A hypothalamus-habenula circuit controls aversion.

Encoding and predicting aversive events are critical functions of circuits that support survival and emotional well-being. Maladaptive circuit changes in emotional valence processing can underlie the pathophysiology of affective disorders. The lateral habenula (LHb) has been linked to aversion and mood regulation through modulation of the dopamine and serotonin systems. We have defined the identity and function of glutamatergic (Vglut2) control of the LHb, comparing the role of inputs originating in the globus pallidus internal segment (GPi), and lateral hypothalamic area (LHA), respectively. We found that LHb-projecting LHA neurons, and not the proposed GABA/glutamate co-releasing GPi neurons, are responsible for encoding negative value. Monosynaptic rabies tracing of the presynaptic organization revealed a predominantly limbic input onto LHA Vglut2 neurons, while sensorimotor inputs were more prominent onto GABA/glutamate co-releasing GPi neurons. We further recorded the activity of LHA Vglut2 neurons, by imaging calcium dynamics in response to appetitive versus aversive events in conditioning paradigms. LHA Vglut2 neurons formed activity clusters representing distinct reward or aversion signals, including a population that responded to mild foot shocks and predicted aversive events. We found that the LHb-projecting LHA Vglut2 neurons encode negative valence and rapidly develop a prediction signal for negative events. These findings establish the glutamatergic LHA-LHb circuit as a critical node in value processing.

Indications for and clinical procedures resulting from magnetic resonance imaging of the knee in older patients: Are we choosing wisely?

OBJECTIVE: To analyze the indications for and clinical procedures resulting from knee magnetic resonance imaging (MRI) in older patients. DESIGN: We retrospectively analyzed 215 medical records of patients 50 years of age and older who had undergone a unilateral knee MRI in 2009. SETTING: Centre hospitalier universitaire de Sherbrooke in Quebec. PARTICIPANTS: Patients 50 years of age and older who underwent a knee MRI in 2009. MAIN OUTCOME MEASURES: The main outcome measure was an invasive procedure in the same knee that underwent an MRI. Medical charts were reviewed up to 2014 for patient characteristics, MRI indication, ordering physician specialty, radiography before MRI, MRI findings, and clinical procedures resulting from the MRI. RESULTS: The patients' mean (SD) age was 60.6 (7.5) years. The main MRI indications were meniscopathy (148 [68.8%]) and chronic pain (92 [42.8%]). The main MRI findings were osteoarthritis (OA) (185 [86.0%]) and meniscal lesions (170 [79.1%]). Only 82 (38.1%) patients had a plain radiograph in the 24 months preceding the MRI, usually without a standing anteroposterior view. Findings on pre-MRI radiography (n = 201) demonstrated OA in 144 (71.6%) patients. Overall, 87 (40.5%) patients were seen by an orthopedic surgeon and 27 (31.0%) of these patients underwent an invasive intervention. Among the 81 patients with moderate to severe OA on MRI, 36 (44.4%) had radiographic evidence of moderate to severe OA and only 3 (3.7%) underwent arthroscopic meniscectomy. CONCLUSION: Our study reproduces the known association between OA and degenerative meniscal changes in older patients. We have found a surprising underuse of the standing anteroposterior view on radiography. Most patients in our cohort could have been appropriately diagnosed and treated based on such radiographic information, as demonstrated by pre-MRI findings, thus avoiding the MRI and subsequent evaluation by an orthopedic surgeon. Meniscectomy was rarely performed, particularly in patients with advanced OA. Educational and pragmatic measures must be emphasized to encourage the use of radiography and to limit the inappropriate use of MRI, a costly technique.

BET 3: Bedside lung ultrasound for the diagnosis of pneumonia in children.

A short cut review was carried to examine the evidence for the use of ultrasound in diagnosing pneumonia in paediatric patients. A literature search was performed that found one systematic review and meta-analysis based on eight papers and a further five relevant papers. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these papers are tabulated. The clinical bottom line is that lung ultrasound appears to have an acceptable sensitivity and specificity for the diagnosis of pneumonia in children when performed by an experienced sonographer.

Towards evidence based emergency medicine: Best BETs from the Manchester Royal Infirmary. BET 3: Advantages of ultrasound-assisted lumbar puncture.

A short cut review was carried out to establish ultrasound can assist. 9 papers were found of which 4 presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these best papers are tabulated. The clinical bottom line is that using ultrasound assisted landmarks prior to LP improves success rate and reduces the number of attempts and traumatic taps.

Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 1: Impact of point-of-care ultrasound on length of stay for paediatric appendicitis.

A short cut review was carried out to establish whether point-of-care abdominal ultrasound could affect the emergency department (ED) length of stay (LOS) of children attending with suspected appendicitis. Using the reported searches, one paper presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of this best paper are tabulated. It is concluded that point-of-care abdominal ultrasound has sufficient specificity to be used to reduce LOS of paediatric patients in the ED with positive results for appendicitis. It is insufficiently sensitive to be used to rule out appendicitis.

[Regulators in access to anticancer drugs in Canada]. / Les régulateurs dans l’accès aux médicaments contre le cancer au Canada.

Based exclusively on drugs approved by provincial public health insurance systems, many authors have reported significant variability in terms of access to anticancer drugs (ACD) among Canadian citizens, raising problems of equal access to these drugs.In this paper, we emphasize that the mere presence on the list of public drug plans cannot be considered to be a sufficient indicator to determine the real availability of anticancer drugs (ACD) for the patient. We describe and compare four sets of regulators defined in each province and determine their effects on the accessibility of ACD for patients in each province. The term regulator comprises the conditions which must be observed for access via the public health insurance system as well as the rules (strategies) decided by the third-party payer for the management of these conditions.The results of our analyses lead to the conclusion that there is indeed a variation between provinces in terms of access to drugs financed by public funds, but that this variability primarily impacts less important treatments.

Simvastatin treatment enhances NMDAR-mediated synaptic transmission by upregulating the surface distribution of the GluN2B subunit.

The ramifications of statins on plasma cholesterol and coronary heart disease have been well documented. However, there is increasing evidence that inhibition of the mevalonate pathway may provide independent neuroprotective and procognitive pleiotropic effects, most likely via inhibition of isoprenoids, mainly farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). FPP and GGPP are the major donors of prenyl groups for protein prenylation. Modulation of isoprenoid availability impacts a slew of cellular processes including synaptic plasticity in the hippocampus. Our previous work has demonstrated that simvastatin (SV) administration improves hippocampus-dependent spatial memory, rescuing memory deficits in a mouse model of Alzheimer's disease. Treatment of hippocampal slices with SV enhances long-term potentiation (LTP), and this effect is dependent on the activation of Akt (protein kinase B). Further studies showed that SV-induced enhancement of hippocampal LTP is driven by depletion of FPP and inhibition of farnesylation. In the present study, we report the functional consequences of exposure to SV at cellular/synaptic and molecular levels. While application of SV has no effect on intrinsic membrane properties of CA1 pyramidal neurons, including hyperpolarization-activated cyclic-nucleotide channel-mediated sag potentials, the afterhyperpolarization (AHP), and excitability, SV application potentiates the N-methyl D-aspartate receptor (NMDAR)-mediated contribution to synaptic transmission. In mouse hippocampal slices and human neuronal cells, SV treatment increases the surface distribution of the GluN2B subunit of the NMDAR without affecting cellular cholesterol content. We conclude that SV-induced enhancement of synaptic plasticity in the hippocampus is likely mediated by augmentation of synaptic NMDAR components that are largely responsible for driving synaptic plasticity in the CA1 region.

Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) presenting as diffuse myositis.

BACKGROUND: Eosinophilic granulomatosis with polyangiitis is a complex multisystemic syndrome with heterogeneous presentation. Most often, there is a clinical history of asthma or other atopic conditions, and current presentation generally includes signs of cutaneous or pulmonary involvement. Very few reports described myalgia or weakness as the chief complaint. Of these, only a few included muscle biopsy evaluation and none showed convincing evidence of primary myositis. We believe this report is the first to demonstrate true myositis in the setting of early eosinophilic granulomatosis with polyangiitis. CASE PRESENTATION: This report describes a 74 year old Caucasian man, with no known allergies, presenting severe myalgia, muscle weakness, jaw claudication, and fever. Blood work showed marked eosinophilia and high creatine kinase levels. Biceps brachialis muscle biopsy revealed eosinophilic necrotizing vasculitis and true myositis with myophagocytosis of non-necrotic fibers and strong sarcolemmal MHC-1 overexpression by immunohistochemistry. This patient was successfully treated with prednisone and azathioprine. CONCLUSION: Our finding of true myositis in a case of eosinophilic granulomatosis with polyangiitis suggests that primary auto-immunity against muscle fibers, distinct from the secondary effects of vasculitis, can occur in this entity and may represent an overlap syndrome. Early recognition of eosinophilic granulomatosis with polyangiitis in patients presenting with myositis may provide an opportunity to treat the vasculitis before onset of severe multisystemic disease. We recommend the use of muscle biopsy with immunohistochemistry for MHC-1 to confirm the diagnosis of myositis in the setting of eosinophilic granulomatosis with polyangiitis.

Dabigatran versus warfarin under standard or pharmacogenetic-guided management for the prevention of stroke and systemic thromboembolism in patients with atrial fibrillation: a cost/utility analysis using an analytic decision model.

BACKGROUND: Atrial fibrillation (AF) is the most common form of heart arrhythmia and a leading cause of stroke and systemic embolism. Chronic anticoagulation is recommended for preventing those complications. Our study aimed to compare the cost/utility (CU) of three main anticoagulation options: 1) standard warfarin dosing (SD-W) 2) warfarin dosage under the guidance of CYP2C9 and VKORC1 genotyping (GT-W) and 3) dabigatran 150 mg twice a day. METHODS: A Markov state transition model was built to simulate the expected C/U of dabigatran, SD-W and GT-W anticoagulation therapy for the prevention of stroke and systemic thromboembolism in patients with atrial fibrillation over a period of 5 years under the perspective of the public health care system. Model inputs were derived from extensive literature search and government's data bases. Outcomes considered were the number of total major events (thromboembolic and hemorrhagic events), total costs in Canadian dollars (1CAD$ = 1$US), total quality-adjusted life years (QALYs), costs/QALYs and incremental costs/QALYs gained (ICUR). RESULTS: Raw base case results show that SD-W has the lowest C/U ratio. However, the dabigatran option might be considered as an alternative, as its cost per additional QALY gained compared to SD-W is CAD $ 4 765, i.e. less than 50 000, the ICUR threshold generally accepted to adopt an intervention. At the same threshold, GT-W doesn't appear to be an alternative to SD-W. Our results were robust to one-way and multi-way sensitivity analyses. CONCLUSION: SD-W has the lowest C/U ratio among the 3 options. However, dabigatran might be considered as an alternative. GT-W is not C/U and should not currently be recommended for the routine anticoagulotherapy management of AF patients.

Methods of Therapeutic Drug Monitoring to Guide Vancomycin Dosing Regimens: Trough Concentration versus Ratio of Area Under the Curve to Minimum Inhibitory Concentration.

Background: The most recent vancomycin monitoring guideline recommends targeting a value for area under the curve (AUC) of 400 to 600 mg*h/L, with an assumed minimum inhibitory concentration (MIC) of 1 mg/L. Few studies have investigated the effect of this method on vancomycin dosing regimens, relative to a target trough concentration of 15 to 20 mg/L. Objective: To compare vancomycin dosing regimens generated with the 2 monitoring methods. Methods: This retrospective chart review included hospitalized patients who received vancomycin between May 2019 and April 2020. The dosing regimens were compared, with the paired Student t test, in terms of unit dose, daily dose, and dosing interval. Variables of interest were collected from electronic medical charts. A pharmacy resident used first-order pharmacokinetic equations to determine dosing regimens based on AUC monitoring. Local pharmacists retrospectively determined dosing regimens for trough-based monitoring. Results: Of 100 courses of treatment initially identified, 66 were included in the analysis. The unit dose was similar with the 2 methods (1086 mg with AUC-based monitoring versus 1100 mg with trough-based monitoring; p = 0.62). AUC monitoring was associated with a 12.8% lower daily dose (2294 mg versus 2630 mg; p < 0.001) and a 13.5% longer dosing interval (13.24 h versus 11.67 h; p < 0.001) relative to trough-based monitoring. AUC monitoring also generated a lower extrapolated trough concentration (12.90 mg/L versus 16.22 mg/L; p < 0.001). Conclusions: A target trough concentration of 15 to 20 mg/L was confirmed as being unnecessarily high. AUC monitoring could allow a reduction in daily vancomycin dose and an extension of the dosing interval relative to trough-based monitoring.

Contexte: La plus récente directive en matière de surveillance de la vancomycine recommande de cibler une valeur de surface sous la courbe (en anglais, AUC) de 400 à 600 mg*h/L, avec une concentration minimale inhibitrice (CMI) supposée de 1 mg/L. Peu d'études ont étudié l'effet de cette méthode sur les schémas posologiques de la vancomycine, par rapport à une concentration minimale cible de 15 à 20 mg/L. Objectif: Comparer les schémas posologiques de la vancomycine générés avec les 2 méthodes de surveillance. Méthodes: Cette revue rétrospective des dossiers comprenait des patients hospitalisés ayant reçu de la vancomycine entre mai 2019 et avril 2020. Un test de Student pour données appariées a été réalisé afin de comparer les schémas posologiques sur le plan de la dose unitaire, de la dose quotidienne et de l'intervalle de dosage. Les variables d'intérêt ont été recueillies à partir de dossiers médicaux électroniques. Un résident en pharmacie a utilisé des équations pharmacocinétiques de premier ordre pour déterminer les schémas posologiques en fonction de la surveillance de l'AUC. Les pharmaciens locaux ont déterminé rétrospectivement les schémas posologiques pour la surveillance basée sur la concentration résiduelle. Résultats: Sur 100 cours de traitement initialement identifiés, 66 ont été inclus dans l'analyse. La dose unitaire était similaire avec les 2 méthodes (1086 mg avec surveillance basée sur l'AUC contre 1100 mg avec surveillance basée sur la concentration résiduelle; p = 0,62). La surveillance de l'AUC était associée à une dose quotidienne inférieure de 12,8 % (2294 mg contre 2630 mg; p < 0,001) et à un intervalle de dosage plus long de 13,5 % (13,24 h contre 11,67 h; p < 0,001) par rapport à la surveillance basée sur la concentration résiduelle. La surveillance de l'AUC a également généré une concentration minimale extrapolée plus faible (12,90 mg/L contre 16,22 mg/L; p < 0,001). Conclusions: Une concentration résiduelle cible de 15 à 20 mg/L a été confirmée comme étant inutilement élevée. La surveillance de l'AUC pourrait permettre une réduction de la dose quotidienne de vancomycine et un allongement de l'intervalle de dosage par rapport à la surveillance basée sur la concentration résiduelle.

Identification of the hippocampal input to medial prefrontal cortex in vitro.

To delineate the cellular mechanisms underlying the function of medial prefrontal cortex (mPFC) networks, it is critical to understand how synaptic inputs from various afferents are integrated and drive neuronal activity in this region. Using a newly developed slice preparation, we were able to identify a bundle of axons that contain extraneocortical fibers projecting to neurons in the prelimbic cortex. The anatomical origin and functional connectivity of the identified fiber bundle were probed by in vivo track tracing in combination with optic and whole-cell recordings of neurons in layers 2/3 and 5/6. We demonstrate that the identified bundle contains afferent fibers primarily from the ventral hippocampus but does not include contributions from the mediodorsal nucleus of the thalamus, amygdala, or lateral hypothalamus/medial forebrain bundle. Further, we provide evidence that activation of this fiber bundle results in patterned activity of neurons in the mPFC, which is distinct from that of laminar stimulation of either the deep layers 5/6 or the superficial layer 1. Evoked excitatory postsynaptic potentials are monosynaptic and glutamatergic and exhibit bidirectional changes in synaptic efficacy in response to physiologically relevant induction protocols. These data provide the necessary groundwork for the characterization of the hippocampal pathway projecting to the mPFC.

OR Traffic and Surgical Site Infections: A Quality Improvement Project.

Operating rooms are dynamic places with a lot of movement and people working as a concerted team. Operating room traffic can be necessary (eg, retrieving an unusual supply) or unnecessary (eg, a social visit). This quality improvement project aimed to reduce the amount of OR traffic to only necessary traffic and reduce the surgical site infection rates for the orthopedic ORs in a northern California community hospital. There were three principle interventions: door signs discouraging traffic, staff member relief in batches, and preference card review for accuracy. During the six-week post-intervention period, there were no reported surgical site infections for orthopedic procedures, and the standardized infection ratio decreased from 1.75 to 0 in 10 weeks. Operating room traffic decreased after implementation by 46.9%. The number of door openings per minute decreased from 1.96 per minute to 1.04 per minute at the project's conclusion. Staff members' awareness of OR traffic increased.

The first case of bacillus Calmette-Guérin-induced small-vessel central nervous system vasculitis.

To present an unrecognized vascular complication of bacillus Calmette-Guérin (BCG) therapy administered for superficial bladder carcinoma. We also review the potential mimickers for primary angiitis of the central nervous system (PACNS) as well as complications of intravesical BCG therapy. An 89-year-old Caucasian man with a history of relapsing high-grade bladder carcinoma treated with intravesical BCG presented with recurring episodes of right upper limb paresthesia with clumsiness and dysarthria. Magnetic resonance imaging of the head revealed multiple predominantly left-sided frontotemporal micronodular peri-vascular lesions. Left frontal lobe biopsy showed non-necrotizing granulomatous vasculitis. Ziehl staining was negative. Initially, he was treated for PACNS but his symptoms relapsed during every attempt to taper the corticosteroids. Six months later, he developed bilateral mycobacterial endophthalmitis, caused by Mycobacterium bovis. Brain biopsy was reviewed and confirmed the presence of perivascular mycobacteria. A retrospective diagnosis of BCG-induced central nervous system vasculitis was made and he was treated with high-dose corticosteroids, moxifloxacin, isoniazid, ethambutol, and rifampicin. BCG is a live attenuated form of Mycobacterium bovis widely used as tuberculosis vaccination and intravesical therapy for superficial forms of bladder cancer. Systemic complications affect roughly 5% of patients and can manifest months or years after the last instillation. Cases of endophthalmitis, meningitis, aortitis, or mycotic aneurysms have been described, but no reports of CNS vasculitis have been found. In disseminated forms of BCG infections, referred to as BCGitis, histopathology usually reveals granulomatous inflammation. Mycobacterial cultures are often negative, making this a diagnostic challenge. This is the first documented case of BCG-induced small-vessel CNS vasculitis. Mycobacterium bovis infection is rare and findings are often nonspecific, making the diagnosis very difficult. Other infectious and non-infectious causes must be ruled out appropriately before considering this entity.

Loss of human ICOSL results in combined immunodeficiency.

Primary immunodeficiencies represent naturally occurring experimental models to decipher human immunobiology. We report a patient with combined immunodeficiency, marked by recurrent respiratory tract and DNA-based viral infections, hypogammaglobulinemia, and panlymphopenia. He also developed moderate neutropenia but without prototypical pyogenic infections. Using whole-exome sequencing, we identified a homozygous mutation in the inducible T cell costimulator ligand gene (ICOSLG; c.657C>G; p.N219K). Whereas WT ICOSL is expressed at the cell surface, the ICOSLN219K mutation abrogates surface localization: mutant protein is retained in the endoplasmic reticulum/Golgi apparatus, which is predicted to result from deleterious conformational and biochemical changes. ICOSLN219K diminished B cell costimulation of T cells, providing a compelling basis for the observed defect in antibody and memory B cell generation. Interestingly, ICOSLN219K also impaired migration of lymphocytes and neutrophils across endothelial cells, which normally express ICOSL. These defects likely contributed to the altered adaptive immunity and neutropenia observed in the patient, respectively. Our study identifies human ICOSLG deficiency as a novel cause of a combined immunodeficiency.

Feasibility of emergency department point-of-care ultrasound for rib fracture diagnosis in minor thoracic injury.

OBJECTIVES: The main objective of this study was to evaluate the feasibility of emergency department (ED) point-of-care ultrasound (PoCUS) for rib fracture diagnosis in patients with minor thoracic injury (mTI). Secondary objectives were to 1) evaluate patients' pain during the PoCUS procedure, 2) identify the limitations of the use of PoCUS technique, and 3) compare the diagnosis obtained with PoCUS to radiography results. METHODS: Adult patients who presented with clinical suspicion of rib fractures after mTI were included. All patients underwent PoCUS performed by emergency physicians (EPs) prior to a rib view X-ray. A visual analogue scale (VAS) ranging from 0 to 100 was used to ascertain feasibility, patients' pain and clinicians' degree of certitude. Feasibility was defined as a score of more than 50 on the VAS. We documented the radiologists' interpretation of rib view X-ray. Radiologists were blinded to the PoCUS results. RESULTS: Ninety-six patients were included. A majority (65%) of EPs concluded that the PoCUS technique to diagnose rib fracture was feasible (VAS score > 50). Median score for feasibility was 63. Median score was 31 (Interquartile range [IQR] 5-57) for patients' pain related to the PoCUS. The main limiting factor of the PoCUS technique was pain during patient examination (15%). CONCLUSION: PoCUS examination appears to be a feasible technique for a rib fracture diagnosis in the ED.

A Heart Stopping Case of the Bezold-Jarisch Reflex.

The Bezold-Jarisch reflex is a parasympathetic reflex induced by intense mechanical stimulation of the ventricular myocytes. Exceptionally, cases have been described in patients receiving dobutamine infusion during a stress echocardiography. All were healthy middle-aged women and recovered without sequelae. A healthy 60-year-old woman suffered two 5.9-second episodes of asystole during her 20 mcg/kg/min infusion of dobutamine. Recovery was quick and without sequelae. Echocardiography and coronary angiography were both normal. In conclusion, this is the fourth documented case of a severe Bezold-Jarisch reflex causing asystole during dobutamine infusion. Diagnosis can only be made after excluding all other possible diagnoses, most importantly ischemia. This serves as a reminder of the importance of close monitoring during dobutamine infusion.

Cholinergic and ghrelinergic receptors and KCNQ channels in the medial PFC regulate the expression of palatability.

The medial prefrontal cortex (mPFC) is a key brain region for the control of consummatory behavior. Neuronal activity in this area is modulated when rats initiate consummatory licking and reversible inactivations eliminate reward contrast effects and reduce a measure of palatability, the duration of licking bouts. Together, these data suggest the hypothesis that rhythmic neuronal activity in the mPFC is crucial for the control of consummatory behavior. The muscarinic cholinergic system is known to regulate membrane excitability and control low-frequency rhythmic activity in the mPFC. Muscarinic receptors (mAChRs) act through KCNQ (Kv7) potassium channels, which have recently been linked to the orexigenic peptide ghrelin. To understand if drugs that act on KCNQ channels within the mPFC have effects on consummatory behavior, we made infusions of several muscarinic drugs (scopolamine, oxotremorine, physostigmine), the KCNQ channel blocker XE-991, and ghrelin into the mPFC and evaluated their effects on consummatory behavior. A consistent finding across all drugs was an effect on the duration of licking bouts when animals consume solutions with a relatively high concentration of sucrose. The muscarinic antagonist scopolamine reduced bout durations, both systemically and intra-cortically. By contrast, the muscarinic agonist oxotremorine, the cholinesterase inhibitor physostigmine, the KCNQ channel blocker XE-991, and ghrelin all increased the durations of licking bouts when infused into the mPFC. Our findings suggest that cholinergic and ghrelinergic signaling in the mPFC, acting through KCNQ channels, regulates the expression of palatability.

The medial prefrontal cortex is crucial for the maintenance of persistent licking and the expression of incentive contrast.

We examined the role of the medial prefrontal cortex (mPFC) in reward processing and the control of consummatory behavior. Rats were trained in an operant licking procedure in which they received alternating access to solutions with relatively high and low levels of sucrose (20 and 4%, w/v). Each level of sucrose was available for fixed intervals of 30 s over 30 min test sessions. Over several days of training, rats came to lick persistently when the high level of sucrose was available and suppressed licking when the low level of sucrose was available. Pharmacological inactivations of the mPFC, specifically the rostral part of the prelimbic area, greatly reduced intake of the higher value fluid and only slightly increased intake of the lower value fluid. In addition, the inactivations altered within-session patterns and microstructural measures of licking. Rats licked equally for the high and low levels of sucrose at the beginning of the test sessions and "relearned" to reduce intake of the low value fluid over the test sessions. Durations of licking bouts (clusters of licks with inter-lick intervals <0.5 s) were reduced for the high value fluid and there were many more brief licking bouts (<1 s) when the low value fluid was available. These effects were verified using an alternative approach (optogenetic silencing using archaerhodopsin) and were distinct from inactivation of the ventral striatum, which simply increased overall intake. Our findings suggest that the mPFC is crucial for the maintenance of persistent licking and the expression of learned feeding strategies.

Yohimbine administration prevents over-responsiveness to epinephrine induced by simulated microgravity.

BACKGROUND: Simulated microgravity produces sustained inhibition of sympathoneural release, turnover, and synthesis of norepinephrine (NE) and hypersensitization of beta-adrenergic pathways. These changes may explain the orthostatic intolerance experienced by astronauts returning from spaceflights. HYPOTHESIS: Chronic administration of yohimbine would prevent the increase of beta-adrenergic hypersensitivity to epinephrine (Epi) induced by simulated microgravity. METHODS: Eight healthy young subjects received 8 mg of yohimbine (an antagonist of alpha2adrenoceptors) orally twice a day during the simulated microgravity achieved through -6 degrees head-down bed rest (HDBR). The catecholamine-induced lipolysis was studied on isolated fat cells from subcutaneous adipose tissue before HDBR and on the fifth day of HDBR. Epi was infused at three graded rates (0.01, 0.02, and 0.03 microg x kg(-1) x min(-1) for 40 min each) before and at the end of the HDBR period. The effects of Epi on the sympathetic nervous system (SNS) activity-assessed by plasma NE levels and spectral analysis of systolic BP and heart rate variability-and on plasma levels of glycerol, non-esterified fatty acids, glucose, and insulin and on energy expenditure were evaluated. RESULTS: Under yohimbine treatment, HDBR failed to modify urinary NE excretion and spectral variability of systolic BP in the mid-frequency range. The beta- and alpha-adrenergic sensitivity of fat cells were not modified by HDBR nor were plasma NE levels and spectral variability of systolic BP induced by Epi infusion. No alteration of Epi-induced changes in heart rate and systolic and diastolic BPs were observed after HDBR. Epi-induced increases in plasma glucose, insulin, glycerol, and non-esterified fatty acid levels as well as energy expenditure were also unmodified by HDBR. Only the Epi-induced plasma lactate level was increased by HDBR. CONCLUSION: Our data suggest that the increase in the effects of Epi induced during microgravity could be attenuated by chronic administration of yohimbine. An explanation for this effect could be SNS activation brought about by the alpha2-adrenoceptor antagonist properties of yohimbine.