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Objectives Treatment approach of myasthenia gravis (MG) is still debated; corticosteroids alone or in combination with immunosuppressive agents are the most used drugs. Azathioprine (AZA) has been shown to be effective for MG with a significant steroid-sparing activity, although burdened by side effects. Few studies on methotrexate (MTX) administration showed controversial results. In this cohort, we evaluated the role of MTX as a effective steroid-sparing agent. Methods Fifteen MG patients treated with MTX, previously treated with AZA for at least 12 months, with poor benefits and uncomfortable side effects AZA related, have been selected. Each patient was evaluated through MG-Activity of Daily Living and Quantitative MG scores 5 times/yr. Results Patients treated with MTX had a significant improvement of MG-Activity of Daily Living and Quantitative MG scores. Furthermore, all patients reduced prednisone dosage, and none complained of side effects. Conclusions We suggest MTX is effective and well tolerated and could be considered as a steroid-sparing agent in MG treatment.

Myasthenia gravis (MG) is a chronic autoimmune disorder of the neuromuscular junction characterised by an autoantibody against acetylcholine receptor (AChR-Ab), autoantibody against muscle-specific kinase (MuSK-Ab), lipoprotein-related protein 4 or agrin in the postsynaptic membrane at the neuromuscular junction. Many patients are resistant to conventional treatment and effective therapies are needed. Rituximab (RTX) is a monoclonal antibody directed against CD20 antigen on B cells which has been successfully employed in anti-MuSK-Ab+MG, but the efficacy in anti-AChR-Ab+MG is still debated. The purpose of this systematic review was to describe the best evidence for RTX in the acetylcholine receptor subtype. The authors undertook a literature search during the period of 1999–2019 according to the Preferred Reporting Items for Systematic Reviews and Meta-Analys methodology, employing (myasthenia)+(gravis)+(RTX) as search terms. The analysis was confined to studies that include at least five patients with confirmed anti-AChR-Ab+MG. Thirteen studies have been selected, showing a good safety. The data obtained were heterogeneous in terms of posology, administration scheme and patients’ evaluation, ranging from a minimum of two to a maximum of three cycles. RTX led to a sustained clinical improvement with prolonged time to relapse, in parallel to a reduction or discontinuation of other immunosuppressive therapies. Treatment with RTX appears to work in some but not all patients with anti-AChR-Ab+MG, but randomised controlled trials are needed. Future studies should take into account the subtype of MG and employ reliable measures of outcome and severity focusing on how to identify patients who may benefit from the treatment. Trial registration number: NCT02110706.

The nonmedical (i.e., recreational) misuse of synthetic cannabinoids (SCs) is a worldwide public health problem. When compared to cannabis, the misuse of SCs is associated with a higher incidence o...

Background The decriminalization and legalization of cannabis and the expansion of availability of medical cannabis in North America have led to an increase in cannabis use and the availability of high-potency strains. Cannabis potency is determined by the concentration of Δ9-tetrahydrocannabinol (Δ9-THC), a psychoactive constituent that activates cannabinoid CB1 and CB2 receptors. The use of high-potency cannabis is associated with cannabis use disorder and increased susceptibility to psychiatric illness. The nucleus accumbens (NAc) is part of a brain reward circuit affected by Δ9-THC through modulation of glutamate afferents arising from corticolimbic brain areas implicated in drug addiction and psychiatric disorders. Moreover, brain imaging studies show alterations in corticolimbic and NAc properties in human cannabis users. Methods Using in vitro electrophysiology and optogenetics, we examined how Δ9-THC alters corticolimbic input to the NAc in rats. Results We found that long-term exposure to Δ9-THC weakens prefrontal cortex glutamate input to the NAc shell and strengthens input from basolateral amygdala and ventral hippocampus. Further, whereas long-term exposure to Δ9-THC had no effect on net strength of glutamatergic input to NAc shell arising from midbrain dopamine neurons, it alters fundamental properties of these synapses. Conclusions Long-term exposure to Δ9-THC shifts control of the NAc shell from cortical to limbic input, likely contributing to cognitive and psychiatric dysfunction that is associated with cannabis use.

Inherited neuromuscular disorders (INMD) are a heterogeneous group of rare diseases that involve muscles, motor neurons, peripheral nerves or the neuromuscular junction. Several different lab abnormalities have been linked to INMD: sometimes they are typical of the disorder, but they usually appear to be less specific. Sometimes serum biomarkers can point out abnormalities in presymtomatic or otherwise asymptomatic patients (e.g., carriers). More often a biomarker of INMD is evaluated by multiple clinicians other than expert in NMD before the diagnosis, because of the multisystemic involvement in INMD. The authors performed a literature search on biomarkers in inherited neuromuscular disorders to provide a practical approach to the diagnosis and the correct management of INMD. A considerable number of biomarkers have been reported that support the diagnosis of INMD, but the role of an expert clinician is crucial. Hence, the complete knowledge of such abnormalities can accelerate the diagnostic workup supporting the referral to specialists in neuromuscular disorders.

Background The burden of cardiovascular (CV) complications in patients hospitalised for community-acquired pneumonia (CAP) is still uncertain. Available studies used different designs and different criteria to define CV complications. We assessed the cumulative incidence of acute of CV complications during hospitalisation for CAP in Internal Medicine Units (IMUs). Methods This was a prospective study carried out in 26 IMUs, enrolling patients consecutively hospitalised for CAP. Defined CV complications were: newly diagnosed heart failure, acute coronary syndrome, new onset of supraventricular or ventricular arrhythmias, new onset hemorrhagic or ischemic stroke or transient ischemic attack. Outcome measures were: in-hospital and 30-day mortality, length of hospital stay and rate of 30-day re-hospitalisation. Results A total of 1266 patients were enrolled, of these 23.8% experienced at least a CV event, the majority (15.5%) represented by newly diagnosed decompensated heart failure, and 75% occurring within 3 days. Female gender, a history of CV disease, and more severe pneumonia were predictors of CV events. In-hospital (12.2% vs 4.7%, p p = 0.0001) mortality was higher in patients with CV events, as well as the re-hospitalisation rate (13.3% vs 9.3%, p = 0.002), and mean hospital stay was 11.4 ± 6.9 vs 9.5 ± 5.6 days (p p = 0.009). Conclusion Cardiovascular events are frequent in CAP, and their occurrence adversely affects outcome. A strict monitoring might be useful to intercept in-hospital CV complications for those patients with higher risk profile. Trial registration NCT03798457 Registered 10 January 2019 - Retrospectively registered

Normative development in adolescence indicates that the prefrontal cortex is still under development thereby unable to exert efficient top-down inhibitory control on subcortical regions such as the basolateral amygdala and the nucleus accumbens. This imbalance in the developmental trajectory between cortical and subcortical regions is implicated in expression of the prototypical impulsive, compulsive, reward seeking and risk-taking adolescent behavior. Here we demonstrate that a chronic mild unpredictable stress procedure during adolescence in male Wistar rats arrests the normal behavioral maturation such that they continue to express adolescent-like impulsive, hyperactive, and compulsive behaviors into late adulthood. This arrest in behavioral maturation is associated with the hypoexcitability of prelimbic cortex (PLC) pyramidal neurons and reduced PLC-mediated synaptic glutamatergic control of BLA and nucleus accumbens core (NAcC) neurons that lasts late into adulthood. At the same time stress exposure in adolescence results in the hyperexcitability of the BLA pyramidal neurons sending stronger glutamatergic projections to the NAcC. Chemogenetic reversal of the PLC hypoexcitability decreased compulsivity and improved the expression of goal-directed behavior in rats exposed to stress during adolescence, suggesting a causal role for PLC hypoexcitability in this stress-induced arrested behavioral development.

Development of self-regulatory competencies during adolescence is partially dependent on normative brain maturation. Here we report that juvenile rats as compared to adults exhibit impulsive and compulsive-like behavioral traits, the latter being associated with lower expression of mRNA levels of the immediate early gene zif268 in the anterior insula (AI). This observation suggests that deficits in AI function in juvenile rats could explain their immature pattern of interoceptive cue integration in rational decision-making and compulsive phenotype. In support of this, here we report hypoexcitability of juvenile layer-V pyramidal neurons in the AI, concomitant with reduced glutamatergic synaptic input to these cells. Chemogenetic activation of the AI attenuated the compulsive trait suggesting that delayed maturation of the AI results in suboptimal integration of sensory and cognitive information in adolescents and this contributes to inflexible behaviors in specific conditions of reward availability.

Under voluntary vaccination, a critical role in shaping the level and trends of vaccine uptake is played by the type and structure of information that is received and used by parents of children eligible for vaccination. In this article we investigate the feedbacks of spatial mobility and the spatial structure of information on vaccination dynamics, by extending to a continuous spatially structured setting existing behavioral epidemiology models for the impact of vaccine adverse events (VAEs) on vaccination choices. We considered the simplest spatial setting, namely classical 'Fickian' diffusion, and focused on the noteworthy case where the infection is absent. This scenario mimics the important case of a population where a previously endemic vaccine preventable infection was successfully eliminated, but the re-emergence of the disease must be prevented. This is, for example, the case of poliomyelitis in most countries worldwide. In such a situation, the dynamics of VAEs and of the related information arguably become the key determinant of vaccination decision and of collective coverage. In relation to this 'information issue', we compared the effects of three main cases: (ⅰ) purely local information, where agents react only to locally occurred events; (ⅱ) a mix of purely local and global, country-wide, information due e.g., to country-wide media and the internet; (ⅲ) a mix of local and non-local information. By representing these different information options through a range of different spatial information kernels, we investigated: the presence and stability of space-homogeneous, nontrivial, behavior-induced equilibria; the existence of bifurcations; the existence of classical and generalized traveling waves; and the effects of awareness campaigns enacted by the Public Health System to sustain vaccine uptake. Finally, we analyzed some analogies and differences between our models and those of the Theory of Innovation Diffusion.

Objectives Apparent life-threatening event (ALTE) refers to a constellation of unexpected events suddenly occurring in infants that extremely alarm the observers. The objectives of this study were to evaluate 1) intervention of Emergency Service (ES) at home, 2) parental behavior before ES intervention, 3) patients' outcome at follow-up of a minimum of 6 months. Methods Retrospective study of infants younger than 12 months whose parents called ES and were evaluated for ALTE from 2005 to 2014. Tactile stimulation (TS) was defined as any maneuver performed by parents or ES staff aimed at rescuing patients without cardiopulmonary resuscitation attempts. Cardiopulmonary resuscitation was defined according to American Heart Association Guidelines 2010. Results One hundred eighty-eight patients were eligible. Emergency Service provided intervention for 178 infants (10 were assisted only by phone). All patients received TS by parents before ES arrival. Mean time for ES to reach patient location was 15 ± 10 minutes. On examination, 136 patients (76.5%) seemed normal and 42 symptomatic. One hundred sixty-three patients were brought to the emergency department where 23 patients were found symptomatic. One hundred six of 163 patients underwent capillary blood gas determination and, in 28 (26%) of 106, alterations were found. No infant had subsequent cardiopulmonary arrest or clinically evident adverse neurological outcome. Six were found to be epileptic. No infant died during the episode or during follow-up. Conclusions Our findings suggest that ALTE is an alarming but self-limiting phenomenon that can be resolved either spontaneously or by simple TS in most cases. Emergency Service should solicit patients' physiological responses through TS first while considering a cardiopulmonary resuscitation maneuver.

The lateral habenula (LHb) plays a central role in balancing reward and aversion by opposing the contributions of brain reward nuclei. Using a rat cocaine self-administration model, we previously found that LHb inhibition or non-selective blockade of LHb muscarinic acetylcholine receptors (mAChRs) led to persistent cocaine seeking despite its signaled unavailability. As understanding roles for the LHb and cholinergic signaling in behavioral control is important to psychiatric illness and addiction, we examine how mAChRs act on LHb neurons using in vitro electrophysiology. We find that different groups of LHb neurons are depolarized or hyperpolarized by the cholinergic agonist carbachol (CCh), and that CCh could inhibit GABAergic and glutamatergic synaptic inputs to these cells. Presynaptic CCh effects were reversed by the M2 mAChR (M2R) antagonist AFDX-116, but not by pirenzepine, an M1R antagonist. Contemporaneous measurement of CCh effects on synaptic inhibition and excitation in LHb neurons showed a smaller effect on inhibition, suggesting a net shift in synaptic integration toward greater inhibition by mAChRs. Synaptic currents elicited by light-activation of ventral tegmental area (VTA) axons in the LHb, following channelrhodopsin-2 transfection of VTA, were also inhibited by M2Rs, suggesting the VTA as at least one M2R-sensitive LHb afferent. Finally, Go-NoGo cocaine seeking studies showed that blockade of LHb M2Rs, and not M1Rs, triggered continued cocaine seeking. These data identify LHb M2Rs as a potential control point of LHb function that enables withholding responses for cocaine and define cellular mechanisms through which mAChRs modulate LHb activity.

α-Pyrrolidinovalerophenone (αPVP) is a psychostimulant and drug of abuse associated with severe intoxications in humans. αPVP exerts long-lasting psychostimulant effects, when compared to the classical dopamine transporter (DAT) inhibitor cocaine. Here, we compared the two enantiomeric forms of αPVP, the R- and the S-αPVP, with cocaine using a combination of in silico, in vitro and in vivo approaches. We found that αPVP enantiomers substantially differ from cocaine in their binding kinetics. The two enantiomers differ from each other in their association rates. However, they show similar slow dissociation rates leading to pseudo-irreversible binding kinetics at DAT. The pseudo-irreversible binding kinetics of αPVP is responsible for the observed non-competitive pharmacology and it correlates with persistent psychostimulant effects in mice. Thus, the slow binding kinetics of αPVP enantiomers profoundly differ from the fast kinetics of cocaine both in vitro and in vivo, suggesting drug-binding kinetics as a potential driver of psychostimulant effects in vivo.

Background: Safety in the care of patients is a priority in the design of any health system, having direct implications on the quality of care. Assessment of nurses in hospital rooms allows to detect diffi culties or problems in preoperative which can endanger the patient’s life or the expected result of the surgery. Is there where you must generate protocols that ensure safety for patients, decreasing the maximum errors and comply with the premise made by WHO in 2008: “Safe surgery saves lives”.

The discovery of functionally biased and physiologically beneficial ligands directed toward G-protein coupled receptors (GPCRs) has provided the impetus to design dopamine D2 receptor (D2R) targeted molecules that may be therapeutically advantageous for the treatment of certain neuropsychiatric or basal ganglia related disorders. Here we describe the synthesis of a novel series of D2R agonists linking the D2R unbiased agonist sumanirole with privileged secondary molecular fragments. The resulting ligands demonstrate improved D2R affinity and selectivity over sumanirole. Extensive in vitro functional studies and bias factor analysis led to the identification of a novel class of highly potent Go-protein biased full D2R agonists with more than 10-fold and 1000-fold bias selectivity toward activation of specific G-protein subtypes and β-arrestin, respectively. Intracellular electrophysiological recordings from midbrain dopamine neurons demonstrated that Go-protein selective agonists can elicit prolonged ligand-induced GIRK activity via D2Rs, which may be beneficial in the treatment of dyskinesias associated with dopamine system dysfunction.

Cannabis is the most widely used illicit drug worldwide. Its principal psychoactive component, Δ9-tetrahydrocannabinol (THC), acts as a partial agonist of the main cannabinoid receptor in the brain, the cannabinoid type-1 receptor (CB1R), that is responsible for the central effects of THC including memory impairment. CB1Rs may form heterodimers with the serotonin 5-HT2A receptor (5-HT2AR) which were found responsible for the memory impairment produced by acute high dose of THC in mice. In this study we investigated whether a repeated low dose of THC (1 mg/kg), with no acute consequence on memory performance, could eventually have deleterious cognitive effects. We found that this dose of THC impaired novel object-recognition memory and fear conditioning memory 24 h after the last of 7 consecutive daily treatments. At that time, a general enhancement of c-Fos expression was also observed in several brain regions of THC-exposed animals, as well as a decreased dendritic spine density on hippocampal CA1 pyramidal neurons that was accompanied by reduced long-term potentiation (LTP) at Schaffer collateral-CA1 synapses. Interestingly, an up-regulation in the expression of CB1R/5-HT2AR heterodimers was observed in the hippocampus after THC exposure and pre-treatment with the 5-HT2AR antagonist MDL 100,907 (0.01 mg/kg) prevented the enhanced heterodimerization and the THC-associated memory impairment. Together, these results reveal the significance of serotonergic signalling through 5-HT2ARs in the memory-impairing effects of repeated low doses of THC.

Animal and human studies show that cannabis or its derivatives can increase relapse to cocaine seeking following withdrawal. Moreover, cannabis use in humans is associated with impulse control deficits and animal studies implicate endogenous cannabinoids (eCB) in several impulsivity constructs. However, the brain areas where cannabinoids might control impulsivity or cocaine seeking are largely unknown. Here, we assess Lateral Habenula (LHb) involvement on performance in the 5-choice serial reaction time task (5CSRTT) in rats and investigate whether LHb cannabinoid CB1 receptors (CB1R) are involved in these effects. Systemic cocaine increased premature responding, a measure of impulsivity, at a dose (5 mg/kg) that did not alter other measures of task performance. Intra-LHb infusion of the CB1R antagonist AM251 blocked this effect. Systemic injection of the psychoactive constituent of cannabis, Δ9-tetrahydrocannabinol (Δ9-THC, 1 mg/kg), also increased 5CSRTT premature responding at a dose that did not otherwise disrupt task performance. This was blocked by intra-LHb infusion of AM251 in a subgroup of rats showing the largest increases in Δ9-THC-evoked premature responses. Systemic Δ9-THC also prompted impulsive cocaine seeking in a Go/NoGo cocaine self-administration task and this was blocked by intra-LHb AM251. These data show that LHb CB1Rs are involved in deficits in impulse control initiated by cocaine and Δ9-THC, as assessed by the 5CSRTT, and play a role in impulsive cocaine seeking during cocaine self-administration. This suggests that the LHb eCB system contributes to the control of impulsive behavior, and thus represents a potential target for therapeutic treatment of substance use disorders (SUDs) in humans.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), is responsible for the first pandemic of the 21st century. As found in adults, signs and symptoms related to the disease mainly involve the respiratory tract in the paediatric population. However, a considerable number of children present with gastrointestinal symptoms such as vomiting, abdominal pain, and diarrhea. The purpose of this review is an accurate description, from pathogenesis to clinical presentation, diagnosis and treatment, of COVID-19 effects on the gastrointestinal system at a paediatric age. SARS-CoV-2 can be identified in stool specimens of affected children by real-time polymerase chain reaction techniques. Positivity can last for several weeks after the end of the symptomatic phase. Gastrointestinal signs and symptoms are generally self-limited, can correlate with blood tests and imaging alterations, and may require supportive treatment such as hydration. However, they can precede severe disease manifestations such as the COVID-19-related multisystem inflammatory syndrome. Children belonging to risk categories such as those affected by celiac disease, inflammatory bowel disease, and hepatic disease seem to not have a more severe course than the others, even if they are undergoing immunosuppressant treatment. Medical follow-ups of patients with chronic diseases need to be revised during the pandemic period in order to postpone unnecessary tests, mainly endoscopic ones.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by a multisystemic involvement. In TSC, reduced function of TSC1 and TSC2 genes products (hamartin and tuberin, respectively) leads to an hyperactivation of the mechanistic target of rapamycin (mTOR) pathway and to a consequent cell growth dysregulation. In TSC patients, neurological and neuropsychiatric manifestations, especially epilepsy and neuropsychiatric comorbidities such as autism or intellectual disability, represent the most disabling features. In particular, epilepsy occurrs up to 80% of patients, is often drug resistant and is frequently associated with neurological impairment. Due to the burden of this morbidity, different treatment strategies have been proposed with the purpose to make patients epilepsy free, such as the use of different antiepileptic drugs like vigabatrin, carbamazepine, valproic acid, and levetiracetam. More recently, a mTOR inhibitor (i.e. everolimus) has showed promising results in terms of seizures reduction.

Background and aim Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the degeneration of both upper and lower motoneurons in the brain and spinal cord leading to motor and extra-motor symptoms. Although traditionally considered a pure motor disease, recent evidences suggest that ALS is a multisystem disorder. Neuropsychological alterations, in fact, are observed in more than 50% of patients: while executive dysfunctions have been firstly identified, alterations in verbal fluency, behavior, and pragmatic and social cognition have also been described. Detecting and monitoring ALS cognitive and behavioral impairment even at early disease stages is likely to have staging and prognostic implications, and it may impact the enrollment in future clinical trials. During the last 10 years, humoral, radiological, neurophysiological, and genetic biomarkers have been reported in ALS, and some of them seem to potentially correlate to cognitive and behavioral impairment of patients. In this review, we sought to give an up-to-date state of the art of neuropsychological alterations in ALS: we will describe tests used to detect cognitive and behavioral impairment, and we will focus on promising non-invasive biomarkers to detect pre-clinical cognitive decline. Conclusions To date, the research on humoral, radiological, neurophysiological, and genetic correlates of neuropsychological alterations is at the early stage, and no conclusive longitudinal data have been published. Further and longitudinal studies on easily accessible and quantifiable biomarkers are needed to clarify the time course and the evolution of cognitive and behavioral impairments of ALS patients.

Introduction The purpose of this study was to examine whether previous lumbar spinal fusion (LSF) was an independent risk factor for complications in patients undergoing total hip arthroplasty (THA) or hemiarthroplasty for displaced femoral neck fractures. Methods and materials An administrative database was queried from 2010 to Q2 of 2019 to analyze and compare complications in patients undergoing either THA or hemiarthroplasty for femoral neck fracture with a history of LSF versus no history of LSF. Joint complications including periprosthetic fracture, prosthetic joint infection (PJI), prosthetic joint dislocation (PJD), aseptic loosening, and prosthetic revision were examined at 90 days and 1 year post-operatively. Results In the THA cohort, patients with prior LSF had significantly higher likelihood of aseptic loosening at 90 days and 1 year post-operatively in comparison to those without prior LSF (90-day: OR 2.22; 1-year: OR 1.95). Patients in the hemiarthroplasty cohort with prior LSF had significantly higher likelihood of PJI (90-day: OR 2.18; 1-year: OR 2.37), aseptic loosening (90-day: OR 3.42; 1-year: OR 4.68), and prosthetic revision (90-day: OR 2.27; 1-year: OR 2.25) in both the 90-day and 1-year postoperative period in comparison to those without prior LSF. Additionally, for the same cohort, periprosthetic fracture (1-year: OR 2.32) and PJD (1-year: OR 2.31) were significantly higher at 1-year postoperative. Conclusion Presence of LSF was found to be an independent risk factor for increased joint complications in patients undergoing either a THA or hemiarthroplasty for displaced femoral neck fractures.

A 35-year-old man was diagnosed with psoriatic arthritis treated with methotrexate and cyclosporine, the latter was then interrupted. Subsequently, etanercept was introduced, administered for 10 years and then replaced with ustekinumab. Six months after treatment with ustekinumab, patient underwent a chest CT scan for pneumonia, showing an anterior mediastinal mass which turned out to be a thymoma. He was referred to our department with fatigue, difficulty in raising arms and transient episodes of diplopia after exertion. Clinical history revealed that these symptoms had begun about 7 years previously but were ascribed to psoriatic arthritis. A diagnosis of anti-acetylcholine receptor antibodies positive myasthenia gravis was made; a higher dosage of methotrexate and prednisone were started with regression of symptoms. Our case increases the number of clinical reports of myasthenia gravis onset in patients with a history of rheumatic disease treated with anti-TNFα drugs. We speculate that ustekinumab could contribute to clinical worsening.

The increasing use of cannabis, its derivatives, and synthetic cannabinoids for medicinal and recreational purposes has led to burgeoning interest in understanding the addictive potential of this class of molecules. It is estimated that ∼10% of marijuana users will eventually show signs of dependence on the drug, and the diagnosis of cannabis use disorder (CUD) is increasing in the United States. The molecule that sustains the use of cannabis is Δ9-tetrahydrocannabinol (Δ9-THC), and our knowledge of its effects, and those of other cannabinoids on brain function has expanded rapidly in the past two decades. Additionally, the identification of endogenous cannabinoid (endocannabinoid) systems in brain and their roles in physiology and behavior, demonstrate extensive involvement of these lipid signaling molecules in regulating CNS function. Here, we examine roles for endogenous cannabinoids in shaping synaptic activity in cortical and subcortical brain circuits, and we discuss mechanisms in which exogenous cannabinoids, such as Δ9-THC, interact with endocannabinoid systems to disrupt neuronal network oscillations. We then explore how perturbation of the interaction of this activity within brain reward circuits may lead to impaired learning. Finally, we propose that disruption of cellular plasticity mechanisms by exogenous cannabinoids in cortical and subcortical circuits may explain the difficulty in establishing viable cannabinoid self-administration models in animals.

The interaction between C-X-C chemokine receptor type 4 (CXCR4) and its cognate ligand C-X-C motif chemokine ligand 12 (CXCL12) plays a critical role in regulating hematopoietic stem cell activation and subsequent cellular mobilization. Extensive studies of these genes have been conducted in mammals, but much less is known about the expression and function of CXCR4 and CXCL12 in non-mammalian vertebrates. In the present study, we identify simultaneous expression of CXCR4 and CXCL12 orthologs in the epigonal organ (the primary hematopoietic tissue) of the little skate, Leucoraja erinacea. Genetic and phylogenetic analyses were functionally supported by significant mobilization of leukocytes following administration of Plerixafor, a CXCR4 antagonist and clinically important drug. Our results provide evidence that, as in humans, Plerixafor disrupts CXCR4/CXCL12 binding in the little skate, facilitating release of leukocytes into the bloodstream. Our study illustrates the value of the little skate as a model organism, particularly in studies of hematopoiesis and potentially for preclinical research on hematological and vascular disorders.

Consumption of high fat, high sugar (western) diets is a major contributor to the current high levels of obesity. Here, we used a multidisciplinary approach to gain insight into the molecular mechanisms underlying susceptibility to diet-induced obesity (DIO). Using positron emission tomography (PET), we identified the dorsal striatum as the brain area most altered in DIO-susceptible rats and molecular studies within this region highlighted regulator of G-protein signaling 4 (Rgs4) within laser-capture micro-dissected striatonigral (SN) and striatopallidal (SP) medium spiny neurons (MSNs) as playing a key role. Rgs4 is a GTPase accelerating enzyme implicated in plasticity mechanisms of SP MSNs, which are known to regulate feeding and disturbances of which are associated with obesity. Compared to DIO-resistant rats, DIO-susceptible rats exhibited increased striatal Rgs4 with mRNA expression levels enriched in SP MSNs. siRNA-mediated knockdown of striatal Rgs4 in DIO-susceptible rats decreased food intake to levels comparable to DIO-resistant animals. Finally, we demonstrated that the human Rgs4 gene locus is associated with increased body weight and obesity susceptibility phenotypes, and that overweight humans exhibit increased striatal Rgs4 protein. Our findings highlight a novel role for involvement of Rgs4 in SP MSNs in feeding and DIO-susceptibility.

Background Given the complexity of Alzheimer's disease (AD), it is a key object to explore broad outcomes, such as patient health-related quality of life (HRQoL) in relation to other variables including the feeling of burden experienced by caregivers. Methods Validated tests and questionnaires were used in this survey for the assessment of clinical variables of patients, the severity of the caregiver burden, and the measurement of the HRQoL of mild-to-moderate AD patients. This study was carried on also in order to evaluate the appropriateness of the questionnaires (DEMQOL and DEMQOL-Proxy) utilized in measuring HRQoL in AD and of their capability to identify whether there is agreement between ratings obtained by patients and caregivers. Results The amount of burden for caregivers was found to be positively correlated with several measures of cognitive, psychological, behavioral, and motor impairment of the patients. Carers evaluated HRQoL worse than AD sufferers. A significant correlation was demonstrated between the caregiver stress and severity of depressive symptoms in the patients. The DEMQOL-PROXY was found to be significantly correlated with the patient level of depressive symptoms. Conclusions Depressive symptoms mostly worsen the caregiver tolerability of the patient mental impoverishment. It is of great importance to assess patients with mild-to-moderate AD carefully in terms of depressive symptoms because they may have a great clinical implication. There was relatively low agreement between ratings concerning HRQoL obtained by patients and caregivers despite the capacity of the questionnaire to yield many clinical shades concerning the patient HRQoL.

There has been a marked increase in the availability of synthetic drugs designed to mimic the effects of marijuana. These cannabimimetic drugs, sold illicitly as 'Spice' and related products, are associated with serious medical complications in some users. In vitro studies suggest that synthetic cannabinoids in these preparations are potent agonists at central cannabinoid CB1 receptors (CB1Rs), but few investigations have delineated their cellular effects, particularly in comparison with the psychoactive component of marijuana, Δ9 -tetrahydrocannabinol (Δ9 -THC). We compared the ability of three widely abused synthetic cannabinoids and Δ9 -THC to alter glutamate release and long-term potentiation in the mouse hippocampus. JWH-018 was the most potent inhibitor of hippocampal synaptic transmission (EC50 ~15 nM), whereas its fluoropentyl derivative, AM2201, inhibited synaptic transmission with slightly lower potency (EC50 ~60 nM). The newer synthetic cannabinoid, XLR-11, displayed much lower potency (EC50 ~900 nM) that was similar to Δ9 -THC (EC50 ~700 nM). The effects of all compounds occurred via activation of CB1Rs, as demonstrated by reversal with the selective antagonist/inverse agonist AM251 or the neutral CB1R antagonist PIMSR1. Moreover, AM2201 was without effect in the hippocampus of transgenic mice lacking the CB1R. Hippocampal slices exposed to either synthetic cannabinoids or Δ9 -THC exhibited significantly impaired long-term potentiation (LTP). We find that, compared with Δ9 -THC, the first-generation cannabinoids found in Spice preparations display higher potency, whereas a recent synthetic cannabinoid is roughly equipotent with Δ9 -THC. The disruption of synaptic function by these synthetic cannabinoids is likely to lead to profound impairments in cognitive and behavioral function.

The ability of neurons to dynamically and flexibly encode synaptic inputs via short- and long-term plasticity is critical to an organism's ability to learn and adapt to the environment. Whereas synaptic plasticity may be encoded by pre- or postsynaptic mechanisms, current evidence suggests that optimization of learning requires both forms of plasticity. Endogenous cannabinoids (eCBs) play critical roles in modulating synaptic transmission via activation of cannabinoid CB1 receptors (CB1Rs) in many central nervous system (CNS) regions, and the eCB system has been implicated, either directly or indirectly, in several forms of synaptic plasticity. Because of this, perturbations within the eCB signaling system can lead to impairments in a variety of learned behaviors. One agent of altered eCB signaling is exposure to "exogenous cannabinoids" such as the primary psychoactive constituent of cannabis, Δ9-THC, or illicit synthetic cannabinoids that in many cases have higher potency and efficacy than Δ9-THC. Thus, by targeting the eCB system, these agonists can produce widespread impairment of synaptic plasticity by disrupting ongoing eCB function. Here, we review studies in which Δ9-THC and synthetic cannabinoids impair synaptic plasticity in a variety of neuronal circuits and examine evidence that this contributes to their well-documented ability to disrupt cognition and behavior.

We report a one-pot emulsion-templating strategy for the preparation of ZIF-8 microcapsules both in the presence and absence of surfactants. Capsule diameter is tuneable in the range 1–10 μm, and they can be post-synthetically etched with excess imidazole to form hierarchical architectures resembling Oleaceae pollen grains.

Summary Phasic dopamine (DA) release accompanies approach toward appetitive cues. However, a role for DA in the active avoidance of negative events remains undetermined. Warning signals informing footshock avoidance are associated with accumbal DA release, whereas depression of DA is observed with unavoidable footshock. Here, we reveal a causal role of phasic DA in active avoidance learning; specifically, optogenetic activation of DA neurons facilitates avoidance, whereas optical inhibition of these cells attenuates it. Furthermore, stimulation of DA neurons during presentation of a fear-conditioned cue accelerates the extinction of a passive defensive behavior (i.e., freezing). Dopaminergic control of avoidance requires endocannabinoids (eCBs), as perturbing eCB signaling in the midbrain disrupts avoidance, which is rescued by optical stimulation of DA neurons. Interestingly, once the avoidance task is learned, neither DA nor eCB manipulations affect performance, suggesting that once acquisition occurs, expression of this behavior is subserved by other anatomical frameworks. Our findings establish an instrumental role for DA release in learning active responses to aversive stimuli and its control by eCB signaling.

SUMMARY Cocaine is a highly addictive drug that acts upon the brain’s reward circuitry via the inhibition of mono-amine uptake. Endogenous cannabinoids (eCB) are lipid molecules released from midbrain dopamine (DA) neurons that modulate cocaine’s effects through poorly understood mechanisms. We find that cocaine stimulates release of the eCB, 2-arach-idonoylglycerol (2-AG), in the rat ventral midbrain to suppress GABAergic inhibition of DA neurons, through activation of presynaptic cannabinoid CB1 receptors. Cocaine mobilizes 2-AG via inhibition of norepinephrine uptake and promotion of a cooperative interaction between Gq/11-coupled type-1 metabotropic glutamate and α1-adrenergic receptors to stimulate internal calcium stores and activate phospholipase C. The disinhibition of DA neurons by cocaine-mobilized 2-AG is also functionally relevant because it augments DA release in the nucleus accumbens in vivo. Our results identify a mechanism through which the eCB system can regulate the rewarding and addictive properties of cocaine., Graphical Abstract