Cortisol secretion is related to electroencephalographic alertness in human subjects during daytime wakefulness

ABSTRACT To determine whether human hypothalamo-pituitary-adrenal axis activity is related to the alertness level during wakefulness, 10 healthy young men were studied under resting conditions in the daytime (0900 -1800 h) after an 8-h nighttime sleep (2300 -0700 h). A serial 70-sec gaze fixation task was required every 10 min throughout the daytime experimental session. The corresponding waking electroencephalographic (EEG) segments were submitted to quantitative spectral analysis, from which EEG ␤ activity (absolute power density in the 13-35 Hz frequency band), an index of central alertness, was computed. Blood was collected continuously through an indwelling venous catheter and sampled at 10-min intervals. Plasma cortisol concentrations were measured by RIA, and the corresponding secretory rates were determined by a deconvolution procedure. Analysis of individual profiles demonstrated a declining tendency for EEG ␤ activity and cortisol secretory rate, with an overall temporal relationship indicated by positive and significant cross-correlation coefficients between the two variables in all subjects (average r ϭ 0.565, P Ͻ 0.001). Changes in cortisol secretion lagged behind fluctuations in EEG ␤ activity, with an average delay of 10 min for all the subjects. On the average, 4.6 Ϯ 0.4 cortisol secretory pulses and 4.9 Ϯ 0.5 peaks in EEG ␤ activity were identified by a detection algorithm. A significant, although not systematic, association between the episodes in the two variables was found: 44% of the peaks in EEG ␤ activity (relative amplitude, near 125%; P Ͻ 0.001) occurred during an ascending phase of cortisol secretion, cortisol secretory rates increasing by 40% (P Ͻ 0.01) 10-min after peaks in EEG ␤ activity. However, no significant change in EEG ␤ activity was observed during the period from 50 min before to 50 min after pulses in cortisol secretion. In conclusion, the present study describes a temporal coupling between cortisol release and central alertness, as reflected in the waking EEG ␤ activity. These findings suggest the existence of connections between the mechanisms involved in the control of hypothalamo-pituitary-adrenal activity and the activation processes of the brain, which undergoes varying degrees of alertness throughout daytime wakefulness. (J Clin Endocrinol Metab 83: [4263][4264][4265][4266][4267][4268] 1998) C ORTISOL is released in pulses by adrenocortical glands under pituitary ACTH control, with a periodicity of 80 -110 min in man (1). The 24-h pattern of cortisol levels shows an early-morning acrophase and an evening nadir (2). This is the consequence of an amplitude modulation of ACTH secretory bursts (3), probably driven by the suprachiasmatic nucleus of the hypothalamus, which controls CRH and arginine vasopressin cells of the paraventricular nucleus (4). Although cortisol secretion is known to be primarily under a circadian influence (5), independent of sleeping and waking, several studies in humans have suggested that sleep, especially slow-wave sleep, may exert an inhibitory influence on cortisol secretion (6, 7). Other authors argue that an underlying mechanism decreases cortisol secretion and facilitates sleep onset and slow-wave sleep installation (8 -10). Dynamic relationships have been described between human sleep electroencephalographic (EEG) activity, which reflects central nervous sleep processes, and cortisol secretory activity Although sleep EEG has been extensively studied (14), the time course of the waking EEG activity has been studied far less, because of artifacts contaminating EEG recordings. However, diurnal fluctuations of the human background EEG, a neurophysiological indicator of the brain's functional state (15), have been shown to occur spontaneously, with patterns depending on the EEG spectrum frequency ban

ArfGAP1 restricts Mycobacterium tuberculosis entry by controlling the actin cytoskeleton

International audienceThe interaction of Mycobacterium tuberculosis (Mtb) with pulmonary epithelial cells is critical for early stages of bacillus colonization and during the progression of tuberculosis. Entry of Mtb into epithelial cells has been shown to depend on F-actin polymerization, though the molecular mechanisms are still unclear. Here, we demonstrate that mycobacterial uptake into epithelial cells requires rearrangements of the actin cytoskeleton, which are regulated by ADP-ribosylation factor 1 (Arf1) and phos-pholipase D1 (PLD1), and is dependent on the M3 muscarinic receptor (M 3 R). We show that this pathway is controlled by Arf GTPase-activating protein 1 (ArfGAP1), as its silencing has an impact on actin cytoskeleton reorganization leading to uncontrolled uptake and replication of Mtb. Furthermore, we provide evidence that this pathway is critical for mycobacterial entry, while the cellular infection with other pathogens, such as Shigella flexneri and Yersinia pseudotuberculosis, is not affected. Altogether, these results reveal how cortical actin plays the role of a barrier to prevent mycobacterial entry into epithelial cells and indicate a novel role for ArfGAP1 as a restriction factor of host–pathogen interactions

A Bacterial Toxin with Analgesic Properties: Hyperpolarization of DRG Neurons by Mycolactone

International audienceMycolactone, a polyketide molecule produced by Mycobacterium ulcerans, is the etiological agent of Buruli ulcer. This lipid toxin is endowed with pleiotropic effects, presents cytotoxic effects at high doses, and notably plays a pivotal role in host response upon colonization by the bacillus. Most remarkably, mycolactone displays intriguing analgesic capabilities: the toxin suppresses or alleviates the pain of the skin lesions it inflicts. We demonstrated that the analgesic capability of mycolactone was not attributable to nerve damage, but instead resulted from the triggering of a cellular pathway targeting AT 2 receptors (angiotensin II type 2 receptors; AT 2 R), and leading to potassium-dependent hyperpolarization. This demonstration paves the way to new nature-inspired analgesic protocols. In this direction, we assess here the hyperpolarizing properties of mycolactone on nociceptive neurons. We developed a dedicated medium-throughput assay based on membrane potential changes, and visualized by confocal microscopy of bis-oxonol-loaded Dorsal Root Ganglion (DRG) neurons. We demonstrate that mycolactone at non-cytotoxic doses triggers the hyperpolarization of DRG neuron

Mycobacterium tuberculosis Controls Phagosomal Acidification by Targeting CISH-Mediated Signaling

Pathogens have evolved a range of mechanisms to counteract host defenses, notably to survive harsh acidic conditions in phagosomes. In the case of Mycobacterium tuberculosis, it has been shown that regulation of phagosome acidification could be achieved by interfering with the retention of the V-ATPase complexes at the vacuole. Here, we present evidence that M. tuberculosis resorts to yet another strategy to control phagosomal acidification, interfering with host suppressor of cytokine signaling (SOCS) protein functions. More precisely, we show that infection of macrophages with M. tuberculosis leads to granulocyte-macrophage colony-stimulating factor (GM-CSF) secretion, inducing STAT5-mediated expression of cytokine-inducible SH2-containing protein (CISH), which selectively targets the V-ATPase catalytic subunit A for ubiquitination and degradation by the proteasome. Consistently, we show that inhibition of CISH expression leads to reduced replication of M. tuberculosis in macrophages. Our findings further broaden the molecular understanding of mechanisms deployed by bacteria to survive

Combination therapy for tuberculosis treatment: pulmonary administration of ethionamide and booster co-loaded nanoparticles

Erratum in : Publisher Correction: Combination therapy for tuberculosis treatment: pulmonary administration of ethionamide and booster co-loaded nanoparticles. [Sci Rep. 2018]International audienceTuberculosis (TB) is a leading infectious cause of death worldwide. The use of ethionamide (ETH), a main second line anti-TB drug, is hampered by its severe side effects. Recently discovered "booster" molecules strongly increase the ETH efficacy, opening new perspectives to improve the current clinical outcome of drug-resistant TB. To investigate the simultaneous delivery of ETH and its booster BDM41906 in the lungs, we co-encapsulated these compounds in biodegradable polymeric nanoparticles (NPs), overcoming the bottlenecks inherent to the strong tendency of ETH to crystallize and the limited water solubility of this Booster. The efficacy of the designed formulations was evaluated in TB infected macrophages using an automated confocal high-content screening platform, showing that the drugs maintained their activity after incorporation in NPs. Among tested formulations, "green" β-cyclodextrin (pCD) based NPs displayed the best physico-chemical characteristics and were selected for in vivo studies. The NPs suspension, administered directly into mouse lungs using a Microsprayer®, was proved to be well-tolerated and led to a 3-log decrease of the pulmonary mycobacterial load after 6 administrations as compared to untreated mice. This study paves the way for a future use of pCD NPs for the pulmonary delivery of the [ETH:Booster] pair in TB chemotherapy