The hunger games.

Although AgRP and POMC neurons in the hypothalamus have long been associated with regulation of food intake, in this issue of Cell, Chen et al. use direct imaging in vivo to demonstrate rapid changes in their activity upon food presentation. The rapidity of their altered responses challenges classic notions of their functions and raises new hypotheses.

The Incentive-Sensitization Theory of Addiction 30 Years On.

The incentive-sensitization theory (IST) of addiction was first published in 1993, proposing that (a) brain mesolimbic dopamine systems mediate incentive motivation ("wanting") for addictive drugs and other rewards, but not their hedonic impact (liking) when consumed; and (b) some individuals are vulnerable to drug-induced long-lasting sensitization of mesolimbic systems, which selectively amplifies their "wanting" for drugs without increasing their liking of the same drugs. Here we describe the origins of IST and evaluate its status 30 years on. We compare IST to other theories of addiction, including opponent-process theories, habit theories of addiction, and prefrontal cortical dysfunction theories of impaired impulse control. We also address critiques of IST that have been raised over the years, such as whether craving is important in addiction and whether addiction can ever be characterized as compulsive. Finally, we discuss several contemporary phenomena, including the potential role of incentive sensitization in behavioral addictions, the emergence of addiction-like dopamine dysregulation syndrome in medicated Parkinson's patients, the role of attentional capture and approach tendencies, and the role of uncertainty in incentive motivation.

Affective valence in the brain: modules or modes?

How do brain systems evaluate the affective valence of a stimulus - that is, its quality of being good or bad? One possibility is that a neural subsystem, or 'module' (such as a subregion of the brain, a projection pathway, a neuronal population or an individual neuron), is permanently dedicated to mediate only one affective function, or at least only one specific valence - an idea that is termed here the 'affective modules' hypothesis. An alternative possibility is that a given neural module can exist in multiple neurobiological states that give it different affective functions - an idea termed here the 'affective modes' hypothesis. This suggests that the affective function or valence mediated by a neural module need not remain permanently stable but rather can change dynamically across different situations. An evaluation of evidence for the 'affective modules' versus 'affective modes' hypotheses may be useful for advancing understanding of the affective organization of limbic circuitry.

Spatiotemporal Control of Vascular CaV1.2 by α1C S1928 Phosphorylation.

BACKGROUND: L-type CaV1.2 channels undergo cooperative gating to regulate cell function, although mechanisms are unclear. This study tests the hypothesis that phosphorylation of the CaV1.2 pore-forming subunit α1C at S1928 mediates vascular CaV1.2 cooperativity during diabetic hyperglycemia. METHODS: A multiscale approach including patch-clamp electrophysiology, super-resolution nanoscopy, proximity ligation assay, calcium imaging' pressure myography, and Laser Speckle imaging was implemented to examine CaV1.2 cooperativity, α1C clustering, myogenic tone, and blood flow in human and mouse arterial myocytes/vessels. RESULTS: CaV1.2 activity and cooperative gating increase in arterial myocytes from patients with type 2 diabetes and type 1 diabetic mice, and in wild-type mouse arterial myocytes after elevating extracellular glucose. These changes were prevented in wild-type cells pre-exposed to a PKA inhibitor or cells from knock-in S1928A but not S1700A mice. In addition, α1C clustering at the surface membrane of wild-type, but not wild-type cells pre-exposed to PKA or P2Y11 inhibitors and S1928A arterial myocytes, was elevated upon hyperglycemia and diabetes. CaV1.2 spatial and gating remodeling correlated with enhanced arterial myocyte Ca2+ influx and contractility and in vivo reduction in arterial diameter and blood flow upon hyperglycemia and diabetes in wild-type but not S1928A cells/mice. CONCLUSIONS: These results suggest that PKA-dependent S1928 phosphorylation promotes the spatial reorganization of vascular α1C into "superclusters" upon hyperglycemia and diabetes. This triggers CaV1.2 activity and cooperativity, directly impacting vascular reactivity. The results may lay the foundation for developing therapeutics to correct CaV1.2 and arterial function during diabetic hyperglycemia.

Outcomes of children with constipation and autism spectrum disorder treated with antegrade continence enemas.

BACKGROUND: Treatment of functional constipation (FC) in children with autism spectrum disorder (ASD) is challenging due to sensory and behavioral issues. We aimed to understand whether antegrade continence enemas (ACEs) are successful in the treatment of FC in children with ASD. METHODS: A single-institution retrospective review was performed in children diagnosed with ASD and FC who underwent appendicostomy or cecostomy placement from 2007 to 2019. Descriptive statistics regarding soiling and complications were calculated. RESULTS: There were 33 patients included, with a median age of 9.7 years at the time of ACE initiation. The average intelligence quotient was 63.6 (SD = 18.0, n = 12), the average behavioral adaptive score was 59.9 (SD = 11.1, n = 13), and the average total Child Behavioral Checklist score was 72.5 (SD = 7.1, n = 10). Soiling rates were significantly lower following ACE initiation (42.3% vs. 14.8%, p = 0.04). Behavioral issues only prevented 1 patient (3.0%) from proper ACE use. Eleven patients (36.6%) were able to transition to laxatives. There were significant improvements in patient-reported outcomes measures and quality of life. CONCLUSION: Placement of an appendicostomy or cecostomy for management of FC in children with severe ASD was successful in treating constipation and improving quality of life.

Mid-term outcomes of microfracture for the treatment of focal, full-thickness cartilage defects isolated to the humeral head.

BACKGROUND: While microfracture has been shown to be an effective treatment for chondral lesions in the knee, evidence to support its use for chondral defects in the shoulder is limited to short-term outcomes studies. The purpose of this study is to determine if microfracture provides pain relief and improved shoulder function in patients with isolated focal chondral defects of the humeral head at a minimum 5-year follow-up. METHODS: Patients who underwent microfracture procedure for isolated focal chondral defects of the humeral head with a minimum follow-up of 5 years between 02/2006 and 08/2016 were included. At minimum 5-year follow-up, pre- and postoperative patient-reported outcome (PRO) measures were collected, including the American Shoulder and Elbow Surgeons (ASES), Single Assessment Numeric Evaluation (SANE), Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH), Short Form-12 (SF-12) Physical Component Summary (PCS), Visual Analog Scale (VAS) for pain, and patient satisfaction level (1 = unsatisfied, 10 = very satisfied). Demographic, injury, and surgical data were retrospectively reviewed. Surgical failure was defined as revision surgery for humeral chondral defects or conversion to arthroplasty. Kaplan-Meier analysis was performed to determine survivorship at 5 years. RESULTS: A total of 17 patients met inclusion/exclusion criteria. There were 15 men and 2 women with an average age of 51 years (range 36-69) and an average follow-up of 9.4 years (range 5.0-15.8). The median ASES score improved from 62 (range: 22-88) preoperatively to 90 (range: 50-100) postoperatively (P = .011). Median satisfaction was 8 out of 10 (range: 2-10). There was no correlation between patient age or defect size and PROs. Postoperatively, patients reported significant improvements in recreational and sporting activity as well as the ability to sleep on the affected shoulder (P ≤ .05). Three patients failed and required revision surgery. The Kaplan-Meier analysis determined an overall survivorship rate of 80% at 5 years. CONCLUSION: The presented study illustrates significant improvements for PROs, improved ability to perform recreational and sporting activities, and a survival rate of 80% at a mean of 9.4 years after microfracture for focal chondral humeral head defects.

Assessment of glove stretch and storage temperature on fentanyl permeation: Implications for standard test methods and PPE recommendations.

The National Institute for Occupational Safety and Health recommends the use of nitrile gloves with a minimum thickness of 5.0 ± 2.0 mil [0.127 ± 0.051 millimeters] in situations where it is suspected or known that fentanyl or other illicit drugs are present. However, there is limited data available on fentanyl permeation through gloves. Current test methods used to measure fentanyl permeation do not consider the effect of glove fit and flexion. Furthermore, first responders need to have PPE readily available in the field, and storage conditions may affect the protective performance of the gloves. The objective of this study was to evaluate the effects of glove stretch and storage temperatures on glove durability and barrier performance against fentanyl. Nine nitrile glove models previously shown to be resistant to fentanyl permeation were selected for this investigation. These nine models were stretched 25% in one linear direction, to consider glove fit and flexion, and tested against fentanyl hydrochloride permeation. Additionally, four of the nine glove models were stored at 48 °C, 22 °C, and -20 °C, and evaluated for tensile strength, ultimate elongation, and puncture resistance after up to 16 wk of storage and fentanyl permeation after up to 8 wk of storage. At least one sample for six of the nine tested models had maximum permeation over the test method fail threshold when stretched. The tested storage temperatures showed no effect on glove tensile strength, ultimate elongation, and puncture resistance. The findings of this study can be used to inform PPE recommendations, with consideration to storage practices and proper sizing for first responders with potential exposure to fentanyl and other illicit drugs. The results of this study can be used to assess the need for new standard test methods to evaluate the barrier performance of gloves and shelf-life determination with consideration to glove fit.

Mfge8 is expressed by pericytes in gastric antrum submucosa from patients with obesity.

The main function of the stomach is to digest ingested food. Gastric antrum muscular contractions mix ingested food with digestive enzymes and stomach acid and propel the chyme through the pyloric sphincter at a rate in which the small intestine can process the chyme for optimal nutrient absorption. Mfge8 binding to α8ß1 integrins helps regulate gastric emptying by reducing the force of antral smooth muscle contractions. The source of Mfge8 within gastric muscles is unclear. Since Mfge8 is a secreted protein, Mfge8 could be delivered via the circulation, or be locally secreted by cells within the muscle layers. In this study, we identify a source of Mfge8 within human gastric antrum muscles using spatial transcriptomic analysis. We show that Mfge8 is expressed in subpopulations of Mef2c+ perivascular cells within the submucosa layer of the gastric antrum. Mef2c is expressed in subpopulations of NG2+ and PDGFRB+ pericytes. Mfge8 is expressed in NG2+/Mef2c+ pericytes, but not in NG2+/Mef2c-, PDGFRB+/Mef2c-, or PDGFRB+/Mef2c+ pericytes. Mfge8 is absent from CD34+ endothelial cells but is expressed in a small population of perivascular ACTA2+ cells. We also show that α8 integrin is not expressed by interstitial cells of Cajal (ICC), supporting the findings that Mfge8 attenuates gastric antrum smooth muscle contractions by binding to α8ß1 integrins on enteric smooth muscle cells. These findings suggest a novel, supplementary mechanism of regulation of gastric antrum motility by cellular regulators of capillary blood flow, in addition to the regulation of gastric antrum motility by the enteric nervous system and the SMC, ICC, and PDGFRα+ cell (SIP) syncytium.

Evaluation of Chronic Constipation in Children With Autism Spectrum Disorder.

OBJECTIVES: Chronic constipation occurs frequently in children with autism spectrum disorder (ASD). The primary objective was to determine whether chronic constipation is associated with a higher rate of abnormal colonic motor activity in ASD children than in non-ASD children. A secondary goal was to determine if clinical variables could identify children with ASD at risk for possessing abnormal colonic motility. METHODS: A retrospective, propensity-matched, case-control study compared colonic manometry (CM) of an ASD cohort and non-ASD controls with chronic constipation. Clinical variables were evaluated as potential predictors for abnormal colonic motility. RESULTS: Fifty-six patients with ASD and 123 controls without the diagnosis of ASD who underwent CM were included. Propensity score resulted in 35 matched cohorts of ASD and controls. The rate of abnormal CM findings between ASD and matched controls (24% vs 20%, P = 0.78) did not differ significantly. A prediction model of abnormal CM that included ASD diagnosis, duration of constipation, and soiling achieved a sensitivity of 0.94 and specificity of 0.65. The risk for abnormal colonic motility increased 11% for every 1-year increase in duration of constipation. Odds for abnormal motility were 30 times higher in ASD children with soiling than controls with soiling (P < 0.0001). CONCLUSIONS: Chronic constipation does not appear to be associated with a higher rate of abnormal colonic motility in children with ASD. Clinical information of disease duration and presence of soiling due to constipation show promise in identifying patients with ASD at a greater risk for abnormal colonic motility.

Exploring the Relationship Between Mental Toughness and Self-Compassion in the Context of Sport Injury.

Helping athletes cope effectively with injury is likely of great interest to many sport stakeholders. Mental toughness is one psychological factor positively associated with resilience and sport performance, though stubborn persistence through injury might not always be conducive to adaptive athlete outcomes. Self-compassion-a balanced, nonjudgmental approach in relating to oneself when experiencing suffering-might help circumvent these pitfalls and complement injury recovery. The purpose of this study was to explore the relationship between mental toughness and self-compassion in a sport injury context. This study consisted of 2 phases-phase I quantitatively assessed the relationships between mental toughness, self-compassion, and other psychological constructs, while phase II used qualitative interviews to corroborate and inform these findings. In phase I, competitive athletes who were injured at the time of data collection (n = 81) completed mental toughness, self-compassion, coping resources, self-esteem, and self-criticism questionnaires. Self-compassion was positively correlated with mental toughness (r = .48, P < .01), coping resources (r = .54, P < .05), and self-esteem (r = .60, P < .01). Self-compassion and self-criticism were negatively correlated with each other (r = -.52, P < .01). Results from hierarchical multiple regression analyses revealed that self-compassion was a significant predictor of mental toughness (ΔR2 = .07, P < .01), coping resources (ΔR2 = .10, P < .01), and self-criticism (ΔR2 = .06, P < .01), beyond the effects of self-esteem. Four injured athletes who scored above the median on mental toughness and self-compassion measures were interviewed in phase II. Thematic analysis generated 2 themes: (1) self-compassion grants access to wise mental toughness and (2) mental toughness helps activate self-compassionate actions during injury. These findings are consistent with recent research and suggest that both mental toughness and self-compassion can work together to help athletes cope with sport injury.

Metalloendopeptidase ADAM-like Decysin 1 (ADAMDEC1) in Colonic Subepithelial PDGFRα+ Cells Is a New Marker for Inflammatory Bowel Disease.

Metalloendopeptidase ADAM-Like Decysin 1 (ADAMDEC1) is an anti-inflammatory peptidase that is almost exclusively expressed in the gastrointestinal (GI) tract. We have recently found abundant and selective expression of Adamdec1 in colonic mucosal PDGFRα+ cells. However, the cellular origin for this gene expression is controversial as it is also known to be expressed in intestinal macrophages. We found that Adamdec1 mRNAs were selectively expressed in colonic mucosal subepithelial PDGFRα+ cells. ADAMDEC1 protein was mainly released from PDGFRα+ cells and accumulated in the mucosal layer lamina propria space near the epithelial basement membrane. PDGFRα+ cells significantly overexpressed Adamdec1 mRNAs and protein in DSS-induced colitis mice. Adamdec1 was predominantly expressed in CD45- PDGFRα+ cells in DSS-induced colitis mice, with only minimal expression in CD45+ CD64+ macrophages. Additionally, overexpression of both ADAMDEC1 mRNA and protein was consistently observed in PDGFRα+ cells, but not in CD64+ macrophages found in human colonic mucosal tissue affected by Crohn's disease. In summary, PDGFRα+ cells selectively express ADAMDEC1, which is localized to the colon mucosa layer. ADAMDEC1 expression significantly increases in DSS-induced colitis affected mice and Crohn's disease affected human tissue, suggesting that this gene can serve as a diagnostic and/or therapeutic target for intestinal inflammation and Crohn's disease.

Desire or Dread from Nucleus Accumbens Inhibitions: Reversed by Same-Site Optogenetic Excitations.

Microinjections of a glutamate AMPA antagonist (DNQX) in medial shell of nucleus accumbens (NAc) can cause either intense appetitive motivation (i.e., 'desire') or intense defensive motivation (i.e., 'dread'), depending on site along a flexible rostrocaudal gradient and on environmental ambience. DNQX, by blocking excitatory AMPA glutamate inputs, is hypothesized to produce relative inhibitions of NAc neurons. However, given potential alternative explanations, it is not known whether neuronal inhibition is in fact necessary for NAc DNQX microinjections to generate motivations. Here we provide a direct test of whether local neuronal inhibition in NAc is necessary for DNQX microinjections to produce either desire or dread. We used optogenetic channelrhodopsin (ChR2) excitations at the same local sites in NAc as DNQX microinjections to oppose relative neuronal inhibitions induced by DNQX in female and male rats. We found that same-site ChR2 excitation effectively reversed the ability of NAc DNQX microinjections to generate appetitive motivation, and similarly reversed ability of DNQX microinjections to generate defensive motivation. Same-site NAc optogenetic excitations also attenuated recruitment of Fos expression in other limbic structures throughout the brain, which was otherwise elevated by NAc DNQX microinjections that generated motivation. However, to successfully reverse motivation generation, an optic fiber tip for ChR2 illumination needed to be located within <1 mm of the corresponding DNQX microinjector tip; that is, both truly at the same NAc site. Thus, we confirm that localized NAc neuronal inhibition is required for AMPA-blocking microinjections in medial shell to induce either positively-valenced 'desire' or negatively-valenced 'dread'.SIGNIFICANCE STATEMENT A major hypothesis posits neuronal inhibitions in nucleus accumbens generate intense motivation. Microinjections in nucleus accumbens of glutamate antagonist, DNQX, which might suppress local neuronal firing, generate either appetitive or defensive motivation, depending on site and environmental factors. Is neuronal inhibition in nucleus accumbens required for such pharmacologically-induced motivations? Here we demonstrate that neuronal inhibition is necessary to generate appetitive or defensive motivations, using local optogenetic excitations to oppose putative DNQX-induced inhibitions. We show that excitation at the same site prevents DNQX microinjections from recruiting downstream limbic structures into neurobiological activation, and simultaneously prevents generation of either appetitive or defensive motivated behaviors. These results may be relevant to roles of nucleus accumbens mechanisms in pathological motivations, including addiction and paranoia.

An Iron(IV)-Oxo Intermediate Initiating l-Arginine Oxidation but Not Ethylene Production by the 2-Oxoglutarate-Dependent Oxygenase, Ethylene-Forming Enzyme.

Ethylene-forming enzyme (EFE) is an ambifunctional iron(II)- and 2-oxoglutarate-dependent (Fe/2OG) oxygenase. In its major (EF) reaction, it converts carbons 1, 2, and 5 of 2OG to CO2 and carbons 3 and 4 to ethylene, a four-electron oxidation drastically different from the simpler decarboxylation of 2OG to succinate mediated by all other Fe/2OG enzymes. EFE also catalyzes a minor reaction, in which the normal decarboxylation is coupled to oxidation of l-arginine (a required activator for the EF pathway), resulting in its conversion to l-glutamate semialdehyde and guanidine. Here we show that, consistent with precedent, the l-Arg-oxidation (RO) pathway proceeds via an iron(IV)-oxo (ferryl) intermediate. Use of 5,5-[2H2]-l-Arg slows decay of the ferryl complex by >16-fold, implying that RO is initiated by hydrogen-atom transfer (HAT) from C5. That this large substrate deuterium kinetic isotope effect has no impact on the EF:RO partition ratio implies that the same ferryl intermediate cannot be on the EF pathway; the pathways must diverge earlier. Consistent with this conclusion, the variant enzyme bearing the Asp191Glu ligand substitution accumulates ∼4 times as much of the ferryl complex as the wild-type enzyme and exhibits a ∼40-fold diminished EF:RO partition ratio. The selective detriment of this nearly conservative substitution to the EF pathway implies that it has unusually stringent stereoelectronic requirements. An active-site, like-charge guanidinium pair, which involves the l-Arg substrate/activator and is unique to EFE among four crystallographically characterized l-Arg-modifying Fe/2OG oxygenases, may serve to selectively stabilize the transition state leading to the unique EF branch.

Neurobiology of rodent self-grooming and its value for translational neuroscience.

Self-grooming is a complex innate behaviour with an evolutionarily conserved sequencing pattern and is one of the most frequently performed behavioural activities in rodents. In this Review, we discuss the neurobiology of rodent self-grooming, and we highlight studies of rodent models of neuropsychiatric disorders--including models of autism spectrum disorder and obsessive compulsive disorder--that have assessed self-grooming phenotypes. We suggest that rodent self-grooming may be a useful measure of repetitive behaviour in such models, and therefore of value to translational psychiatry. Assessment of rodent self-grooming may also be useful for understanding the neural circuits that are involved in complex sequential patterns of action.

Polyethylene Glycol 3350 Changes Stool Consistency and the Microbiome but not Behavior of CD1 Mice.

OBJECTIVES: Polyethylene Glycol 3350 (PEG3350) is a laxative commonly used to treat constipation in children. The Food and Drug Administration has received reports of increased anxiety, aggression, and obsessive--compulsive behaviors in children administered PEG3350. Thus, we assessed whether daily administration of PEG3350 leads to anxiety-like behavior in mice. METHODS: Outbred CD-1 IGS mice were administered either a high or a low dose of PEG3350 via daily oral gavage for 2 weeks. As a laxative comparison and control, additional mice were given a high or low dose of magnesium citrate or vehicle (water). Weight and stool consistency were assessed after each gavage to determine laxative effectiveness. Anxiety-like behaviors were assessed using light/dark, open field, and elevated plus maze (EPM) tests at baseline, after 2 weeks of daily gavage, and after a 2 week washout in experiment 1, and after 2 weeks of daily gavage in experiment 2. Stool samples were collected for microbiome analysis in experiment 2 at baseline, after 2 weeks of daily gavage, and after 2 weeks washout. RESULTS: PEG3350 and magnesium citrate significantly changed stool consistency, as well as microbiome alpha and beta diversity. Anxiety-like behaviors were not, however, different in mice administered low or high doses of PEG3350 or magnesium citrate. CONCLUSIONS: Although changes in stool consistency and the gut microbiome occurred, administration of PEG3350 did not alter anxiety-like behaviors.

Mapping excessive "disgust" in the brain: Ventral pallidum inactivation recruits distributed circuitry to make sweetness "disgusting".

The ventral pallidum (VP) is an important structure in processing reward. The VP may be the only brain structure where localized lesions in rats replace normal facial "liking" expressions to sweetness with excessive "disgust" reactions, such as gapes and chin rubs, that are normally reserved for unpalatable tastes. The posterior half of the VP (pVP) contains a hedonic hot spot where opioid or related neurochemical stimulations can amplify positive "liking" reactions to sweet taste. This is the same site where lesions or pharmacological inactivations replace positive hedonic reactions to sucrose with intense negative "disgust." In the present study, we aimed to identify brain networks recruited by pVP inactivation to generate excessive "disgust," using neuronal Fos expression as a marker of neurobiological activation. Microinjections in pVP of inhibitory GABAA/B agonists (muscimol and baclofen) caused rats to exhibit excessive "disgust" reactions to sucrose. Excessive "disgust" was accompanied by recruitment of neural Fos activation in several subcortical structures, including the posterior medial shell of nucleus accumbens (which also contains another GABAergic "disgust"-inducing "hedonic cold spot"), the bed nucleus of stria terminalis, lateral habenula, hypothalamus, and midbrain ventral tegmentum. Fos suppression was found in cortical limbic regions, including previously identified hedonic hot spots in the anteromedial orbitofrontal cortex and posterior insula. Finally, in addition to inducing excessive "disgust," pVP inactivation abolished motivational "wanting" to eat palatable food, reduced positive social interactions, and reordered sensorimotor relations. Our findings identify potential "disgust" generators in the brain that are released into excitation by pVP inhibition and may serve as targets for future research.

The identification of neuronal control pathways supplying effector tissues in the stomach.

The stomach acts as a buffer between the ingestion of food and its processing in the small intestine. It signals to the brain to modulate food intake and it in turn regulates the passage of a nutrient-rich fluid, containing partly digested food, into the duodenum. These processes need to be finely controlled, for example to restrict reflux into the esophagus and to transfer digesta to the duodenum at an appropriate rate. Thus, the efferent pathways that control gastric volume, gastric peristalsis and digestive juice production are critically important. We review these pathways with an emphasis on the identities of the final motor neurons and comparisons between species. The major types of motor neurons arising from gastric enteric ganglia are as follows: immunohistochemically distinguishable excitatory and inhibitory muscle motor neurons; four neuron types innervating mucosal effectors (parietal cells, chief cells, gastrin cells and somatostatin cells); and vasodilator neurons. Sympathetic efferent neurons innervate intramural arteries, myenteric ganglia and gastric muscle. Vagal efferent neurons with cell bodies in the brain stem do not directly innervate gastric effector tissues; they are pre-enteric neurons that innervate each type of gastric enteric motor neuron. The principal transmitters and co-transmitters of gastric motor neurons, as well as key immunohistochemical markers, are the same in rat, pig, human and other species.

Opioid and orexin hedonic hotspots in rat orbitofrontal cortex and insula.

Hedonic hotspots are brain sites where particular neurochemical stimulations causally amplify the hedonic impact of sensory rewards, such as "liking" for sweetness. Here, we report the mapping of two hedonic hotspots in cortex, where mu opioid or orexin stimulations enhance the hedonic impact of sucrose taste. One hedonic hotspot was found in anterior orbitofrontal cortex (OFC), and another was found in posterior insula. A suppressive hedonic coldspot was also found in the form of an intervening strip stretching from the posterior OFC through the anterior and middle insula, bracketed by the two cortical hotspots. Opioid/orexin stimulations in either cortical hotspot activated Fos throughout a distributed "hedonic circuit" involving cortical and subcortical structures. Conversely, cortical coldspot stimulation activated circuitry for "hedonic suppression." Finally, food intake was increased by stimulations at several prefrontal cortical sites, indicating that the anatomical substrates in cortex for enhancing the motivation to eat are discriminable from those for hedonic impact.

The role of growth and maturation during adolescence on team-selection and short-term sports participation.

BACKGROUND: During adolescence, deselection from sport occurs during team try-outs when month of birth, stage of growth and maturation may influence selection. AIM: The purpose of this study was to identify differences in growth and maturity related factors between those selected and deselected in youth sports teams and identify short-term associations with continued participation. SUBJECTS AND METHODS: Eight hundred and seventy participants, aged 11-17 years, were recruited from six sports try-outs in Saskatchewan, Canada: baseball, basketball, football, hockey, soccer and volleyball. Two hundred and forty-four of the initial 870 (28%) returned for follow-up at 36 months. Chronological (years from birth), biological (years from age at peak height velocity (APHV)) and relative (month of birth as it relates to the selection band) ages were calculated from measures of date of birth, date of test, height, sitting height and weight. Parental heights were measured or recalled and participant's adult height predicted. Reference standards were used to calculate z-scores. Sports participation was self-reported at try-outs and at 36-month follow-up. RESULTS: There was an over-representation of players across all sports born in the first and second quartiles of the selection bands (p < 0.05), whether they were selected or deselected. z-scores for predicted adult height ranged from 0.1 (1.1) to 1.8 (1.2) and were significantly different between sports (p < 0.05). Height and APHV differences (p < 0.05) were found between selected and deselected male participants. In females only weight differed between selected and deselected female hockey players (p < 0.05); no further differences were found between selected and deselected female participants. Four per cent of deselected athletes exited sports participation and 68% of deselected athletes remained in the same sport at 36 months, compared with 84% of selected athletes who remained in the same sport. CONCLUSIONS: It was found that youth who attended sports team's try-outs were more likely to be born early in the selection year, be tall for their age, and in some sports early maturers. The majority of both the selected and deselected participants continued to participate in sport 36 months after try-outs, with the majority continuing to participate in their try-out sport.

Fentanyl and carfentanil permeation through commercial disposable gloves.

In 2018, the Centers for Disease Control and Prevention reported that opioid overdose deaths (including fentanyl and carfentanil) comprised 46,802 (69%) of the 67,367 total drug overdose deaths. The opioid overdose epidemic affects Americans not only at home but also in the workplace. First responders may be at risk of opioid exposure during incidents such as vehicle searches and responses to overdose calls. To reduce direct exposure to opioids and other hazardous drugs, first responders rely in part on personal protective equipment (PPE) as their last line of defense. First responders seek guidance from the National Institute for Occupational Safety and Health (NIOSH) regarding appropriate PPE selection for potential opioid exposure. There is limited empirical glove performance data for illicit drugs. Empirical data are needed to validate NIOSH's current recommendations regarding gloves to help prevent exposure to illicit drugs (i.e., powder-free nitrile gloves with a minimum thickness of 5 ± 2 mil [0.127 ± 0.051 millimeters]); however, no industry standard or test method currently exists for specifically evaluating PPE performance against fentanyl and its analogs. To understand the permeation qualities of gloves when challenged against fentanyl and carfentanil solutions, the ASTM International (formerly American Society for Testing and Materials) ASTM D6978-19 standard for chemotherapy drug glove permeation was adapted to test fentanyl and carfentanil hydrochloride solution permeation through twelve disposable glove models, including five models in which the manufacturers claim fentanyl protection. No nitrile glove models showed fentanyl or carfentanil permeation rates above the chemotherapy drug threshold criterion of 0.01 µg/cm2/min (i.e., thereby meeting the performance requirement) as calculated using the ASTM D6978-19 standard within the 240-min test. Latex and vinyl glove materials exhibited fentanyl and carfentanil permeation with permeation rates above this threshold. These findings are among the first empirical data to support NIOSH's current opioid glove recommendations and define procedures that could be used to support industry standards for evaluating opioid permeation through air-impermeable PPE materials.