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Although we have learned much about how the brain fuels its functions over the last decades, there remains much still to discover in an organ that is so complex. This article lays out major gaps in our knowledge of interrelationships between brain metabolism and brain function, including biochemical, cellular, and subcellular aspects of functional metabolism and its imaging in adult brain, as well as during development, aging, and disease. The focus is on unknowns in metabolism of major brain substrates and associated transporters, the roles of insulin and of lipid droplets, the emerging role of metabolism in microglia, mysteries about the major brain cofactor and signaling molecule NAD+ , as well as unsolved problems underlying brain metabolism in pathologies such as traumatic brain injury, epilepsy, and metabolic downregulation during hibernation. It describes our current level of understanding of these facets of brain energy metabolism as well as a roadmap for future research.

Introduction: Historically, Parkinson's Disease (PD) research has focused on the dysfunction of dopamine-producing cells in the substantia nigra pars compacta, which is linked to motor regulation in the basal ganglia. Therapies have mainly aimed at restoring dopamine (DA) levels, showing effectiveness but variable outcomes and side effects. Recent evidence indicates that PD complexity implicates disruptions in DA, noradrenaline (NA), and serotonin (5-HT) systems, which may underlie the variations in therapy effects. Methods: We present a system-level bio-constrained computational model that comprehensively investigates the dynamic interactions between these neurotransmitter systems. The model was designed to replicate experimental data demonstrating the impact of NA and 5-HT depletion in a PD animal model, providing insights into the causal relationships between basal ganglia regions and neuromodulator release areas. Results: The model successfully replicates experimental data and generates predictions regarding changes in unexplored brain regions, suggesting avenues for further investigation. It highlights the potential efficacy of alternative treatments targeting the locus coeruleus and dorsal raphe nucleus, though these preliminary findings require further validation. Sensitivity analysis identifies critical model parameters, offering insights into key factors influencing brain area activity. A stability analysis underscores the robustness of our mathematical formulation, bolstering the model validity. Discussion: Our holistic approach emphasizes that PD is amultifactorial disorder and opens promising avenues for early diagnostic tools that harness the intricate interactions amongmonoaminergic systems. Investigating NA and 5-HT systems alongside the DA system may yield more effective, subtype-specific therapies. The exploration of multisystem dysregulation in PD is poised to revolutionize our understanding and management of this complex neurodegenerative disorder. [ABSTRACT FROM AUTHOR]

Objective: The endothelial glycocalyx layer (EGL) is the interface between the blood and the endothelium that regulates permeability. This study compared the effects of liberal and restrictive fluid therapies on atrial natriuretic peptide (ANP) release and EGL products in radical cystectomy surgery. We hypothesized that a liberal regimen would damage the glycocalyx layer, resulting in a higher serum EGL product concentration than restrictive therapy. Materials and Methods: Patients were randomized into two groups for restrictive (group R) or liberal (group L) regimens. Group R received 2 mL/kg/h Ringer’s lactate and 2 mcg/kg/h norepinephrine infusion, whereas group L received only Ringer’s lactate infusion at 10 mL/kg/h rate during the surgery. Preoperative and postoperative blood samples were obtained to evaluate ANP levels and glycocalyx degradation products. The stroke volume index, cardiac index, stroke volume variation, and systemic vascular resistance index parameters were recorded at 30-min intervals throughout the surgery. The length of stay in the hospital and intensive care unit and postoperative complications were recorded. Results: The study was completed with 39 patients. Postoperative ANP levels were higher in group L in both between- and within group examination (p<0.05). EGL constituents; syndecan-1 and hyaluronan concentrations, were higher in group L (p<0.05). Advanced hemodynamic parameters indicated insignificant changes between the groups (p>0.05). Postoperative complications and length of stay data were similar (p>0.05). Conclusion: ANP, hyaluronan, and syndecan-1 concentrations can be used as an indirect measurement method to show EGL damage and hypervolemia in major urologic surgeries. Advanced hemodynamic monitoring was ineffective for confirming hypervolemia. [ABSTRACT FROM AUTHOR]

A method was developed to fabricate a glassy carbon electrode with electrodeposited palladium particles and a molecularly imprinted polymer derived from nicotinamide. This approach enables the determination of dopamine in the presence of structurally related compounds. The incorporation of a polymer featuring specific recognition sites tailored to the template molecule significantly enhanced the sensitivity and selectivity of dopamine detection. The immobilization of palladium particles on the electrode surface further improved the selectivity of voltammetric dopamine determination, even in the presence of adrenaline and noradrenaline, which exhibited a 200 mV difference in oxidation peak potentials. The analytical signal showed a linear bilogarithmic dependence on dopamine concentration within the range 5.0 × 10–9 to 5.0 × 10–3 M. This method was successfully applied to an analysis of urine samples, demonstrating its practical utility in real-world applications. [ABSTRACT FROM AUTHOR]

Vulnerability to chronic pain is found to depend on age and sex. Most patients with chronic pain are elderly women, especially with posttraumatic pain after bone fracture that prevails beyond the usual recovery period and develops into a complex regional pain syndrome (CRPS). There, a distal bone fracture seems to initiate a pathophysiological process with unknown mechanism. To investigate whether sex, age, and alpha adrenergic receptors also contribute to a CRPS-like phenotype in animals, we performed experiments on tibia-fractured mice. Those mice commonly are resilient to the development of a CRPS-like phenotype. However, we found them to be vulnerable to long-lasting pain after distal bone fracture when they were of old age. These mice expressed mechanical and thermal hypersensitivity, as well as weight-bearing and autonomic impairment following bone trauma, which persisted over 3 months. Site-specific and body side-specific glycinergic and α1D-noradrenergic receptor expression in the spinal cord and the contralateral locus coeruleus were misbalanced. Aged female tibia-fractured mice lost descending noradrenergic inhibition and displayed enhanced spinal activity on peripheral pressure stimuli. Together, changes in the noradrenergic, hence, glycinergic system towards excitation in the pain pathway--ascending and descending--might contribute to the development or maintenance of long-lasting pain. Conclusively, changes in the noradrenergic system particularly occur in aged female mice after trauma and might contribute to the development of long-lasting pain. Our data support the hypothesis that some patients with chronic pain would benefit from lowering the adrenergic/sympathetic tone or antagonizing α1(D). [ABSTRACT FROM AUTHOR]

Summary: Background: Noradrenaline is a standard treatment for hypotension in acute care. The precise effects of noradrenaline on cerebral blood flow in health and disease remain unclear. Methods: We systematically reviewed and synthesised data from studies examining changes in cerebral blood flow in healthy participants and patients with traumatic brain injury and critical illness. Results: Twenty‐eight eligible studies were included. In healthy subjects and patients without critical illness or traumatic brain injury, noradrenaline did not significantly change cerebral blood flow velocity (‐1.7%, 95%CI ‐4.7–1.3%) despite a 24.1% (95%CI 19.4–28.7%) increase in mean arterial pressure. In patients with traumatic brain injury, noradrenaline significantly increased cerebral blood flow velocity (21.5%, 95%CI 11.0–32.0%), along with a 33.8% (95%CI 14.7–52.9%) increase in mean arterial pressure. In patients who were critically ill, noradrenaline significantly increased cerebral blood flow velocity (20.0%, 95%CI 9.7–30.3%), along with a 32.4% (95%CI 25.0–39.9%) increase in mean arterial pressure. Our analyses suggest intact cerebral autoregulation in healthy subjects and patients without critical illness or traumatic brain injury., and impaired cerebral autoregulation in patients with traumatic brain injury and who were critically ill. The extent of mean arterial pressure changes and the pre‐treatment blood pressure levels may affect the magnitude of cerebral blood flow changes. Studies assessing cerebral blood flow using non‐transcranial Doppler methods were inadequate and heterogeneous in enabling meaningful meta‐analysis. Conclusions: Noradrenaline significantly increases cerebral blood flow in humans with impaired, not intact, cerebral autoregulation, with the extent of changes related to the severity of functional impairment, the extent of mean arterial pressure changes and pre‐treatment blood pressure levels. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to demonstrate the establishment of adrenal sparing in intrauterine growth restricted (IUGR) human fetuses. IUGR fetuses are a subgroup of small for gestational age (SGA) fetuses that are unable to reach their own growth potential because of chronic hypoxia and undernutrition. We hypothesized that in IUGR fetuses the adrenal gland is relatively larger and secretion of noradrenaline (NA), adrenaline (A), and cortisol is increased. Study Design: This is a prospective observational study including 65 singleton pregnancies (42 IUGR and 23 controls). Using two‐dimensional ultrasound, we measured fetal adrenal diameters and adrenal/abdominal circumference (AD/AC) ratio between 25 and 37 weeks. We considered only one measurement per fetus. In 21 pregnancies we also measured NA, A, and cortisol levels in arterial and venous fetal cord blood collected at the time of delivery. Results: The AD/AC ratio was significantly higher in IUGR fetuses than in controls. Cord NA and A levels were significantly higher in IUGR fetuses than in controls. An increase in cortisol secretion in IUGR fetuses was observed but the difference was not statistically significant. Conclusions: Adrenal sparing correlates with a relative increase in adrenal measurements and function. Synopsis: The adrenal gland of intrauterine growth‐restricted fetuses is relatively larger compared with controls and its function is enhanced. [ABSTRACT FROM AUTHOR]

Rationale: Therapeutic approaches to mitigating traumatic memories have often faced resistance. Exploring safe reconsolidation blockers, drugs capable of reducing the emotional valence of the memory upon brief retrieval and reactivation, emerges as a promising pharmacological strategy. Towards this objective, preclinical investigations should focus on aversive memories resulting in maladaptive outcomes and consider sex-related differences to enhance their translatability. Objectives: After selecting a relatively high training magnitude leading to the formation of a more intense and generalized fear memory in adult female and male rats, we investigated whether two clinically approved drugs disrupting its reconsolidation remain effective. Results: We found resistant reconsolidation impairment by the α2-adrenergic receptor agonist clonidine or cannabidiol, a major non-psychotomimetic Cannabis sativa component. However, pre-retrieval administration of D-cycloserine, a partial agonist at the glycine-binding site of the N-methyl-D-aspartate (NMDA) receptor complex, facilitated their impairing effects on reconsolidation. A similar reconsolidation blockade by clonidine or cannabidiol was achieved following exposure to a non-conditioned but generalized context after D-cycloserine administration. This suggests that sufficient memory destabilization can accompany generalized fear expression. Combining clonidine with cannabidiol without potentiating memory destabilization by D-cycloserine was ineffective. Conclusions: These findings highlight the importance of NMDA receptor signaling in memory destabilization and underscore the efficacy of a dual-step pharmacological intervention in attenuating traumatic-like memories, even in a context different from the original learning environment. [ABSTRACT FROM AUTHOR]

This study aimed to modify a laser Doppler flowmeter designed and assembled at our institute. After measuring sensitivity evaluation in ex vivo experiments, we confirmed the efficacy of this new device for monitoring real-time esophageal mucosal blood flow changes after thoracic stent graft implantation by simulating various clinical situations in an animal model. Thoracic stent graft implantation was performed in a swine model (n = 8). Esophageal mucosal blood flow decreased significantly from baseline (34.1 ± 18.8 ml/min/100 g vs. 16.7 ± 6.6 ml/min/100 g, P < 0.05) in the lower esophagus (Th6–Th8) where the stent graft covered the aorta. In the hemorrhagic shock model (shock index ≥ 1.0), esophageal mucosal blood flow showed a remarkable change from baseline in the upper esophagus (Th1–Th3), where the stent graft did not cover the aorta (20.8 ± 9.8 ml/min/100 g vs. 12.9 ± 8.6 ml/min/100 g, P < 0.01); however, it returned to the baseline value within a 30-min period. Mucosal blood flow remained stable in the esophagus, where the stent graft did not cover the aorta. After elevating the mean blood pressure to > 70 mmHg with continuous intravenous noradrenaline infusion, esophageal mucosal blood flow increased significantly in both regions; however, the reaction was different between the two regions. Our newly developed laser Doppler flowmeter could measure real-time esophageal mucosal blood flow changes in various clinical situations during thoracic stent graft implantation in a swine model. Hence, this device can be applied in many medical fields by downsizing it. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions The vasopressor dose needed is a common measure to assess the severity of cardiovascular failure, but there is no consensus on the ranges of vasopressor doses determining different levels of cardiovascular support. We aimed to identify cutoffs for determining low, intermediate and high doses of noradrenaline (norepinephrine), the primary vasopressor used in intensive care, based on association with hospital mortality.We conducted a binational registry study to determine cutoffs between low, intermediate and high noradrenaline doses. We required the cutoffs to be statistically rational and practical (rounded to the first decimal and easy to remember), and to result in increasing mortality with increasing doses. The highest noradrenaline dose in the first 24 h after intensive care unit (ICU) admission was used. The cutoffs were developed using data from 8079 ICU patients treated in the ICU at Kuopio University Hospital, Finland, between 2013 and 2019. Subsequently, the cutoffs were validated in the eICU database, including 39,007 ICU admissions to 29 ICUs in the United States of America in 2014–2015. The log‐rank statistic, with the Contal and O'Quigley method, was used to determine the cutoffs resulting in the most significant split between the noradrenaline dose groups with regard to hospital mortality.The two most prominent peaks in the log‐rank statistic corresponded to noradrenaline doses 0.20 and 0.44 μg/kg/min. Accordingly, we determined three dose ranges: low (<0.2 μg/kg/min), intermediate (0.2–0.4 μg/kg/min) and high (>0.4 μg/kg/min). Mortality increased, whereas the number of patients decreased consistently with increasing noradrenaline doses in both cohorts. In the development cohort, hospital mortality was 6.5% in the group without noradrenaline administered and 14.0%, 26.4% and 40.2%, respectively, in the low‐dose, intermediate‐dose and high‐dose groups. Compared to patients who received no noradrenaline, the hazard ratio for in‐hospital death was 1.4 for the low‐dose group, 4.0 for the intermediate‐dose group and 7.5 for the high‐dose group in the validation cohort (p < .001).The highest noradrenaline dose is a useful measure for quantifying circulatory failure. Cutoffs 0.2 and 0.4 μg/kg/min seem to be suitable for defining low, intermediate and high doses. [ABSTRACT FROM AUTHOR]

The physiological effects of glucagon-like peptide-1 (GLP-1) are mainly centered on its ability to decrease blood glucose levels and facilitate satiety. Additional physiological functions have been identified by means of GLP-1 agonists such as exenatide (exendin-4; Ex4). In particular, Ex4 reduces the intake of natural and artificial rewards, effects that to some extent involve activation of GLP-1 receptors in the nucleus tractus solitarius (NTS). Although Ex4 acts in the brain, the neurochemical mechanisms underlying this activation are not fully elucidated. Investigating Ex4-induced neurochemical alterations in the nucleus accumbens (NAc) would be valuable for understanding its impact on reward-related behaviors. The aim of the present exploratory in vivo microdialysis study was therefore to study how Ex4, administered either systemically or locally into the NTS, influences classical neurotransmitters like dopamine, serotonin, noradrenaline, glutamate and GABA as well as additional players such as glycine, taurine and serine in NAc of male rats. We showed that Ex4 reduced extracellular levels of serine, taurine and glycine, where the latter two declines appear to involve activation of GLP-1R in the NTS. Besides, after systemic Ex4 injection the metabolites DOPAC, HVA, and 5HIAA are elevated. Where the increase in metabolites related to dopamine, but not serotonin, involves GLP-1 receptors in other areas than the NTS. Although the descriptive nature of the present data does not provide causality, it may however serve as an indication of mechanisms underlying how Ex4 may modulate reward-related behaviors. [ABSTRACT FROM AUTHOR]

Cannabinoids and the endocannabinoid system (ECS) have been intensively studied for their neuroregulatory roles in the central nervous system (CNS), especially in regulating learning and memory. However, many experimental and clinical studies obtained conflicting results indicating a complex network of interaction underlying the regulation of learning and memory by different cannabinoids and the ECS. The ECS influences neuronal synaptic communications, and therefore may exert different regulation via their different impact on other neurotransmitters. The monoaminergic system includes a variety of neurotransmitters, such as dopamine, norepinephrine, and serotonin, which play important roles in regulating mood, cognition, and reward. The interaction among cannabinoids, ECS and the monoaminergic system has drawn particular attention, especially their contributions to learning and memory. In this review, we summarized the current understanding of how cannabinoids, ECS and the monoaminergic system contribute to the process of learning and memory, and discussed the influences of monoaminergic neurotransmission by cannabinoids and ECS during this process. [ABSTRACT FROM AUTHOR]

Genetic generalized epilepsies (GGE) exhibit widespread morphometric alterations in the subcortical structures. Subcortical structures are essential for understanding GGE pathophysiology, but their fine-grained morphological diversity has yet to be comprehensively investigated. Furthermore, the relationships between macroscale morphological disturbances and microscale molecular chemoarchitectures are unclear. High-resolution structural images were acquired from patients with GGE (n = 97) and sex- and age-matched healthy controls (HCs, n = 184). Individual measurements of surface shape features (thickness and surface area) of seven bilateral subcortical structures were quantified. The patients and HCs were then compared vertex-wise, and shape anomalies were co-located with brain neurotransmitter profiles. We found widespread morphological alterations in GGE and prominent disruptions in the thalamus, putamen, and hippocampus. Shape area dilations were observed in the bilateral ventral, medial, and right dorsal thalamus, as well as the bilateral lateral putamen. We found that the shape area deviation pattern was spatially correlated with the norepinephrine transporter and nicotinic acetylcholine (Ach) receptor (α4β2) profiles, but a distinct association was seen in the muscarinic Ach receptor (M1). The findings provided a comprehensive picture of subcortical morphological disruptions in GGE, and further characterized the associated molecular mechanisms. This information may increase our understanding of the pathophysiology of GGE. Genetic generalized epilepsies (GGE)exhibited widespread shape alterations in subcortical structures and these morphological anomalies linked to specific neurotransmitter profiles [ABSTRACT FROM AUTHOR]

Stress impairs fertility, at least in part, via inhibition of gonadotropin secretion. Luteinizing hormone (LH) is an important gonadotropin that is released in a pulsatile pattern in males and in females throughout the majority of the ovarian cycle. Several models of stress, including acute metabolic stress, suppress LH pulses via inhibition of neurons in the arcuate nucleus of the hypothalamus that coexpress kisspeptin, neurokinin B, and dynorphin (termed KNDy cells) which form the pulse generator. The mechanism for inhibition of KNDy neurons during stress, however, remains a significant outstanding question. Here, we investigated a population of catecholamine neurons in the nucleus of the solitary tract (NTS), marked by expression of the enzyme dopamine beta-hydroxylase (DBH), in female mice. First, we found that a subpopulation of DBH neurons in the NTS is activated (express c-Fos) during metabolic stress. Then, using chemogenetics, we determined that activation of these cells is sufficient to suppress LH pulses, augment corticosterone secretion, and induce sickness-like behavior. In subsequent studies, we identified evidence for suppression of KNDy cells (rather than downstream signaling pathways) and determined that the suppression of LH pulses was not dependent on the acute rise in glucocorticoids. Together these data support the hypothesis that DBH cells in the NTS are important for regulation of neuroendocrine and behavioral responses to stress. [ABSTRACT FROM AUTHOR]

Background: The development of postpartum depression has been linked to fluctuations in the levels of neurotransmitters in the human body, such as 5-hydroxytryptamine (5-HT), dopamine (DA), noradrenaline (Norepinephrine, NE), and brain derived neurotrophic factor (BDNF). Research has indicated that the antidepressant effect of esketamine are mediated by monoamine transmitters and neurotrophic factors. Therefore, we postulate that intravenous administration of esketamine in patients with postpartum depression may alter the serum concentrations of these neurotransmitters. Methods: Three hundred fifteen patients with postpartum depression were selected and divided into two groups based on randomized numerical expression: esketamine (E) group (0. 25 mg/kg esketamine) and control (C) group (a same volume of 0.9% saline), all the drugs were pumped for 40 min. After the end of drug pumping, all patients were continuously observed for 2 h. Changes in serum levels of 5-HT, DA, NE, BDNF were recorded before drug administration and on the 3rd day after drug administration. The scores of Edinburgh Postnatal Depression Scale (EPDS) were calculated before drug administration, and on the 3rd day and on the 30th day after drug administration. Dizziness, headache, nausea, vomiting, drowsiness, and feeling of detachment occurred were recorded within 2 h after drug administration. Results: Before drug administration, the serum concentrations of 5-HT,DA,BDNF,NE in Group E and Group C were namely (0. 91 ± 0. 19 vs. 0. 98 ± 0. 21, P = 0. 181), (2. 38 ± 0. 35 vs. 2. 32 ± 0. 32, P = 0. 491), (3. 07 ± 0. 89 vs 3. 02 ± 0. 88, P = 0. 828), (39. 79 ± 7. 78 vs 41. 34 ± 10. 03, P = 0. 506). On the third day post-medication, the serum concentrations of 5-HT,DA,BDNF,NE in Group E and Group C were namely (1. 42 ± 0. 35 vs. 0. 96 ± 0. 24, P < 0. 001), (3. 99 ± 0. 17 vs. 2. 41 ± 0. 28, P < 0. 001),(5. 45 ± 0. 81 vs 3. 22 ± 0. 76, P < 0. 001),(44. 36 ± 9. 98 vs 40. 69 ± 11. 75, P = 0. 198). Before medication, the EPDS scores were (16. 15 ± 3. 02 vs 17. 85 ± 3. 89, P = 0. 064). on the third day after medication, the Group E had significantly reduced scores (12. 98 ± 2. 39 vs 16. 73 ± 3. 52, P < 0. 001). On the 30rd day after medication, EPDS scores between the two groups were (16. 34 ± 3. 43 vs 16. 91 ± 4. 02, p = 0. 203). Within 2 h of medication, the rate of adverse events was similar between the two groups. Conclusions: Small doses of esketamine can increase the serum concentration of 5-HT,DA,BDNF, and in the short term, decrease EPDS scores, and improve postpartum depressive symptoms. Trial registration: Retrospectively registered in the Chinese Clinical Trial Registry (ChiCTR2300078343, 2023/12/05). [ABSTRACT FROM AUTHOR]

Background: Fluid administration is the first line treatment in intensive care unit (ICU) patients with sepsis and septic shock. While fluid boluses administration can be titrated by predicting preload dependency, the amount of other forms of fluids may be more complex to be evaluated. We conducted a retrospective analysis in a tertiary hospital, to assess the ratio between fluids given as boluses and total administered fluid intake during early phases of ICU stay, and to evaluate the impact of fluid strategy on ICU mortality. Data related to fluid administration during the first four days of ICU stay were exported from an electronic health records system (ICCA®, Philips Healthcare). Demographic data, severity score, norepinephrine dose at ICU admission, overall fluid balance and the percentage of different fluid components of the overall volume administered were included in a multivariable logistic regression model, evaluating the association with ICU survival. Results: We analyzed 220 patients admitted with septic shock and sepsis-induced hypotension from 1st July 2021 to 31st December 2023. Fluid boluses and maintenance represented 49.3% ± 22.8 of the overall fluid intake, being balanced solution the most represented (40.4% ± 22.0). The fluid volume for drug infusion represented 34.0% ± 2.9 of the total fluid intake, while oral or via nasogastric tube fluid intake represented 18.0% ± 15.7 of the total fluid intake. Fluid volume given as boluses represented 8.6% of the total fluid intake over the four days, with a reduction from 25.1% ± 24.0 on Day 1 to 4.8% ± 8.7 on Day 4. A positive fluid balance [OR 1.167 (1.029–1.341); p = 0.021] was the most important factor associated with ICU mortality. Non-survivors (n = 66; 30%) received a higher amount of overall inputs than survivors only on Day 1 [2493 mL vs. 1855 mL; p = 0.022]. Conclusions: This retrospective analysis of fluids given over the early phases of septic shock and sepsis-induced hypotension showed that the overall volume given by boluses ranges from about 25% on Day 1 to about 5% on Day 4 from ICU admission. Our data confirms that a positive fluid balance over the first 4 days of ICU is associated with mortality. [ABSTRACT FROM AUTHOR]

Hypoglycemia is common in people with type 1 diabetes. Sometimes, severe hypoglycemia can be fatal. The underlying mechanisms by which severe hypoglycemia can lead to death are unclear. The sympathetic nervous system is thought to be proarrhythmic. We hypothesized that norepinephrine is the main mediator of severe hypoglycemia‐induced fatal cardiac arrhythmias. To test this hypothesis, adult, non‐diabetic Sprague–Dawley rats were subjected to hyperinsulinemic‐severe hypoglycemic clamps (3 h, 10–15 mg/dL) during two different experiments: (1) intracerebroventricular (ICV) norepinephrine (n = 26) or artificial cerebrospinal fluid (aCSF) (n = 20) infusion or (2) blockade of norepinephrine release by intraperitoneal reserpine (n = 20) or control (n = 29). In experiment 1, brain norepinephrine infusion during severe hypoglycemia led to a 2.5‐fold increase in third‐degree heart block and a 24% incidence of ST elevation compared to no ST elevation in aCSF controls. In experiment 2, reserpine successfully reduced plasma and cardiac norepinephrine levels. During severe hypoglycemia, reserpine completely prevented second and third‐degree heart block and T wave increases, a marker of myocardial infarction, compared to controls. In conclusion, norepinephrine increases while reserpine, used to reduce norepinephrine nerve terminal release, reduces heart block and markers of myocardial infarction during severe hypoglycemia. [ABSTRACT FROM AUTHOR]

Simple Summary: It has been suggested that a circus has a limited ability to make improvements in animal welfare. Though the horse is a domesticated species, the activities as well as the management that horses are subjected to could perturb homeostasis, alerting the organism and resulting in stress conditions. In the current study, the plasma concentrations of noradrenaline, dopamine and serotonin, as well as the reactive oxygen metabolites (d-Roms) and the biological antioxidant potential (BAP), were assessed in horses managed in different circuses. According to the results herein found, it appears that the welfare of horses under circus management was not compromised; nevertheless, better attention to the management of old horses is advocated, as they could be more susceptible to oxidative stress. Due to the paucity of information on circus management effects on the welfare of horses, this study investigated the plasma concentrations of noradrenaline, dopamine and serotonin, known to be indices of mental status, as well as the reactive oxygen metabolites (d-Roms) and the biological antioxidant potential (BAP), likely to denote the oxidant/antioxidant equilibrium of organisms, in horses managed in different Italian circuses. For the study, 56 circus horses of different breeds and ages were enrolled and divided into six groups according to the horses' management (circus management, groups G1–G5; classic riding management representing the control group, CG). From each horse, blood samples were collected in order to assess the concentration of selected parameters. One-way ANOVA showed no differences (p > 0.05) in serotonin, dopamine, noradrenaline, d-Roms and BAP values between circus and control horses. No differences related to the breed of the horses enrolled in the study were found in the values of all investigated parameters (p > 0.05). Furthermore, neurotransmitters showed overlapping levels between the different age classes of investigated horses (p > 0.05); contrariwise, the age of the horse displayed a significant effect on BAP values, with the oldest horses (16–21 age class) exhibiting lower BAP values compared to 4–5, 6–10 and 11–15 age classes (p < 0.05), whereas the d-Roms showed similar values in horses of different age classes (p > 0.05). The results gathered in the present study suggest that the mental status of horses under circus management was not compromised; however, better attention and care in the management of older horses is advocated, as they showed a lower biological antioxidant potential than younger horses; thus, they could be more susceptible to oxidative stress. [ABSTRACT FROM AUTHOR]

To adapt to threats in the environment, animals must predict them and engage in defensive behavior. While the representation of a prediction error signal for reward has been linked to dopamine, a neuromodulatory prediction error for aversive learning has not been identified. We measured and manipulated norepinephrine release during threat learning using optogenetics and a novel fluorescent norepinephrine sensor. We found that norepinephrine response to conditioned stimuli reflects aversive memory strength. When delays between auditory stimuli and footshock are introduced, norepinephrine acts as a prediction error signal. However, temporal difference prediction errors do not fully explain norepinephrine dynamics. To explain noradrenergic signaling, we used an updated reinforcement learning model with uncertainty about time and found that it explained norepinephrine dynamics across learning and variations in temporal and auditory task structure. Norepinephrine thus combines cognitive and affective information into a predictive signal and links time with the anticipation of danger. [ABSTRACT FROM AUTHOR]

This case report details the challenging management of a 45-year-old male construction worker who suffered severe multiple injuries after a fall and subsequent collision with cement mixers. The patient presented with extensive injuries, including amputation, fractures and internal bleeding, leading to a state known as the 'triangle of death'. Despite the initial grim prognosis, evidenced by an ISS score of 28 and a mortality risk coefficient of 89.56%, the patient was successfully resuscitated and managed through a multidisciplinary approach. This included damage control resuscitation, emergency vascular interventions and targeted temperature management for brain protection. The patient's recovery highlights the effectiveness of comprehensive trauma management and the critical role of coordinated care in severe multi-trauma cases. [ABSTRACT FROM AUTHOR]

Objective: To assess the safety and effectiveness of peripheral vasoactive drugs initiated during pre‐hospital care and retrieval missions, in Queensland, Australia. Methods: Three years of retrospective data was gathered from two sources. Medical notes were reviewed using a search for any patient having 'inotrope' recorded on an electronic medical record. Each case was reviewed to include only peripheral infusions of adrenaline or noradrenaline. Clinical Governance records were searched for adverse events related to vasoactive drugs, alerted for review to ensure complete capture. Results: A total of 418 patients received peripheral infusions of adrenaline and noradrenaline over the 3‐year period. No major complications were recorded either immediately or at Clinical Governance review. Minor complications were recorded in 4.7% of the cases, of which 3.5% occurred with peripheral vasoactives during the presence of the retrieval team. The frequency of use of peripheral vasoactives increased over the study period. Conclusions: In this retrospective data set there were no major complications of peripheral vasoactive drugs. Minor complications were similar to in‐hospital use and related to vascular access and drug delivery. [ABSTRACT FROM AUTHOR]

Frontal alpha asymmetry (FAA) is an electroencephalography (EEG) measure that quantifies trait-like left versus right hemisphere lateralization in alpha power. Increased FAA indicates relatively greater left than right frontal cortex activation and is associated with enhanced reward-related approach behaviors rather than avoidance or withdrawal. Studies dating back several decades have often suggested that having greater FAA supports enhanced positive affect and protection against major depressive disorder (MDD), whereas having greater right frontal activation (i.e., reduced FAA) is associated with negative affect and risk for MDD. While this hypothesis is widely known, a number of other studies instead have found increased FAA in MDD, or evidence that either leftward or rightward bias in FAA is associated with depression. Here we briefly review the literature on leftward or rightward lateralization in FAA in MDD, and find much evidence that MDD is not always characterized by reduced FAA. We also review the limited literature on FAA and monoaminergic neurotransmitter systems, including pharmacologic agents that act on them. Studies of serotonin in particular provide genetic and pharmacologic evidence for modulation of FAA, where some of these data may suggest that serotonin reduces FAA. In a synthesis of the collective literature on FAA and the monoamines, we suggest that serotonin and norepinephrine may differentially affect FAA, with serotonin tending to promote right frontal activation and norepinephrine biased toward left frontal activation. These putative differences in frontal lateralization may influence MDD phenotypes or potential subtypes of the disorder, and suggest pharmacologic treatment strategies. [ABSTRACT FROM AUTHOR]

Hyperthermia is known as a hyperadrenergic state, yet there is a lack of data on the sympathetic responses to ambient heat stress in humans. Therefore, we investigated the plasma epinephrine and norepinephrine concentrations of healthy young and older adults exposed to 3 h of very hot and dry, as well as hot and humid, heat, both with accompanying activities of daily living. We hypothesized that older adults, compared with young adults, would have augmented increases in epinephrine and norepinephrine concentrations secondary to increased thermal strain. Young (n = 20) and older (n = 18) participants underwent two 3-h heat exposures on different days: very hot and dry [47°C and 15% relative humidity (RH)] and hot and humid (41°C and 40% RH). To mimic heat generation comparable to activities of daily living, participants performed seven 5-min bouts of light cycling (approximately 3 METS) dispersed throughout the heat exposure. We measured plasma concentrations of epinephrine and norepinephrine at baseline, end, and 2-h postheat exposure. There was a group-wide increase in epinephrine from baseline to the end of the heat exposure (Δ19 ± 27 pg/mL; P < 0.001) in the hot and humid condition, but not in the very hot and dry condition (Δ6 ± 19 pg/mL; P = 0.10). There were group-wide decreases in norepinephrine concentrations from baseline to the end of the heat exposure in both the very hot and dry (Δ-131 ± 169 pg/mL; P < 0.001) and the hot and humid (Δ-138 ± 157 pg/mL; P < 0.001) conditions, with both returning to near baseline at 2-h postexposure. These data suggest that ambient heating with accompanying bouts of light intermittent exercise may lead to decreases in circulating concentrations of norepinephrine. NEW & NOTEWORTHY: Herein we present plasma epinephrine and norepinephrine concentrations to 3 h of very hot and dry, as well as hot and humid, heat exposures with accompanying activities of daily living in young and older participants. We found 1) increased plasma concentrations of epinephrine in young and older adults following the hot and humid, but not the very hot and dry exposures and 2) decreased concentrations of norepinephrine in both groups following exposure to both conditions. [ABSTRACT FROM AUTHOR]

Catecholamines (CATs) are neurotransmitters and allostatic hormones whose plasma concentrations are physiologically modified in various species such as human, rats, mice and donkeys, with advancing age. However, currently these mechanisms are less well elucidated in horses and more specifically in mares. The hypothesis of this study was that, as in afore mentioned species, the CATs could experience physiological changes with advancing age. The objective of this study was to evaluate the concentrations of adrenaline (A), noradrenaline (NA), dopamine (DA), and serotonin (5-HT) in mares of different ages. Blood samples were drawn from 56 non-pregnant Spanish Purebred mares belonging to four different age groups: 6 to 9 years, 10 to 12 years, 13 to 16 years and > 16 years. The concentrations of A, NA, DA, and 5-HT were determined by competition EIA-Technical 3-CAt EIA, specifically validated for horses. Mares aged > 16 years showed lower A, DA, and 5-HT but higher NA concentrations than 6–9, 10–12, and 13–16 years (p < 0.05). Mares of 13–16 years showed lower A and higher NA than 6–9 and 10–12 years (p < 0.05). A and NA (r=-0.72; p < 0.05), and NA and 5-HT (r=-0.67; p < 0.05) were negatively correlated, and A and 5-HT (r = 0.74; p < 0.05) were positively correlated. Advanced age leads to a predominance of sympathetic nervous activity and lower serotonergic activity in non-pregnant mares. [ABSTRACT FROM AUTHOR]

Background/objectives: Prolonged fasting triggers a stress response within the human body. Our objective was to investigate the impact of prolonged fasting, in conjunction with stress, on kynurenine pathway metabolites. Subjects/methods: Healthy males were divided into fasting group (zero-calorie-restriction) for 6 days (FAST, n = 14), and control group (CON, n = 10). Blood and saliva samples were collected at baseline, Day 2, Day 4, Day 6 during fasting period, and 1 week after resuming regular diet. Plasma levels of kynurenine pathway metabolites were measured using ultra-performance liquid chromatography-mass spectrometry (UPLC-MS/MS). Plasma and salivary samples were analyzed for stress markers. Results: A pronounced activation of the kynurenine pathway in individuals on FAST trial was revealed. Concentrations of picolinic acid (PIC), kynurenic acid (KYNA) and 3-hydroxykynurenine (3-HK) were significantly increased, with peak levels observed on Day 6 (P < 0.0001). Conversely, concentrations of tryptophan (TRP) and quinolinic acid (QUIN) decreased (P < 0.0001), while kynurenine (KYN) and nicotinamide (NAM) levels remained stable. Cortisol and noradrenaline concentrations remained unchanged. However, adrenaline levels significantly increased on Day 4 within FAST compared to CON (P = 0.005). Notably, all deviations in kynurenine pathway metabolite levels returned to baseline values upon resuming regular diet following the 6-day fasting regimen, even when weight and BMI parameters were not restored. Conclusions: Extended fasting over 6 days induces the kynurenine pathway and has minimal effects on stress markers. Restoration of metabolite concentrations upon regular feeding implies rapid adaptation of the kynurenine pathway synthetic enzymes to maintain homeostasis when faced with perturbations. [ABSTRACT FROM AUTHOR]

Background: Carcinoid tumors are rare neuroendocrine malignancies presenting in an increasing number in our center. The incidence of carcinoid tumors is approximatively between 2.5 and 5 cases per 100,000 people of whom about 50% develop carcinoid syndrome. Once the carcinoid syndrome has developed, a carcinoid cardiomyopathy can occur. Carcinoid heart disease (CaHD) remains a serious and rare complication associated with a significant increase in morbidity and mortality. Although carcinoid tumors have been known and studied for several years, there are still scarce data on the anesthetic management and the peri operative period. Case presentation: We describe a case of a Caucasian 44-year-old woman with an unusual presentation of left CaHD with an ileal neuroendocrine tumor and liver metastases. Our preoperative somatostatin administration protocol, limit the cardiac damage. The maintenance of stable hemodynamics, the use of balanced anesthetic technique, all along with a good understanding of the pathology, played a major role in the successful management of anesthesia. This case report allows us to introduce our decision algorithm for the management of this type of pathology in our tertiary hospital, Cliniques Universitaires Saint-Luc. Conclusion: Despite the paucity of data, anesthetic management of patients with carcinoid tumor can be safely performed with effective hemodynamic monitoring and a good understanding of the pathophysiology. Knowledge and application of a clear institutional algorithm for octreotide administration and multidisciplinary consultation at a referral center are essential for the management of these patients. [ABSTRACT FROM AUTHOR]

BackgroundMethodsResultsConclusionThere is limited literature investigating the catecholamine levels in patients with paroxysmal sympathetic hyperactivity (PSH) after traumatic brain injury (TBI). The primary objective of this study was to correlate the severity of PSH (assessed using the PSH-Assessment measure [AM]) with plasma catecholamine levels at a resting state.In this prospective case−control study, blood samples for epinephrine and norepinephrine estimation were obtained at rest on three consecutive days, only for ‘cases’ of PSH after severe TBI (s-TBI) and for control patients (matched for age, gender, and Glasgow coma scale [GCS].Twenty-seven patients with PSH and 16 controls were recruited. The median PSH-AM score was 20 and 9 in cases and controls, respectively. The epinephrine and norepinephrine levels at rest did not correlate with the severity of PSH assessed during PSH paroxysms (p = 0.949 and 0.975). Norepinephrine levels increased in PSH patients over the 3 consecutive days, once PSH was diagnosed (p = 0.022). The length of hospital stay was longer and the motor-GCS score was lower in PSH patients, with no differences in other outcomes between the groups.Catecholamine levels in the inter-paroxysmal interval cannot be correlated with PSH severity assessed during the paroxysms. However, the results of the study need to be confirmed by a larger sample size as the study is underpowered. [ABSTRACT FROM AUTHOR]

Acute circulatory shock is a life-threatening emergency requiring an efficient and timely management plan, which varies according to shock etiology and pathophysiology. Specific guidelines have been developed for each type of shock; however, there is a need for a clear timeline to promptly implement initial life-saving interventions during the early phase of shock recognition and management. A simple, easily memorable bundle of interventions could facilitate standardized management with clear targets and specified timeline. The authors propose the "MINUTES" acronym which summarizes essential interventions which should be performed within the first 30 min following shock recognition. All the interventions in the MINUTES bundle are suitable for any patient with undifferentiated shock. In addition to the acronym, we suggest a timeline for each step, balancing the feasibility and urgency of each intervention. The MINUTES acronym includes seven sequential steps which should be performed in the first 30 min following shock recognition: Maintain "ABCs", INfuse vasopressors and/or fluids (to support hemodynamic/perfusion) and INvestigate with simple blood tests, Ultrasound to detect the type of shock, Treat the underlying Etiology, and Stabilize organ perfusion. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusion Intraoperative hypotension is a risk factor for kidney, heart and cognitive postoperative complications. Literature suggests that the use of low‐dose peripheral norepinephrine (NOR) reduces organ dysfunction, yet its administration remains unstandardized. In this work we develop a pharmacokinetic (PK)/pharmacodynamic (PD) model of NOR and its effect on mean arterial pressure (MAP).From June 2018 to December 2021, we included patients scheduled for elective neurosurgery and requiring vasopressors for intraoperative hypotension management at Lariboisière Hospital, Paris. Low doses of NOR were administered peripherally, and successive arterial blood samples were collected to track its plasmatic concentration. We used a compartmental modelling approach for NOR PK. We developed and compared 2 models for NOR PD on MAP. Model comparison was done using Bayes information criteria. The resulting PK/PD model parameters were fitted over the entire population and linked to age, weight, height and sex.We included 29 patients (age 52 [46–64] years, 69% female). NOR median time to peak effect on MAP was 74 [53–94] s. After bolus administration, MAP increased by 24% (15–31%). A 2‐comparment model with depot best captured NOR PK. NOR PD effect on MAP was well represented by both Emax and Windkessel models, with better results for the former. We found that age, height and weight as well as history of smoking and hypertension were correlated with model parameters.We have developed a PK/PD model to accurately track norepinephrine plasma concentration and its effect on MAP over time, which could serve for target‐controlled infusion. [ABSTRACT FROM AUTHOR]

Background: Intestinal necrosis in uremic patients has been reported but is rare. Case presentation: A 56-year-old male patient who underwent long-term regular haemodialysis was admitted to the hospital due to involuntary shaking of the limbs and nonsense speech. The patient's symptoms improved after continuous blood purification under heparin anticoagulation, rehydration, sedation, and correction of electrolyte disturbances. However, the patient experienced a sudden onset of abdominal pain and a rapid decrease in blood pressure; high-dose norepinephrine were required to maintain his blood pressure. A plain abdominal radiograph performed at bedside showed intestinal dilation. Colonoscopy revealed inflammation and oedema of the entire colon, with purulent secretions and multiple areas of patchy necrosis. The cause of intestinal ischaemia was not clear. Conclusions: Although rare, previous causes of uremic colitis have been reported. As the patient developed abdominal pain before the onset of shock and the necrosis was seen on colonoscopy, we suspect that this is a case of fulminant uremic colitis. [ABSTRACT FROM AUTHOR]

Rhythmic brain activity is critical to many brain functions and is sensitive to neuromodulation, but so far very few studies have investigated this activity on the cellular level in vitro in human brain tissue samples. This study reveals and characterizes a novel rhythmic network activity in the human neocortex. Using intracellular patch-clamp recordings of human cortical neurons, we identify large rhythmic depolarizations (LRDs) driven by glutamate release but not by GABA. These LRDs are intricate events made up of multiple depolarizing phases, occurring at ~0.3 Hz, have large amplitudes and long decay times. Unlike human tissue, rat neocortex layers 2/3 exhibit no such activity under identical conditions. LRDs are mainly observed in a subset of L2/3 interneurons that receive substantial excitatory inputs and are likely large basket cells based on their morphology. LRDs are highly sensitive to norepinephrine (NE) and acetylcholine (ACh), two neuromodulators that affect network dynamics. NE increases LRD frequency through β-adrenergic receptor activity while ACh decreases it via M4 muscarinic receptor activation. Multi-electrode array recordings show that NE enhances and synchronizes oscillatory network activity, whereas ACh causes desynchronization. Thus, NE and ACh distinctly modulate LRDs, exerting specific control over human neocortical activity. A study discovered in vitro-maintained network activity in human neocortex, with large rhythmic depolarizations mainly in layer 2/3 basket cells, modulated by norepinephrine and acetylcholine. [ABSTRACT FROM AUTHOR]

Sleep disorders affect millions of people around the world and have a high comorbidity with psychiatric disorders. While current hypnotics mostly increase non-rapid eye movement sleep (NREMS), drugs acting selectively on enhancing rapid eye movement sleep (REMS) are lacking. This polysomnographic study in male rats showed that the first-in-class selective melatonin MT1 receptor partial agonist UCM871 increases the duration of REMS without affecting that of NREMS. The REMS-promoting effects of UCM871 occurred by inhibiting, in a dose–response manner, the firing activity of the locus ceruleus (LC) norepinephrine (NE) neurons, which express MT1 receptors. The increase of REMS duration and the inhibition of LC-NE neuronal activity by UCM871 were abolished by MT1 pharmacological antagonism and by an adeno-associated viral (AAV) vector, which selectively knocked down MT1 receptors in the LC-NE neurons. In conclusion, MT1 receptor agonism inhibits LC-NE neurons and triggers REMS, thus representing a novel mechanism and target for REMS disorders and/or psychiatric disorders associated with REMS impairments. [ABSTRACT FROM AUTHOR]

Background: Trauma and emergency surgery are major causes of morbidity and mortality. The objective of this study was to determine whether serum levels of epinephrine and norepinephrine are associated with aging and mortality. Methods: This was a prospective observational cohort study conducted in a surgical critical care unit. We included 90 patients who were admitted for postoperative care, because of major trauma, or both. We collected demographic and clinical variables, as well as serum levels of epinephrine and norepinephrine. Results: For patients in the > 60-year age group, the use of vasoactive drugs was found to be associated with an undetectable epinephrine level (OR [95% CI] = 6.36 [1.12, 36.08]), p = 0.05). For the patients with undetectable epinephrine levels, the in-hospital mortality was higher among those with a norepinephrine level ≥ 2006.5 pg/mL (OR [95% CI] = 4.00 [1.27, 12.58]), p = 0.03). Conclusions: There is an association between age and mortality. Undetectable serum epinephrine, which is more common in older patients, could contribute to poor outcomes. The use of epinephrine might improve the clinical prognosis in older surgical patients with shock. [ABSTRACT FROM AUTHOR]

Central nervous diseases caused by noradrenaline (NA) have attained special attention. NA is involved in many different physiological functions that occur throughout the central nervous system, including modifying sensory input, attention regulation, arousal, and sleep regulation. Hence, rapid, precise, and trustworthy NA detection is crucial. Here we have created Nd(VO4)/GA nanocomposite for the sensitive and selective detection of noradrenaline. Successful fabrication of Nd(VO4)/GA nanocomposite was verified by using transmission electron microscopy (TEM), scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), x-ray photoelectron spectroscopy (XPS) and x-ray diffraction (XRD) techniques. Optical properties were evaluated by colorimetric and fluorometric detection using UV–Vis absorption and photoluminescence spectroscopy. The created sensor has demonstrated superior noradrenaline detection capabilities using fluorometry with an LOD of 48.48 nM in a wide linear range of 6–215 nM, and for colorimetry, the LOD and linear range were 33.89 nM and 10–80 nM. Furthermore, the manufactured sensor has demonstrated exceptional reproducibility, strong stability, anti-interference capabilities, and excellent repeatability for noradrenaline detection. [ABSTRACT FROM AUTHOR]

Prolonged exposure to HIV-1 transactivator of transcription (Tat) protein dysregulates monoamine transmission, a physiological change implicated as a key factor in promoting neurocognitive disorders among people living with HIV. We have demonstrated that in vivo expression of Tat in Tat transgenic mice decreases dopamine uptake through both dopamine transporter (DAT) and norepinephrine transporter (NET) in the prefrontal cortex. Further, our novel allosteric inhibitor of monoamine transporters, SRI-32743, has been shown to attenuate Tat-inhibited dopamine transport through DAT and alleviates Tat-potentiated cognitive impairments. The current study reports the pharmacological profiles of SRI-32743 in basal and Tat-induced inhibition of human NET (hNET) function. SRI-32743 exhibited less affinity for hNET binding than desipramine, a classical NET inhibitor, but displayed similar potency for inhibiting hDAT and hNET activity. SRI-32743 concentration-dependently increased hNET affinity for [3H]DA uptake but preserved the Vmax of dopamine transport. SRI-32743 slowed the cocaine-mediated dissociation of [3H]Nisoxetine binding and reduced both [3H]DA and [3H]MPP+ efflux but did not affect d-amphetamine-mediated [3H]DA release through hNET. Finally, we determined that SRI-32743 attenuated a recombinant Tat1–86-induced decrease in [3H]DA uptake via hNET. Our findings demonstrated that SRI-32743 allosterically disrupts the recombinant Tat1–86–hNET interaction, suggesting a potential treatment for HIV-infected individuals with concurrent cocaine abuse. [ABSTRACT FROM AUTHOR]

Background: Dynamic arterial elastance (Eadyn) has been investigated for its ability to predict hypotension during the weaning of vasopressors. Our study focused on assessing Eadyn's performance in the context of critically ill adult patients admitted to the intensive care unit, regardless of diagnosis. Main body: Our study was conducted in accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analysis checklist. The protocol was registered in PROSPERO (CRD42023421462) on May 26, 2023. We included prospective observational studies from the MEDLINE and Embase databases through May 2023. Five studies involving 183 patients were included in the quantitative analysis. We extracted data related to patient clinical characteristics, and information about Eadyn measurement methods, results, and norepinephrine dose. Most patients (76%) were diagnosed with septic shock, while the remaining patients required norepinephrine for other reasons. The average pressure responsiveness rate was 36.20%. The synthesized results yielded an area under the curve of 0.85, with a sensitivity of 0.87 (95% CI 0.74–0.93), specificity of 0.76 (95% CI 0.68–0.83), and diagnostic odds ratio of 19.07 (95% CI 8.47–42.92). Subgroup analyses indicated no variations in the Eadyn based on norepinephrine dosage, the Eadyn measurement device, or the Eadyn diagnostic cutoff to predict cessation of vasopressor support. Conclusions: Eadyn, evaluated through subgroup analyses, demonstrated good predictive ability for the discontinuation of vasopressor support in critically ill patients. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusions Dopamine beta‐hydroxylase (DβH) inhibitors, like zamicastat, hold promise for treating pulmonary arterial hypertension. This study aimed to validate the mechanism of action of zamicastat by studying its effect on the overdrive of the sympathetic nervous system (SNS).A single‐centre, prospective, double‐blind, randomized, placebo‐controlled, crossover study evaluated the effect of 400 mg zamicastat in 22 healthy male subjects. Cold pressor test (CPT) was performed at screening and each treatment period on Days −1 and 10. Plasma and 24 h‐urine levels of dopamine (DA), epinephrine (EPI) and norepinephrine (NE), and plasma DβH activity, were measured.Compared to placebo, zamicastat showed a − 4.62 mmHg decrease in systolic blood pressure during the cold stimulus vs. rest phases on Day 10 of CPT (P = .020). Zamicastat decreased mean arterial pressure response to cold stimulus during CPT (−2.62 mmHg; P = .025). At Day 10, zamicastat significantly increased plasma DA, before CPT (12.63 ng/L; P = .040) and after CPT (19.22 ng/L; P = .001) as well as the estimated plasma EPI change from baseline after CPT (P = .040). Inhibition of plasma DβH activity ranged from 19.8% to 25.0%. At Day 10, significant reductions in 24‐h urinary excretion of EPI (P = .002) and NE (P = .001) were observed. Zamicastat Cτ geometric mean ± GSD ranged from 45.86 ± 1.46 ng/mL on Day 3 to 58.64 ± 1.52 ng/mL on Day 10, with moderate inter‐individual variability (CV: 32.6%–36.6%). Steady state was already achieved on Day 6.Our results demonstrated the effect of zamicastat on the overdrive sympathetic response to cold stimulus, confirming its potential as SNS modulator. [ABSTRACT FROM AUTHOR]

The prepositus hypoglossi nucleus (PHN) and the interstitial nucleus of Cajal (INC) are involved in the control of horizontal and vertical gaze, respectively. A previous study showed that PHN neurons exhibit depolarized or hyperpolarized responses to noradrenaline (NA). However, the adrenoceptor types that participate in NA-induced responses and the effects of NA on INC neurons have not yet been investigated. Furthermore, the relationship between NA-induced responses and neuron types defined by neurotransmitter phenotypes has not been determined. In this study, we investigated NA-induced current responses in PHN and INC neurons and the relationships between these responses and neuron types using whole cell recordings in wild-type and transgenic rat brainstem slices. Local application of NA to the cell soma induced slow inward (SI) and slow outward (SO) currents that were mainly mediated by α1 and α2 adrenoceptors, respectively. These current responses were observed in both PHN and INC neurons, although the proportion of INC neurons that responded to NA was low. Analyses of the distributions of the current responses revealed that in the PHN, all fluorescently identified inhibitory neurons exhibited SI currents, whereas glutamatergic and cholinergic neurons exhibited both SI and SO currents. In the INC, glutamatergic and inhibitory neurons preferentially exhibited SI and SO currents, respectively. When the PHN and INC neurons were characterized by their firing pattern, we found that the proportions of the currents depended on their firing pattern. These results suggest that various modes of noradrenergic modulation in horizontal and vertical neural integrators are dependent on neuron type. NEW & NOTEWORTHY Noradrenergic modulation of oculomotor neural integrators involved in gaze control has not been elucidated. Here, we report that noradrenaline (NA)-induced slow inward (SI) and outward (SO) currents are mediated mainly by α1 and α2 adrenoceptors in neurons that participate in horizontal and vertical gaze control. The NA-induced current responses differed depending on the neurotransmitter phenotype and firing pattern. These results suggest various modes of noradrenergic modulation in horizontal and vertical integrator neurons. [ABSTRACT FROM AUTHOR]

Non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) has attracted increasing interest as a neurostimulation tool with potential applications in modulating cognitive processes such as attention and memory, possibly through the modulation of the locus–coeruleus noradrenaline system. Studies examining the P300 brain-related component as a correlate of noradrenergic activity, however, have yielded inconsistent findings, possibly due to differences in stimulation parameters, thus necessitating further investigation. In this event-related potential study involving 61 participants, therefore, we examined how changes in taVNS parameters, specifically stimulation type (interval vs. continuous stimulation) and duration, influence P300 amplitudes during a visual novelty oddball task. Although no effects of stimulation were found over the whole cluster and time window of the P300, cluster-based permutation tests revealed a distinct impact of taVNS on the P300 response for a small electrode cluster, characterized by larger amplitudes observed for easy targets (i.e., stimuli that are easily discernible from standards) following taVNS compared to sham stimulation. Notably, our findings suggested that the type of stimulation significantly modulated taVNS effects on the P300, with continuous stimulation showing larger P300 differences (taVNS vs. sham) for hard targets and standards compared to interval stimulation. We observed no interaction effects of stimulation duration on the target-related P300. While our findings align with previous research, further investigation is warranted to fully elucidate the influence of taVNS on the P300 component and its potential utility as a reliable marker for neuromodulation in this field. [ABSTRACT FROM AUTHOR]

Chemotherapy-induced peripheral neuropathy (CIPN) is a side effect of cancer treatment, often linked with pain complaints. Patients report mechanical and thermal hypersensitivity that may emerge during chemotherapy treatment and may persist after cancer remission. Whereas the latter situation disturbs the quality of life, life itself may be endangered by the appearance of CIPN during cancer treatment. The causes of CIPN have almost entirely been ascribed to the neurotoxicity of chemotherapeutic drugs in the peripheral nervous system. However, the central consequences of peripheral neuropathy are starting to be unraveled, namely in the supraspinal pain modulatory system. Based on our interests and experience in the field, we undertook a review of the brain-centered alterations that may underpin pain in CIPN. The changes in the descending pain modulation in CIPN models along with the functional and connectivity abnormalities in the brain of CIPN patients are analyzed. A translational analysis of preclinical findings about descending pain regulation during CIPN is reviewed considering the main neurochemical systems (serotoninergic and noradrenergic) targeted in CIPN management in patients, namely by antidepressants. In conclusion, this review highlights the importance of studying supraspinal areas involved in descending pain modulation to understand the pathophysiology of CIPN, which will probably allow a more personalized and effective CIPN treatment in the future. [ABSTRACT FROM AUTHOR]

Key content: The perinatal period confers an elevated risk of both relapses and new onset of mental illness. Suboptimal treatment can have a profound impact on maternal mortality and morbidity, neonatal outcomes and longer term child development.Most psychotropic medication can be used safely in pregnancy, with some notable exceptions.While decisions on the use of psychotropic medications in pregnancy are often complex and should be multidisciplinary, it is imperative that obstetricians and gynaecologists familiarise themselves with current literature to provide evidence‐based counselling and care.Existing guidelines on the use of psychotropic medication are largely aimed at psychiatrists, and to date there has been a lack of concise, digestible information with a focus on core knowledge for obstetricians and gynaecologists.We summarise existing evidence on the use of antidepressants, antipsychotics, mood stabilisers and sedatives in the perinatal period. For each drug class we describe the teratogenicity, impact on pregnancy, breastfeeding and the newborn. Learning objectives: To be familiar with common psychotropic medication used in pregnancy and the postpartum period.To understand key evidence on the safety profile of psychiatric medication in the perinatal period and apply this to individualised counselling. [ABSTRACT FROM AUTHOR]

Irritable bowel syndrome (IBS) is responsive to treatments using central neuromodulators. Central neuromodulators work by enhancing the synaptic transmission of 5-hydroxytryptamine, noradrenalin, and dopamine, achieving a slower regulation or desensitization of their postsynaptic receptors. Central neuromodulators act on receptors along the braingut axis, so they are useful in treating psychiatric comorbidities, modifying gut motility, improving central downregulation of visceral signals, and enhancing neurogenesis in patients with IBS. Choosing a central neuromodulator for treating IBS should be according to the pharmacological properties and predominant symptoms. The first-line treatment for pain management in IBS is using tricyclic antidepressants. An alternative for pain management is the serotonin and noradrenaline reuptake inhibitors. Selective serotonin reuptake inhibitors are useful when symptoms of anxiety and hypervigilance are dominant but are not helpful for treating abdominal pain. The predominant bowel habit is helpful when choosing a neuromodulator to treat IBS; selective serotonin reuptake inhibitors help constipation, not pain, but may cause diarrhea; tricyclic antidepressants help diarrhea but may cause constipation. A clinical response may occur in 6-8 weeks, but long-term treatment (usually 6-12 months) is required after the initial response to prevent relapse. Augmentation therapy may be beneficial when the therapeutic effect of the first agent is incomplete or associated with side effects. It is recommended to reduce the dose of the first agent and add a second complementary treatment. This may include an atypical antipsychotic or brain-gut behavioral treatment. When tapering central neuromodulators, the dose should be reduced slowly over 4 weeks but may take longer when discontinuation effects occur. [ABSTRACT FROM AUTHOR]

High-risk/massive pulmonary embolism (PE) has a high mortality rate, especially when cardiac arrest occurs. Venoarterial (V-A) extracorporeal membrane oxygenation (ECMO) can rapidly restore and maintain circulation while a decision regarding further care or performance of other interventions takes place. Catheter-based embolectomy (CBE) is a technology that allows for percutaneous access, clot removal, and potential resolution of shock while avoiding sternotomy required for traditional pulmonary embolectomy. Rapid placement of V-A ECMO in patients with high-risk/massive PE prior to CBE may confer circulatory protection before, during, and after the procedure. [ABSTRACT FROM AUTHOR]

The aim of the article is to briefly describe our work together with Dr. Viktor Mutt. He discovered and purified many new gastrointestinal bioactive neuropeptides that have important applications as therapeutic agents in diabetes, epilepsy, migraine and weight control. Dr. Mutt's strategy was to search for Cterminally amidated peptides. We determined neuropeptide Y equilibrium binding for its receptor. Our work also included the LAla scan of pharmacophores of the neuropeptide galanin (128). Finally, the work led to the establishment of the coexistence of pep tides with small molecule neurotransmitters, such as serotonin, acetylcholine, noradrenaline and dopamine in central and peripheral neurons. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) patients are frequently exposed to antidepressant medications (ADMs). Norepinephrine (NE) and serotonin (5HT) systems have a role in levodopa-induced dyskinesias (LID) pathophysiology. Methods: We performed a longitudinal analysis on the PPMI cohort including drug-naïve PD patients, who are progressively exposed to dopamine replacement therapies (DRTs) to test the effect of ADM exposure on LID development by the 4th year of follow-up. Results: LID prevalence (according to MDS UPDRS score 4.1 ≥ 1) was 16% (42/251); these patients were more likely women (p = 0.01), had higher motor (p < 0.001) and depression scores (p = 0.01) and lower putaminal DAT binding ratio (p = 0.01). LID were associated with the exposure time to L-DOPA (2.2 ± 1.07 vs 2.6 ± 0.9, p = 0.02) and to the exposure to ADMs, in particular to SNRI (4.8% vs 21.4%, p < 0.001). The latter persisted after correcting for significant covariates (e.g., disease duration, cognitive status, motor impairment, depression, dopaminergic denervation). A similar difference in LID prevalence in PD patients exposed vs non-exposed to SNRI was observed on matched data by the real-world TriNetX repository (22% vs 13%, p < 0.001). Discussion: This study supports the presence of an effect of SNRI on LID priming in patients with early PD. Independent prospective cohort studies are warranted to further verify such association. [ABSTRACT FROM AUTHOR]

Aims Physical symptoms impact patients with heart failure (HF) despite treatment advancements; however, our understanding of the pathogenic mechanisms underlying HF symptoms remains limited, including sex differences therein. The objective of this study was to quantify associations between sympathetic markers [norepinephrine (NE) and 3,4-dihydroxyphenylglycol (DHPG)] and physical symptoms in patients with HF and to explore sex differences in these associations. Methods and results We performed a secondary analysis of combined data from two studies: outpatients with HF (n = 111), and patients prior to left ventricular assist device implantation (n = 38). Physical symptoms were measured with the Heart Failure Somatic Perception Scale (HFSPS) dyspnoea and early/subtle symptom subscales and the Functional Assessment in Chronic Illness Therapy Fatigue Scale (FACIT-F) to capture dyspnoea, early symptoms of decompensation, and fatigue. Norepinephrine and DHPG were measured with high-performance liquid chromatography with electrochemical detection. Multivariate linear regression was used to quantify associations between symptoms and sympathetic markers. The sample (n = 149) was 60.8 ± 15.7 years, 41% women, and 71% non-ischaemic aetiology. Increased plasma NE and NE:DHPG ratio were associated with worse FACIT-F scores (P = 0.043 and P = 0.013, respectively). Increased plasma NE:DHPG ratio was associated with worse HFSPS early/subtle symptoms (P = 0.025). In sex-stratified analyses, increased NE:DHPG ratio was associated with worse FACIT-F scores (P = 0.011) and HFSPS early/subtle scores (P = 0.022) among women but not men. Conclusion In patients with HF, sympathetic dysfunction is associated with worse fatigue and early/subtle physical symptoms with associations stronger in women than men. [ABSTRACT FROM AUTHOR]

During language comprehension, anomalies and ambiguities in the input typically elicit the P600 event‐related potential component. Although traditionally interpreted as a specific signal of combinatorial operations in sentence processing, the component has alternatively been proposed to be a variant of the oddball‐sensitive, domain‐general P3 component. In particular, both components might reflect phasic norepinephrine release from the locus coeruleus (LC/NE) to motivationally significant stimuli. In this preregistered study, we tested this hypothesis by relating both components to the task‐evoked pupillary response, a putative biomarker of LC/NE activity. 36 participants completed a sentence comprehension task (containing 25% morphosyntactic violations) and a non‐linguistic oddball task (containing 20% oddballs), while the EEG and pupil size were co‐registered. Our results showed that the task‐evoked pupillary response and the ERP amplitudes of both components were similarly affected by both experimental tasks. In the oddball task, there was also a temporally specific relationship between the P3 and the pupillary response beyond the shared oddball effect, thereby further linking the P3 to NE. Because this link was less reliable in the linguistic context, we did not find conclusive evidence for or against a relationship between the P600 and the pupillary response. Still, our findings further stimulate the debate on whether language‐related ERPs are indeed specific to linguistic processes or shared across cognitive domains. However, further research is required to verify a potential link between the two ERP positivities and the LC/NE system as the common neural generator. We investigated the relationship between late, positive ERP components and the task‐evoked pupillary response, a proposed marker of norepinephrine release. While we did find evidence of such a link regarding the oddball‐sensitive P3, evidence regarding the language related P600 was more mixed. Further replication is required to verify whether the two components belong to the same family of positivities, reflecting transient norepinephrine activity in response to rare and motivationally significant stimuli. [ABSTRACT FROM AUTHOR]

This article discusses a study comparing the effectiveness and safety of two treatments, terlipressin and norepinephrine, for hepatorenal syndrome (HRS). The study found that both treatments were equally effective in improving kidney function and stabilizing hemodynamic status without significant adverse effects. The analysis also showed no significant differences between the two groups in terms of baseline characteristics, medical history, and various health parameters. Norepinephrine was found to be a viable alternative to terlipressin, as it was safe, more cost-effective, and easily accessible. However, further research is needed to confirm these findings. [Extracted from the article]

Objective: To describe the clinical course and treatment of 3 dogs with peripheral vasopressor extravasation. Case Series Summary: Although vasopressor extravasation (VE) is a well‐documented complication in human medicine, literature describing VE and its management in veterinary patients is sparse. VE increases patient morbidity by causing local tissue injury and necrosis. The gold standard treatment for VE, phentolamine, has been periodically limited in supply in human medicine and is not consistently available for use in veterinary medicine. An alternative protocol proposed for use in people with VE combines topical nitroglycerin application with subcutaneous terbutaline infiltration. In this report, a treatment protocol utilizing these therapies was used to treat 3 dogs with VE and secondary tissue injury. New or Unique Information Provided: This report describes 3 cases of VE‐induced tissue injury in dogs. In addition, this report describes the use of perivascular terbutaline infiltration and topical nitroglycerin application as therapeutic management for VE in dogs. [ABSTRACT FROM AUTHOR]

In this review, we compare different refractory anaphylaxis (RA) management guidelines focusing on cardiovascular involvement and best practice recommendations, discuss postulated pathogenic mechanisms underlining RA and highlight knowledge gaps and research priorities. There is a paucity of data supporting existing management guidelines. Therapeutic recommendations include the need for the timely administration of appropriate doses of aggressive fluid resuscitation and intravenous (IV) adrenaline in RA. The preferred second‐line vasopressor (noradrenaline, vasopressin, metaraminol and dopamine) is unknown. Most guidelines recommend IV glucagon for patients on beta‐blockers, despite a lack of evidence. The use of methylene blue or extracorporeal life support (ECLS) is also suggested as rescue therapy. Despite recent advances in understanding the pathogenesis of anaphylaxis, the factors that lead to a lack of response to the initial adrenaline and thus RA are unclear. Genetic factors, such as deficiency in platelet activating factor‐acetyl hydrolase or hereditary alpha‐tryptasaemia, mastocytosis may modulate reaction severity or response to treatment. Further research into the underlying pathophysiology of RA may help define potential new therapeutic approaches and reduce the morbidity and mortality of anaphylaxis. [ABSTRACT FROM AUTHOR]