EBI2 is a negative modulator of brown adipose tissue energy expenditure in mice and human brown adipocytes.

Pharmacological activation of brown adipose tissue (BAT) is an attractive approach for increasing energy expenditure to counteract obesity. Given the side-effects of known activators of BAT, we studied inhibitors of BAT as a novel, alternative concept to regulate energy expenditure. We focused on G-protein-coupled receptors that are one of the major targets of clinically used drugs. Here, we identify GPR183, also known as EBI2, as the most highly expressed inhibitory G-protein-coupled receptor in BAT among the receptors examined. Activation of EBI2 using its endogenous ligand 7α,25-dihydroxycholesterol significantly decreases BAT-mediated energy expenditure in mice. In contrast, mice deficient for EBI2 show increased energy dissipation in response to cold. Interestingly, only thermogenic adipose tissue depots - BAT and subcutaneous white adipose tissue -respond to 7α,25-dihydroxycholesterol treatment/EBI2 activation but not gonadal white fat, which has the lowest thermogenic capacity. EBI2 activation in brown adipocytes significantly reduces norepinephrine-induced cAMP production, whereas pharmacological inhibition or genetic ablation of EBI2 results in an increased response. Importantly, EBI2 significantly inhibits norepinephrine-induced activation of human brown adipocytes. Our data identify the 7α,25-dihydroxycholesterol/EBI2 signaling pathway as a so far unknown BAT inhibitor. Understanding the inhibitory regulation of BAT might lead to novel pharmacological approaches to increase the activity of thermogenic adipose tissue and whole body energy expenditure in humans.

Assessment of Epinephrine and Norepinephrine in Gastric Carcinoma.

The aim of our study was to assess the sympathetic nervous system's involvement in the evolution of gastric carcinoma in patients by analyzing the mediators of this system (epinephrine and norepinephrine), as well as by analyzing the histological expression of the norepinephrine transporter (NET). We conducted an observational study including 91 patients diagnosed with gastric carcinoma and an additional 200 patients without cancer between November 2017 and October 2018. We set the primary endpoint as mortality from any cause in the first two years after enrolment in the study. The patients were monitored by a 24-h Holter electrocardiogram (ECG) to assess sympathetic or parasympathetic predominance. Blood was also collected from the patients to measure plasma free metanephrine (Meta) and normetanephrine (N-Meta), and tumor histological samples were collected for the analysis of NET expression. All of this was performed prior to the application of any antineoplastic therapy. Each patient was monitored for two years. We found higher heart rates in patients with gastric carcinoma than those without cancer. Regarding Meta and N-Meta, elevated levels were recorded in the patients with gastric carcinoma, correlating with the degree of tumor differentiation and other negative prognostic factors such as tumor invasion, lymph node metastasis, and distant metastases. Elevated Meta and N-Meta was also associated with a poor survival rate. All these data suggest that the predominance of the sympathetic nervous system's activity predicts increased gastric carcinoma severity.

Transient Overexpression of Vascular Endothelial Growth Factor A in Adipose Tissue Promotes Energy Expenditure via Activation of the Sympathetic Nervous System.

Adipose-derived vascular endothelial growth factor A (VEGF-A) stimulates functional blood vessel formation in obese fat pads, which in turn facilitates healthy expansion of the adipose tissue. However, the detailed mechanism(s) governing the process remains largely unknown. Here, we investigated the role of sympathetic nervous system activation in the process. To this end, we induced overexpression of VEGF-A in an adipose tissue-specific doxycycline (Dox)-inducible transgenic mouse model for a short period of time during high-fat diet (HFD) feeding. We found that local overexpression of VEGF-A in adipose tissue stimulated lipolysis and browning rapidly after Dox induction. Immunofluorescence staining against tyrosine hydroxylase (TH) indicated higher levels of sympathetic innervation in adipose tissue of transgenic mice. In response to an increased norepinephrine (NE) level, expression of ß3-adrenoceptor was significantly upregulated, and the downstream protein kinase A (PKA) pathway was activated, as indicated by enhanced phosphorylation of whole PKA substrates, in particular, the hormone-sensitive lipase (HSL) in adipocytes. As a result, the adipose tissue exhibited increased lipolysis, browning, and energy expenditure. Importantly, all of these effects were abolished upon treatment with the ß3-adrenoceptor antagonist SR59230A. Collectively, these results demonstrate that transient overexpressed VEGF-A activates the sympathetic nervous system, which hence promotes lipolysis and browning in adipose tissue.

[Dapagliflozin, a Sodium-Glucose Co-transporter-2 Inhibitor, Acutely Reduces Energy Expenditure in Brown Adipose Tissue via Neural Signals in Mice].

　Selective sodium glucose transporter-2 inhibitor (SGLT2i) treatment promotes urinary glucose excretion, thereby reducing blood glucose as well as body weight. However, only limited body weight reductions are achieved with SGLT2i administration. Hyperphagia is reportedly one of the causes of this limited weight loss. However, the effects of SGLT2i on systemic energy expenditure have not been fully elucidated. We investigated the acute effects of dapagliflozin, an SGLT2i, on systemic energy expenditure in mice. Eighteen hours after dapagliflozin administration, oxygen consumption and brown adipose tissue (BAT) expression of ucp1, a thermogenesis-related gene, were significantly decreased as compared with those after vehicle administration. In addition, dapagliflozin significantly suppressed norepinephrine (NE) turnover in BAT and c-fos expression in the rostral raphe pallidus nucleus (rRPa), which contains the sympathetic premotor neurons responsible for thermogenesis. These findings indicate that the dapagliflozin-mediated acute decrease in energy expenditure involves a reduction in BAT thermogenesis via decreased sympathetic nerve activity from the rRPa. Furthermore, common hepatic branch vagotomy abolished the reductions in ucp1 expression, NE contents in BAT, and c-fos expression in the rRPa. In addition, alterations in hepatic carbohydrate metabolism, such as decreases in glycogen contents and upregulation of phosphoenolpyruvate carboxykinase, occurred prior to the suppression of BAT thermogenesis, e.g., 6 h after dapagliflozin treatment. Collectively, these results suggest that SGLT2i acutely suppresses energy expenditure in BAT via regulation of an interorgan neural network consisting of the common hepatic vagal branch and sympathetic nerves.

Uncertainty, epistemics and active inference.

Biological systems-like ourselves-are constantly faced with uncertainty. Despite noisy sensory data, and volatile environments, creatures appear to actively maintain their integrity. To account for this remarkable ability to make optimal decisions in the face of a capricious world, we propose a generative model that represents the beliefs an agent might possess about their own uncertainty. By simulating a noisy and volatile environment, we demonstrate how uncertainty influences optimal epistemic (visual) foraging. In our simulations, saccades were deployed less frequently to regions with a lower sensory precision, while a greater volatility led to a shorter inhibition of return. These simulations illustrate a principled explanation for some cardinal aspects of visual foraging-and allow us to propose a correspondence between the representation of uncertainty and ascending neuromodulatory systems, complementing that suggested by Yu & Dayan (Yu & Dayan 2005 Neuron46, 681-692. (doi:10.1016/j.neuron.2005.04.026)).

Brown-adipose-tissue macrophages control tissue innervation and homeostatic energy expenditure.

Tissue macrophages provide immunological defense and contribute to the establishment and maintenance of tissue homeostasis. Here we used constitutive and inducible mutagenesis to delete the nuclear transcription regulator Mecp2 in macrophages. Mice that lacked the gene encoding Mecp2, which is associated with Rett syndrome, in macrophages did not show signs of neurodevelopmental disorder but displayed spontaneous obesity, which was linked to impaired function of brown adipose tissue (BAT). Specifically, mutagenesis of a BAT-resident Cx3Cr1+ macrophage subpopulation compromised homeostatic thermogenesis but not acute, cold-induced thermogenesis. Mechanistically, malfunction of BAT in pre-obese mice with mutant macrophages was associated with diminished sympathetic innervation and local titers of norepinephrine, which resulted in lower expression of thermogenic factors by adipocytes. Mutant macrophages overexpressed the signaling receptor and ligand PlexinA4, which might contribute to the phenotype by repulsion of sympathetic axons expressing the transmembrane semaphorin Sema6A. Collectively, we report a previously unappreciated homeostatic role for macrophages in the control of tissue innervation. Disruption of this circuit in BAT resulted in metabolic imbalance.

ATF4/ATG5 Signaling in Hypothalamic Proopiomelanocortin Neurons Regulates Fat Mass via Affecting Energy Expenditure.

Although many biological functions of activating transcription factor 4 (ATF4) have been identified, a role of hypothalamic ATF4 in the regulation of energy homeostasis is poorly understood. In this study, we showed that hypothalamic proopiomelanocortin (POMC) neuron-specific ATF4 knockout (PAKO) mice are lean and have higher energy expenditure. Furthermore, PAKO mice were resistant to high-fat diet-induced obesity, glucose intolerance, and leptin resistance. Moreover, the expression of autophagy protein 5 (ATG5) was increased or decreased by ATF4 knockdown or overexpression, respectively, and ATF4 inhibited the transcription of ATG5 by binding to the basic zipper-containing protein sites on its promoter. Importantly, mice with double knockout of ATF4 and ATG5 in POMC neurons gained more fat mass and reduced energy expenditure compared with PAKO mice under a high-fat diet. Finally, the effect of ATF4 deletion in POMC neurons was possibly mediated via enhanced ATG5-dependent autophagy and α-melanocyte-stimulating hormone production in the hypothalamus. Taken together, these results identify the beneficial role of hypothalamic ATF4/ATG5 axis in the regulation of energy expenditure, obesity, and obesity-related metabolic disorders, which suggests that ATF4/ATG5 axis in the hypothalamus may be a new potential therapeutic target for treating obesity and obesity-related metabolic diseases.

Ventromedial hypothalamic melanocortin receptor activation: regulation of activity energy expenditure and skeletal muscle thermogenesis.

KEY POINTS: The ventromedial hypothalamus (VMH) and the central melanocortin system both play vital roles in regulating energy balance by modulating energy intake and utilization. Recent evidence suggests that activation of the VMH alters skeletal muscle metabolism. We show that intra-VMH melanocortin receptor activation increases energy expenditure and physical activity, switches fuel utilization to fats, and lowers work efficiency such that excess calories are dissipated by skeletal muscle as heat. We also show that intra-VMH melanocortin receptor activation increases sympathetic nervous system outflow to skeletal muscle. Intra-VMH melanocortin receptor activation also induced significant changes in the expression of mediators of energy expenditure in muscle. These results support the role of melanocortin receptors in the VMH in the modulation of skeletal muscle metabolism. ABSTRACT: The ventromedial hypothalamus (VMH) and the brain melanocortin system both play vital roles in increasing energy expenditure (EE) and physical activity, decreasing appetite and modulating sympathetic nervous system (SNS) outflow. Because of recent evidence showing that VMH activation modulates skeletal muscle metabolism, we propose the existence of an axis between the VMH and skeletal muscle, modulated by brain melanocortins, modelled on the brain control of brown adipose tissue. Activation of melanocortin receptors in the VMH of rats using a non-specific agonist melanotan II (MTII), compared to vehicle, increased oxygen consumption and EE and decreased the respiratory exchange ratio. Intra-VMH MTII enhanced activity-related EE even when activity levels were held constant. MTII treatment increased gastrocnemius muscle heat dissipation during controlled activity, as well as in the home cage. Compared to vehicle-treated rats, rats with intra-VMH melanocortin receptor activation had higher skeletal muscle norepinephrine turnover, indicating an increased SNS drive to muscle. Lastly, intra-VMH MTII induced mRNA expression of muscle energetic mediators, whereas short-term changes at the protein level were primarily limited to phosphorylation events. These results support the hypothesis that melanocortin peptides act in the VMH to increase EE by lowering the economy of activity via the enhanced expression of mediators of EE in the periphery including skeletal muscle. The data are consistent with the role of melanocortins in the VMH in the modulation of skeletal muscle metabolism.

Dorsal and medial raphe nuclei participate differentially in reproductive functions of the male rat.

BACKGROUND: Innervation of the hypothalamus and median eminence arise from the dorsal and medial raphe nuclei (DRN and MRN, respectively). The hypothalamus regulates the secretion of gonadotropins, which in turn regulate the reproductive function of males and females. However, it is not known the role of raphe nuclei in male reproductive function. Our goal was to investigate the role of the DRN and MRN in the regulation of the testicular function and secretion of gonadotropins in prepubertal rats. METHODS: Dihydroxytryptamine (5,6-DHT) in ascorbic acid was used to chemically lesion the DRN or MRN. Rats were treated at 30 days-of-age and sacrificed at 45 or 65 days-of-age. Sham-treated controls were injected with ascorbic acid only. Negative controls were untreated rats. The damage induced by the 5,6-DHT was monitored in coronal serial sections of DRN and MRN; only the animals in which lesion of the DRN or MRN was detected were included in this study. As output parameters, we measured the concentrations of noradrenaline (NA), dopamine (DA) and serotonin (5-HT) in the anterior (AH) and medial (MH) hypothalamus by high performance liquid chromatography (HPLC); whereas, circulating concentrations of gonadotropins and sexual steroids were measured by radioimmunoassay. Seminiferous epithelium and sperm quality were also evaluated. RESULTS: Lesion of DRN or MRN does not induced changes in concentrations of LH, progesterone, and testosterone. Compared with the control group, the sham or lesion of the DRN or MRN did not modify noradrenaline or dopamine concentrations in the AH and MH at 45 or 65 days of age. Meanwhile, serotonin concentrations decreased significantly in lesioned rats. Lesion of DRN induced significantly lower concentrations of FSH regardless of age; similar lesion in the MRN had no impact on FSH levels. Sperm concentration and motility were significantly decreased in the same animals. The lesion of the MRN does not induced changes in the seminiferous epithelium or gonadotropin levels. Our results suggest that raphe nuclei regulate differentially the male reproductive functions. CONCLUSIONS: The DRN but not the MRN regulates the secretion of gonadotropins and testicular function.

Binding assessment of two arachidonic-based synthetic derivatives of adrenalin with ß-lactoglobulin: Molecular modeling and chemometrics approach.

A computational approach to predict the main binding modes of two adrenalin derivatives, arachidonoyl adrenalin (AA-AD) and arachidonoyl noradrenalin (AA-NOR) with the ß-lactoglubuline (BLG) as a nano-milk protein carrier is presented and assessed by comparison to the UV-Vis absorption spectroscopic data using chemometric analysis. Analysis of the spectral data matrices by using the multivariate curve resolution-alternating least squares (MCR-ALS) algorithm led to the pure concentration calculation and spectral profiles resolution of the chemical constituents and the apparent equilibrium constants computation. The negative values of entropy and enthalpy changes for both compound indicated the essential role of hydrogen bonding and van der Waals interactions as main driving forces in stabilizing protein-ligand complex. Computational studies predicted that both derivatives are situated in the calyx pose and remained in that pose during the whole time of simulation with no any significant protein structural changes which pointed that the BLG could be considered as a suitable carrier for these catecholamine compounds.

Dopamine antagonism decreases willingness to expend physical, but not cognitive, effort: a comparison of two rodent cost/benefit decision-making tasks.

Successful decision making often requires weighing a given option's costs against its associated benefits, an ability that appears perturbed in virtually every severe mental illness. Animal models of such cost/benefit decision making overwhelmingly implicate mesolimbic dopamine in our willingness to exert effort for a larger reward. Until recently, however, animal models have invariably manipulated the degree of physical effort, whereas human studies of effort have primarily relied on cognitive costs. Dopamine's relationship to cognitive effort has not been directly examined, nor has the relationship between individuals' willingness to expend mental versus physical effort. It is therefore unclear whether willingness to work hard in one domain corresponds to willingness in the other. Here we utilize a rat cognitive effort task (rCET), wherein animals can choose to allocate greater visuospatial attention for a greater reward, and a previously established physical effort-discounting task (EDT) to examine dopaminergic and noradrenergic contributions to effort. The dopamine antagonists eticlopride and SCH23390 each decreased willingness to exert physical effort on the EDT; these drugs had no effect on willingness to exert mental effort for the rCET. Preference for the high effort option correlated across the two tasks, although this effect was transient. These results suggest that dopamine is only minimally involved in cost/benefit decision making with cognitive effort costs. The constructs of mental and physical effort may therefore comprise overlapping, but distinct, circuitry, and therapeutic interventions that prove efficacious in one effort domain may not be beneficial in another.

Hormone-induced mitochondrial fission is utilized by brown adipocytes as an amplification pathway for energy expenditure.

Adrenergic stimulation of brown adipocytes (BA) induces mitochondrial uncoupling, thereby increasing energy expenditure by shifting nutrient oxidation towards thermogenesis. Here we describe that mitochondrial dynamics is a physiological regulator of adrenergically-induced changes in energy expenditure. The sympathetic neurotransmitter Norepinephrine (NE) induced complete and rapid mitochondrial fragmentation in BA, characterized by Drp1 phosphorylation and Opa1 cleavage. Mechanistically, NE-mediated Drp1 phosphorylation was dependent on Protein Kinase-A (PKA) activity, whereas Opa1 cleavage required mitochondrial depolarization mediated by FFAs released as a result of lipolysis. This change in mitochondrial architecture was observed both in primary cultures and brown adipose tissue from cold-exposed mice. Mitochondrial uncoupling induced by NE in brown adipocytes was reduced by inhibition of mitochondrial fission through transient Drp1 DN overexpression. Furthermore, forced mitochondrial fragmentation in BA through Mfn2 knock down increased the capacity of exogenous FFAs to increase energy expenditure. These results suggest that, in addition to its ability to stimulate lipolysis, NE induces energy expenditure in BA by promoting mitochondrial fragmentation. Together these data reveal that adrenergically-induced changes to mitochondrial dynamics are required for BA thermogenic activation and for the control of energy expenditure.

Assessment of the 18F-labeled PET tracer LMI1195 for imaging norepinephrine handling in rat hearts.

UNLABELLED: A novel (18)F-labeled tracer, LMI1195 (N-[3-bromo-4-(3-(18)F-fluoro-propoxy)-benzyl]-guanidine), is being developed for sympathetic nerve imaging; its high specificity for neural uptake-1 mechanism has previously been demonstrated in cell associative studies and in rabbit and nonhuman primate studies assessing heart uptake. The aim of this study was to investigate the mechanisms of (18)F-LMI1195 cardiac uptake in the rat, which is known to contain norepinephrine uptake mechanisms beyond uptake-1. METHODS: Tracer accumulation in the heart was studied over time after intravenous administration of (18)F-LMI1195 in healthy male Wistar rats by quantitative in vivo PET imaging. The uptake mechanism was assessed by pretreatment with the nonselective norepinephrine uptake-1 and norepinephrine uptake-2 inhibitor phenoxybenzamine (50 mg/kg intravenously; n = 4), the selective norepinephrine uptake-1 inhibitor desipramine (2 mg/kg intravenously; n = 4), or saline control (intravenously; n = 4). RESULTS: (18)F-LMI1195 produced high and sustained heart uptake allowing clear delineation of the left ventricular wall over 60 min after tracer administration. Pretreatment with phenoxybenzamine markedly reduced the (18)F-LMI1195 cardiac uptake when compared with controls. In contrast, there was preserved (18)F-LMI1195 uptake after desipramine pretreatment. CONCLUSION: In rats, cardiac uptake of (18)F-LMI1195 was significantly inhibited by phenoxybenzamine but not desipramine, suggesting (18)F-LMI1195 is a substrate for the uptake-2 mechanism and is consistent with the rat heart having a dominant level of the mechanism.

Cannabinoid receptor blockade reduces the opportunity cost at which rats maintain operant performance for rewarding brain stimulation.

There is ample evidence that blockade of CB(1) receptors reduces reward seeking. However, the reported effects of CB(1) blockade on performance for rewarding electrical brain stimulation stand out as an exception. By applying a novel method for conceptualizing and measuring reward seeking, we show that AM-251, a CB(1) receptor antagonist, does indeed decrease performance for rewarding electrical stimulation of the medial forebrain bundle in rats. Reward seeking depends on multiple sets of variables, including the intensity of the reward, its cost, and the value of competing rewards. In turn, reward intensity depends both on the sensitivity and gain of brain reward circuitry. We show that drug-induced changes in sensitivity cannot account for the suppressive effect of AM-251 on reward seeking. Therefore, the role of CB(1) receptors must be sought among the remaining determinants of performance. Our analysis provides an explanation of the inconsistencies between prior reports, which likely arose from the following: (1) the averaging of data across subjects showing heterogeneous effects and (2) the use of methods that cannot distinguish between the different determinants of reward pursuit. By means of microdialysis, we demonstrate that blockade of CB(1) receptors attenuates nucleus accumbens dopamine release in response to rewarding medial forebrain bundle stimulation, and we propose that this action is responsible for the ability of the drug to decrease performance for the electrical reward.

Histamine in Macaca mulatto monkey cardiac sympathetic nerve system: a morphological and functional assessment.

Our previous study demonstrated the co-localization of histamine with norepinephrine (NE) within superior cervical ganglia (SCG), and the release of histamine from sympathetic nerve endings of guinea pig evoked by stimulations. We have now further investigated that whether the histamine can be synthesized, stored and released from the sympathetic nerve systems of Macaca mulatto monkey, and investigated the modulation of the sympathetic endogenous histamine release through histamine H(3) receptor in the monkey cardiac sympathetic nerve system. Double-labeled immunofluorescence technique was applied to investigate co-localization of histamine and NE in SCG of Macaca mulatto monkey. The cardiac sympathetic nerve terminals (synaptosomes) of Macaca mulatto monkey was prepared and depolarized with 50 mmol/L K(+). Histamine released from synaptosomes was detected by spectrofluorometer and regulations of histamine release through Ca(2+), Ca(2+)-channel blockers, H(3)-receptor agonist (R)-alpha-methylhistamine and histamine H(3)-receptor antagonist, thioperamide were observed. Co-localization of histamine and NE was identified within the same neuron of SCG. Release of histamine was Ca(2+)-dependent and inhibited by N-type Ca(2+)-channel blocker omega-conotoxin, but not affected by the L-type Ca(2+)-channel blocker lacidipine. Compound 48/80, a mast cell releaser, did not affect cardiac synaptosome histamine exocytosis. Cardiac synaptosome histamine release was augmented by the enhanced synthesis of histamine or the inhibition of histamine metabolism. Histamine H(3)-receptor activation by (R)-alpha-methylhistamine inhibited high K(+)-evoked histamine release and thioperamide blocked the effects of (R)-alpha-methylhistamine. These results firstly showed that histamine co-existed with NE within sympathetic neurons of monkey and the exocytosis of histamine from sympathetic terminals could be regulated by presynaptic histamine H(3) receptors. Sympathetic histamine may act as a neurotransmitter to modulate sympathetic neurotransmission.

Assessment of the effects of L- and N-type Ca2+ channel blocking drugs using canine blood-perfused papillary muscle preparations.

It is important to accurately and conveniently assess the effects of L- and N-type Ca(2+) channel blocking drugs, which are commonly used for treatment of hypertension, but no method is available to simultaneously assess the effects of them in the same preparation. We have therefore designed an ex vivo method to measure the changes in contractile response of anterior papillary muscle of right ventricle and myocardial interstitial norepinephrine (NE) level using canine blood-perfused papillary muscle preparations. Papillary muscle-developed tension (PMDT) induced by an electronic stimulator was measured with force transducer. Myocardial interstitial NE effluent was collected by microdialysis fiber, which was implanted at the base of the papillary muscle, and measured with high performance liquid chromatography. Cilnidipine, a typical L- and N-type Ca(2+) channel blocker, was used to prove the efficiency of this method. First, to assess the effects of drugs on L-type Ca(2+) channel, the changes in basal PMDT were measured. Cilnidipine and nicardipine, a selective L-type Ca(2+) channel blocker, but not omega-conotoxin GVIA (omega-CTX), a selective N-type Ca(2+) channel blocking peptide, decreased basal PMDT dose-dependently. Second, to assess the effects of drugs on N-type Ca(2+) channel, the changes in PMDT and myocardial interstitial NE level by intracardiac sympathetic ganglion stimulation were measured. Cilnidipine and omega-CTX, but not nicardipine, dose-dependently reduced sympathomimetic increases in PMDT and myocardial interstitial NE level. These results indicate that our method is efficient to assess the effects of various L- and N-type Ca(2+) channel blocking drugs in the same papillary muscle preparation.

Phasic norepinephrine: a neural interrupt signal for unexpected events.

Extensive animal studies indicate that the neuromodulator norepinephrine plays an important role in specific aspects of vigilance, attention and learning, putatively serving as a neural interrupt or reset function. The activity of norepinephrine-releasing neurons in the locus coeruleus during attentional tasks is modulated not only by the animal's level of engagement and the sensory inputs, but also by temporally rich aspects of internal decision-making processes. Here, we propose that it is unexpected changes in the world within the context of a task that activate the noradrenergic interrupt signal. We quantify this idea in a Bayesian model of a well-studied visual discrimination task, demonstrating that the model captures a rich repertoire of noradrenergic responses at the sub-second temporal resolution.

Cost-effectiveness of duloxetine versus routine treatment for U.S. patients with diabetic peripheral neuropathic pain.

UNLABELLED: The purpose of this study was to compare the cost-effectiveness of duloxetine versus routine treatment in management of diabetic peripheral neuropathic pain (DPNP). Two hundred thirty-three patients with DPNP who completed a 12-week, double-blind, placebo-controlled, randomized, multicenter duloxetine trial were re-randomized into a 52-week, open-label trial of duloxetine 60 mg twice daily versus routine treatment. Routine treatment included pain management therapies. Effectiveness was measured by using the bodily pain domain (BP) of the Medical Outcomes Study Short Form 36 (SF-36). Costs were analyzed from 3 perspectives: third party payer (direct medical costs), employer (direct and indirect medical costs), and societal (patient's out-of-pocket costs and total medical costs). Costs of study medications were not included because of limited data. Bootstrap method was applied to calculate statistical inference of the incremental cost-effectiveness ratio (ICER). Routine treatment most frequently used included gabapentin (56%), venlafaxine (36%), and amitripytline (15%). From employer and societal perspectives, duloxetine was cost-effective (ICER= -342 dollars and -429 dollars, respectively, per unit of SF-36 BP; both P

Assessment of cardiovascular autonomic function.

Autonomic assessment has played an important role in elucidating the role of the autonomic nervous system in diverse clinical and research settings. The techniques most widely used in the clinical setting entail the measurement of an end-organ response to a physiological provocation. The non-invasive measures of cardiovascular parasympathetic function involve the analysis of heart rate variability while the measures of cardiovascular sympathetic function assess the blood pressure response to physiological stimuli. Prolonged tilt-table testing, with or without pharmacological provocation, has become an important tool in the investigation of a predisposition to neurally mediated (vasovagal) syncope. Frequency domain analyses of heart rate and blood pressure variability, microneurography, occlusion plethysmography, laser Doppler imaging and flowmetry, and cardiac sympathetic imaging are currently research tools but may find a place in the clinical assessment of autonomic function in the future.