeted metabolomics analysis using ultra-high pressure liquid chromatography coupled with time-of-flight mass spectroscopy on cerebrospinal fluid (CSF) and serum samples of 25 patients at their first-episode psychosis (FEP) manifestation (baseline) and after 18 months (follow-up). CSF and serum samples of 21 healthy control (HC) subjects were also analyzed. By comparing FEP and HC groups at baseline, we found eight CSF and 32 serum psychosis-associated metabolites with non-redundant identifications. Most remarkable was the finding of increased CSF serotonin (5-HT) levels. Most metabolites identified at baseline did not differ between groups at 18-month follow-up with significant improvement of positive symptoms and cognitive functions. Comparing FEP patients at baseline and 18-month follow-up, we identified 20 CSF metabolites and 90 serum metabolites that changed at follow-up. We further utilized Ingenuity Pathway Analysis (IPA) and identified candidate signaling pathways involved in psychosis pathogenesis and progression. In an extended cohort, we validated that CSF 5-HT levels were higher in FEP patients than in HC at baseline by reversed-phase high-pressure liquid chromatography. To conclude, these findings provide insights into the pathophysiology of psychosis and identify potential psychosis-associated biomarkers.

Persistent organic pollutants (POPs) accumulation and hypoxia are two factors proposed to adversely alter adipose tissue (AT) functions in the context of excess adiposity. Studies have shown that preadipocytes exposure to dioxin and dioxin-like POPs have the greatest deleterious impact on rodent and immortalized human preadipocyte differentiation, but evidence on human preadipocytes is lacking. Additionally, hypoxia is known to strongly interfere with the dioxin-response pathway. Therefore, we tested the effects of pre-differentiation polychlorinated biphenyl (PCB)126 exposure at 10 µM for 3 days and subsequent differentiation under hypoxia on human subcutaneous adipocytes (hSA) differentiation, glucose uptake and expression of selected metabolism- and inflammation-related genes. Pre-differentiation PCB126 exposure lowered the adenosine triphosphate (ATP) content, glucose uptake and leptin expression of mature adipocytes but had limited effects on differentiation under normoxia (21% O2). Under hypoxia (3% O2), preadipocytes ability to differentiate was significantly reduced as reflected by significant decreased lipid accumulation and downregulation of key adipocyte genes such as peroxisome proliferator-activated receptor gamma (PPARγ) and adiponectin. Hypoxia increased glucose uptake and glucose transporter 1 (GLUT1) expression but abolished the adipocytes insulin response and GLUT4 expression. The expression of pro-inflammatory adipokine interleukin-6 (IL-6) was slightly increased by both PCB126 and hypoxia, while IL-8 expression was significantly increased only following the PCB126-hypoxia sequence. These observations suggest that PCB126 does not affect human preadipocyte differentiation, but does affect the subsequent adipocytes population, as reflected by lower ATP levels and absolute glucose uptake. On the other hand, PCB126 and hypoxia exert additive effects on AT inflammation, an important player in the development of chronic diseases such as type 2 diabetes and cardiovascular diseases.

Free sugars overconsumption is associated with an increased prevalence of risk factors for metabolic diseases such as the alteration of the blood lipid levels. Natural fruit juices have a free sugar composition quite similar to that of sugar-sweetened beverages. Thus, could fruit juice consumption lead to the same adverse effects on health as sweetened beverages? We attempted to answer this question by reviewing the available evidence on the health effects of both sugar-sweetened beverages and natural fruit juices. We determined that, despite the similarity of fruits juices to sugar-sweetened beverages in terms of free sugars content, it remains unclear whether they lead to the same metabolic consequences if consumed in equal dose. Important discrepancies between studies, such as type of fruit juice, dose, duration, study design, and measured outcomes, make it impossible to provide evidence-based public recommendations as to whether the consumption of fruit juices alters the blood lipid profile. More randomized controlled trials comparing the metabolic effects of fruit juice and sugar-sweetened beverage consumption are needed to shape accurate public health guidelines on the variety and quantity of free sugars in our diet that would help to prevent the development of obesity and related health problems.

Abstract Background Transposable element-embedded regulatory sequences (TEeRS) and their KRAB-containing zinc finger protein (KZFP) controllers are increasingly recognized as modulators of gene expression. We aim to characterize the contribution of this system to gene regulation in early human development and germ cells. Results Here, after studying genes driven by the long terminal repeat (LTR) of endogenous retroviruses, we identify the ape-restricted ZNF676 as the sequence-specific repressor of a subset of contemporary LTR12 integrants responsible for a large fraction of transpochimeric gene transcripts (TcGTs) generated during human early embryogenesis. We go on to reveal that the binding of this KZFP correlates with the epigenetic marking of these TEeRS in the germline, and is crucial to the control of genes involved in ciliogenesis/flagellogenesis, a biological process that dates back to the last common ancestor of eukaryotes. Conclusion These results illustrate how KZFPs and their TE targets contribute to the evolutionary turnover of transcription networks and participate in the transgenerational inheritance of epigenetic traits.

Abstract Background Obstructive sleep apnea (OSA), a sleep disorder frequently observed in individuals living with obesity, consists of repeated involuntary breathing obstructions during sleep, leading to intermittent hypoxia (IH). In humans, acute continuous hypoxia slightly increases plasma triglycerides (TG). However, no study yet compared the postprandial TG response of individuals with or without OSA under intermittent hypoxia. Methods Using a randomized crossover design, seven individuals diagnosed with moderate OSA and eight healthy individuals without OSA were given a meal after which they were exposed for 6 h to normoxia or intermittent hypoxia (e.g., 15 hypoxic events per hour). Blood lipid levels were measured hourly during each session. Results Peak postprandial TG concentrations tended to be 22% higher under IH irrespective of group (IH × time interaction, p = 0.068). This trend toward higher total plasma TG was attributable to increased levels of denser TG-rich lipoproteins such as very low-density lipoproteins (VLDL) and chylomicrons (CM) remnants. Irrespective of group, the postprandial TG concentrations in denser TG-rich lipoproteins was 20% higher under IH (IH × time interaction, p = 0.036), although IH had virtually no impact on denser TG-rich lipoprotein concentrations in the OSA group. Conclusion Acute intermittent hypoxia tends to negatively affect postprandial TG levels in healthy individuals, which is attributable to an increase in denser TG-carrying lipoprotein levels such as VLDL and CM remnants. This altered postprandial TG response to acute intermittent hypoxia was not observed in individuals with OSA.

Introduction: Acute hypoxia is known to increase circulating nonesterified fatty acid (NEFA) levels. Adipose tissue lipolysis is a major source of NEFA into circulation and insulin suppresses this process when the tissue is insulin sensitive. NEFA can be esterified to triglycerides and/or completely/partially oxidized, the latter leading to ketogenesis in the liver. To our knowledge, the effect of hypoxia on ketogenesis, more specifically ß-hydroxybutyrate (ßOHB) levels, remains unknown in humans. Therefore, the objective of this study was to determine the effect of acute intermittent and continuous hypoxia on circulating ßOHB levels under different feeding status.Methods: Plasma samples from three different randomized crossover studies were assessed for ßOHB concentrations. In the first study, 14 healthy men (23 ± 3.5 years) were exposed to 6 h of normoxia or intermittent hypoxia (IH-Fed) (15 hypoxic events/hour) following an isocaloric meal. In the second study, 10 healthy men (26 ± 5.6 years) were exposed to 6 h of continuous normobaric hypoxia (CH-Fasted) (FiO2 = 0.12) or normoxia in the fasting state. In the third study (CH-Fed), 9 healthy men (24 ± 4.5 years) were exposed to 6 h of normoxia or CH in a constant prandial state. ßOHB, NEFA and insulin levels were measured during all sessions.Results: In the IH-Fed study, ßOHB and NEFA levels tended to be greater over 6 h of IH (condition × time interaction, ßOHB p = 0.108 and NEFA p = 0.062) compared to normoxia. In the CH-Fasted study, ßOHB and NEFA levels increased over time in both experimental conditions, this effect being greater under CH (condition × time interaction, ßOHB p = 0.070; NEFA p = 0.046). In the CH-Fed study, ßOHB levels slightly increased up to 180 min before falling back to initial concentrations by the end of the protocol in both normoxia and CH (main effect of time, p = 0.062), while NEFA were significantly higher under CH (p = 0.006).Conclusion: Acute normobaric hypoxia exposure tends to increase plasma ßOHB concentrations over time in healthy men. The stimulating effect of hypoxia on plasma ßOHB levels is however attenuated during postprandial and prandial states.

PRDM9 binding localizes almost all meiotic recombination sites in humans and mice. However, most PRDM9-bound loci do not become recombination hotspots. To explore factors that affect binding and subsequent recombination outcomes, we mapped human PRDM9 binding sites in a transfected human cell line and measured PRDM9-induced histone modifications. These data reveal varied DNA-binding modalities of PRDM9. We also find that human PRDM9 frequently binds promoters, despite their low recombination rates, and it can activate expression of a small number of genes including CTCFL and VCX. Furthermore, we identify specific sequence motifs that predict consistent, localized meiotic recombination suppression around a subset of PRDM9 binding sites. These motifs strongly associate with KRAB-ZNF protein binding, TRIM28 recruitment, and specific histone modifications. Finally, we demonstrate that, in addition to binding DNA, PRDM9's zinc fingers also mediate its multimerization, and we show that a pair of highly diverged alleles preferentially form homo-multimers.

In nephrology, point-of-care ultrasound (POCUS) has multiple applications including the rapid evaluation of acute kidney injury, enhancing the initial evaluation of chronic kidney disease, direct evaluation of vascular access, and improved fluid balance management in acute and chronic settings [1, 2]. Recently, the role of POCUS has been formally acknowledged by the American College of Physicians and curricula specific to nephrology have been proposed [3, 4]. However, the integration of a novel clinical skill into a field comes with its unique set of challenges. Above all, most nephrologists in leadership roles within fellowship training programs lack POCUS experience, which represent a significant barrier for adequate exposure and teaching. Although educational curriculum centered on nephrology have been proposed, the optimal model to ensure adequate POCUS exposure considering the scarcity of expertise among educators is not known.

An amendment to this paper has been published and can be accessed via the original article.

Hypoxia is a condition during which the body or specific tissues are deprived of oxygen. This phenomenon can occur in response to exposure to hypoxic environmental conditions such as high-altitude, or because of pathophysiological conditions such as obstructive sleep apnea. Circumstances such as these can restrict supply or increase consumption of oxygen, leading to oxyhemoglobin desaturation and tissue hypoxia. In certain cases, hypoxia may lead to severe health consequences such as an increased risk of developing cardiovascular diseases and type 2 diabetes. A potential explanation for the link between hypoxia and an increased risk of developing cardiovascular diseases lies in the disturbing effect of hypoxia on circulating blood lipids, specifically its capacity to increase plasma triglyceride concentrations. Increased circulating triglyceride levels result from the production of triglyceride-rich lipoproteins, such as very-low-density lipoproteins and chylomicrons, exceeding their clearance rate. Considerable research in murine models reports that hypoxia may have detrimental effects on several aspects of triglyceride metabolism. However, in humans, the mechanisms underlying the disturbing effect of hypoxia on triglyceride levels remain unclear. In this mini-review, we outline the available evidence on the physiological responses to hypoxia and their impact on circulating triglyceride levels. We also discuss mechanisms by which hypoxia affects various organs involved in the metabolism of triglyceride-rich lipoproteins. This information will benefit scientists and clinicians interested in the mechanistic of the regulatory cascade responsible for the response to hypoxia and how this response could lead to a deteriorated lipid profile and an increased risk of developing hypoxia-related health consequences.

It is increasingly recognized that hypoxia may develop in adipose tissue as its mass expands. Adipose tissue is also the main reservoir of lipophilic pollutants, including polychlorinated biphenyls (PCBs). Both hypoxia and PCBs have been shown to alter adipose tissue functions. The signaling pathways induced by hypoxia and pollutants may crosstalk, as they share a common transcription factor: aryl hydrocarbon receptor nuclear translocator (ARNT). Whether hypoxia and PCBs crosstalk and affect adipokine secretion in human adipocytes remains to be explored. Using primary human adipocytes acutely co-exposed to different levels of hypoxia (24 h) and PCB126 (48 h), we observed that hypoxia significantly inhibits the PCB126 induction of cytochrome P450 (CYP1A1) transcription in a dose-response manner, and that Acriflavine (ACF)—an HIF1α inhibitor—partially restores the PCB126 induction of CYP1A1 under hypoxia. On the other hand, exposure to PCB126 did not affect the transcription of the vascular endothelial growth factor-A (VEGFA) under hypoxia. Exposure to hypoxia increased leptin and interleukin-6 (IL-6), and decreased adiponectin levels dose-dependently, while PCB126 increased IL-6 and IL-8 secretion in a dose-dependent manner. Co-exposure to PCB126 and hypoxia did not alter the adipokine secretion pattern observed under hypoxia and PCB126 exposure alone. In conclusion, our results indicate that (1) hypoxia inhibits PCB126-induced CYP1A1 expression at least partly through ARNT-dependent means, suggesting that hypoxia could affect PCB metabolism and toxicity in adipose tissue, and (2) hypoxia and PCB126 affect leptin, adiponectin, IL-6 and IL-8 secretion differently, with no apparent crosstalk between the two factors.

Although Krüppel-associated box zinc finger proteins (KZFPs) were found to mostly repress transposable elements, recent studies found that KFZPs also play other roles in cells. Here, the authors provide evidence that the KZFP ZFP30 promotes adipogenesis by targeting and activating a retrotransposon-derived Pparg2 enhancer in cooperation with co-regulator KRAB-associated protein 1 (KAP1).

Insertion polynorbornenes (PBNEs) are rigid-rod polymers that have very high glass transition temperatures (Tg). In this study, two functional PNBEs were electrospun in the presence of a variety of cross-linkers, resulting in fibers with Tgs greater than 300 °C. The fibers are long (several mm), rigid, and with diameters that can be tuned in the range 300 nm–10 μm. The electrospinning process can be used to encapsulate dyes or graphene dots. Due to the high cross-linking density of the fiber, dye leaching is prevented. In contrast with other rigid-rod polymers, electrospinning of PNBE is facile and can be performed at injection rates as high as 1 mL/min.

Abstract Transposable elements (TEs) are major components of eukaryotic genomes. However, the extent of their impact on genome evolution, function, and disease remain a matter of intense interrogation. The rise of genomics and large-scale functional assays has shed new light on the multi-faceted activities of TEs and implies that they should no longer be marginalized. Here, we introduce the fundamental properties of TEs and their complex interactions with their cellular environment, which are crucial to understanding their impact and manifold consequences for organismal biology. While we draw examples primarily from mammalian systems, the core concepts outlined here are relevant to a broad range of organisms.

Purpose of review: Initial and subsequent modality decisions are important, impacting both clinical outcomes and quality of life. Transition from chronic kidney disease to dialysis and between dialysis modalities are periods were patients may be especially vulnerable. Reviewing our current knowledge surrounding these critical periods and identifying areas for future research may allow us to develop dialysis strategies beneficial to patients. Sources of information: We searched the electronic database PubMed and queried Google Scholar for English peer-reviewed articles using appropriate keywords (non-exhaustive list): dialysis transitions, peritoneal dialysis, home hemodialysis, integrated care pathway, and health-related quality of life. Primary sources were accessed whenever possible. Methods: In this narrative review, we aim to expose the controversies surrounding home-dialysis first strategies and examine the evidence underpinning home-dialysis first strategies as well as home-to-home and home-to-in-center transitions. Key findings: Diverse factors must be taken into consideration when choosing initial and subsequent dialysis modalities. Given the limitations of available data (and lack of convincing benefit or detriment of one modality over the other), patient-centered considerations may prime over suspected mortality benefits of one modality or another. Limitations: Available data stem almost exclusively from retrospective and observational studies, often using large national and international databases, susceptible to bias. Furthermore, this is a narrative review which takes into account the views and opinions of the authors, especially as it pertains to optimal dialysis pathways. Implications: Emphasis must be placed on individual patient goals and preferences during modality selection while planning ahead to achieve timely and appropriate transitions limiting discomfort and anxiety for patients. Further research is required to ascertain specific interventions which may be beneficial to patients.

El artículo introduce de forma somera el concepto de “guerra justa” e intenta ubicar la ética profesional canadiense con fundamento en la dignidad humana, el servicio de Canadá y la obediencia a la autoridad legal, en el contexto de la intervención en Afganistán. La discusión de textos oficiales que datan de la época en que la implicación de Canadá había sido la más intensa, y la de un caso particular, permite demostrar la “tensión natural” entre la necesidad de obtener resultados y la de respetar normas éticas superiores.

The National Institutes of Health Stroke Scale (NIHSS) is commonly used to triage and monitor the evolution of stroke victims. Data regarding NIHSS knowledge in nurses and physicians working with stroke patients are scarce, and a progressive decline in specific knowledge regarding this challenging scale is to be expected even among NIHSS certified personnel. This protocol was designed according to the CONSORT-eHealth (Consolidated Standards of Reporting Trials) guidelines. It describes the design of a randomized controlled trial whose primary objective is to determine if nurses and physicians who work in stroke units improve their NIHSS knowledge more significantly after following a highly interactive e-learning module than after following the traditional didactic video. Univariate and multivariable linear regression will be used to analyze the primary outcome, which will be the difference between the score on a 50-question quiz answered before and immediately after following the allocated learning material. Secondary outcomes will include knowledge retention at one month, assessed using the same 50-question quiz, user satisfaction, user course duration perception, and probability of recommending the allocated learning method. The study is scheduled to begin during the first semester of 2022.

The kynurenine pathway (KP) is gaining attention in several clinical fields. Recent studies show that physical exercise offers a therapeutic way to improve ratios of neurotoxic to neuroprotective KP metabolites. Antioxidant supplementation can blunt beneficial responses to physical exercise. We here studied the effects of endurance training in the form of sprint interval training (SIT; three sessions of 4–6 × 30 s cycling sprints per week for three weeks) in elderly (~65 years) men exposed to either placebo (n = 9) or the antioxidants vitamin C (1 g/day) and E (235 mg/day) (n = 11). Blood samples and muscle biopsies were taken under resting conditions in association with the first (untrained state) and last (trained state) SIT sessions. In the placebo group, the blood plasma level of the neurotoxic quinolinic acid was lower (~30%) and the neuroprotective kynurenic acid to quinolinic acid ratio was higher (~50%) in the trained than in the untrained state. Moreover, muscle biopsies showed a training-induced increase in kynurenine aminotransferase (KAT) III in the placebo group. All these training effects were absent in the vitamin-treated group. In conclusion, KP metabolism was shifted towards neuroprotection after three weeks of SIT in elderly men and this shift was blocked by antioxidant treatment.

IntroductionElevated plasma triglyceride (TG) concentrations are an important contributor to deleterious metabolic alterations. Evidence in animals suggest that acute exposure to an environment with reduced oxygen inhibits plasma TG clearance and causes important rise in plasma TG, especially in the postprandial state. The objective of this study was to characterize the effects of an acute exposure to normobaric hypoxia on prandial TG levels in 2 distinct lipoprotein subtypes in healthy humans: chylomicrons which are secreted by the intestine and carry dietary lipids, and denser TG carriers (mainly VLDL), which are secreted by the liver and carry endogenous lipids. Plasma lipolytic activity was also assessed. It was hypothesized that hypoxia would reduce prandial plasma lipolytic activity and raise prandial TG levels in both lipoprotein subtypes.MethodsUsing a randomized crossover design, 9 healthy young men were studied for 6 h in a constantly fed state while being exposed to either normobaric hypoxia (FiO2 = 0.12) and normoxic conditions on two different days. Prandial glucose, TG, non-esterified fatty acid (NEFA), and post-heparin plasma lipolytic activity were measured during each session.ResultsSix hours of exposure to hypoxia marginally increase prandial glycemia (+5%, p = 0.06) while increasing insulinemia by 40% (p = 0.04). Hypoxia induced a 30% rise in prandial NEFA levels and tended to slightly increased total prandial TG levels by 15% (p = 0.11). No difference was observed in TG concentrations and metabolism of chylomicrons between conditions. However, TG in the VLDL containing fraction decreased significantly overtime under normoxia but not under hypoxia (time × condition interaction, p = 0.02). No difference was observed in post-heparin plasmatic lipolytic activity between conditions.ConclusionAcute hypoxia in healthy men tends to increase prandial VLDL-TG levels. These results lend support to the increased blood lipid levels reported in animals exposed acutely to lower partial pressures of oxygen.