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Summary: Behçet's syndrome (BS) is a complex disease with different organ involvement. The vascular one is the most intriguing, considering the existence of a specific group of patients suffering from recurrent vascular events involving the venous and, more rarely, the arterial vessels. Several clinical clues suggest the inflammatory nature of thrombosis in BS, especially of the venous involvement, thus BS is considered a model of inflammation‐induced thrombosis. Unique among other inflammatory conditions, venous involvement (together with the arterial one) is currently treated with immunosuppressants, rather than with anti‐coagulants. Although many in‐vitro studies have suggested the different roles of the multiple players involved in clot formation, in‐vivo models are crucial to study this process in a physiological context. At present, no clear mechanisms describing the pathophysiology of thrombo‐inflammation in BS exist. Recently, we focused our attention on BS patients as a human in‐vivo model of inflammation‐induced thrombosis to investigate a new mechanism of clot formation. Indeed, fibrinogen displays a critical role not only in inflammatory processes, but also in clot formation, both in the fibrin network and in platelet aggregation. Reactive oxygen species (ROS)‐derived modifications represent the main post‐translational fibrinogen alterations responsible for structural and functional changes. Recent data have revealed that neutrophils (pivotal in the pathogenetic mechanisms leading to BS damage) promote fibrinogen oxidation and thrombus formation in BS. Altogether, these new findings may help understand the pathogenetic bases of inflammation‐induced thrombosis and, more importantly, may suggest potential targets for innovative therapeutic approaches. Thrombotic events in BS are sustained by an inflammatory process rather than a thrombophilic state. Reactive oxygen species (ROS)‐derived modifications represent the main post‐translational fibrinogen alterations responsible for structural and functional changes. Neutrophils (pivotal in the pathogenetic mechanisms leading to BS damage) promote fibrinogen oxidation and thrombus formation in BS. [ABSTRACT FROM AUTHOR]

While resting-state networks are able to rapidly adapt to experiences and stimuli, it is currently unknown whether metacognitive processes such as confidence in learning and psychological temperament may influence this process. We explore the neural traces of confidence in learning and their variability by: (1) targeting rs-networks in which functional connectivity (FC) modifications induced by a learning task were associated either with the participant's performance or confidence in learning; and (2) investigating the links between FC changes and psychological temperament. Thirty healthy individuals underwent neuropsychological and psychometric evaluations as well as rs-fMRI scans before and after a visuomotor associative learning task. Confidence in learning was positively associated with the degree of FC changes in 11 connections including the cerebellar, frontal, parietal, and subcortical areas. Variability in FC changes was linked to the individual's level of anxiety sensitivity. The present findings indicate that reconfigurations of resting state networks linked to confidence in learning differ from those linked to learning accuracy. In addition, certain temperament characteristics appear to influence these reconfigurations.

Objectives: The primary aim of our study was to evaluate long-term efficacy of secukinumab (SCK) in patients with axial spondyloarthritis (axSpA); secondary aims were to evaluate drug retention rate and to identify differences in the clinical and laboratory assessment according to axSpA clinical features, dosage administered, and biologic treatment lines. Patients and Methods . We collected clinical, demographical, and treatment data from 39 patients affected by axSpA consecutively treated with SCK. Laboratory assessment was based on inflammation parameters; clinical assessment was performed with the Ankylosing Spondylitis Disease Activity Score- (ASDAS-) CRP and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Data were recorded at baseline and every 3 months for the first year and then every 6 months in the second year., Results: Twelve males and 27 females were enrolled; both BASDAI and ASDAS-CRP showed a statistically significant reduction during the observation period ( p < 0.0001 and p < 0.0001, respectively). C-reactive protein significantly decreased ( p = 0.006), with significant reduction at the post hoc analysis between baseline and both 6-month evaluation ( p = 0.02) and 24-month visit ( p = 0.036). No statistical significance was observed in BASDAI and ASDAS-CRP improvement ( p = 0.482 and p = 0.164, respectively) between different dosages administered. No significant differences emerged in the BASDAI and ASDAS-CRP variations between biologic-naïve patients and subjects previously failing to tumour necrosis factor (TNF) inhibitors ( p = 0.53 and p = 0.148, respectively). At the end of our observation, 7 out of 39 patients discontinued SCK. The global retention rate at the end of the study period was 78.2%, without any significant differences between biologic-naïve and anti-TNF-failure patients ( p = 0.619) or between subjects administered with different SCK dosages ( p = 0.614). No adverse events were reported., Conclusions: In our cohort, SCK has proved a remarkable effectiveness regardless biologic treatment line and dosages employed. As suggested by the notable drug retention rate, SCK has been able to maintain its effectiveness over a considerable long period of treatment., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Stefano Gentileschi et al.)

Background: The aim of our research is to evaluate the effectiveness of the spinal anesthesia versus Local Anesthesia within the context of Day Surgery., Materials and Methods: This study is a clinical trial. 140 patients were enrolled (60 female, 80 male). Some parameters have been evaluated with scales ASA, Bromage Scale, Hollmen Scale, Numerical Rate Scale, and Patient Satisfaction that are now internationally recognized as valid to assess both the degree of anesthesia and the patient benefit., Results: Data is mostly matching between the two groups, even though there are some differences. Every patient from the group SUB underwent a single sensory block due to the fact that everyone had a Bromage Score under 2 and Hollmen score between 2 and 3 CONCLUSIONS: Results showed the versatility of the SUB blockage in a Acute postoperative pain is associated to the surgical treatment and is still today unavoidable. We always tried to keep in check or even avoid the pain, thinking it is useless and ethically inacceptable. It is considered dangerous since it starts neurovegetative and neuroendocrinal cascade which lead to delayed functional and psychophysical recoverywider population, compared to the LAs, the better surgical planning, but mostly a better analgesia over the following 24 hours and a better satisfaction. Despite all these findings the patients continue to prefer the local anesthesia., Key Words: Analgesia, Epidural, Post-operative, Ultrasound.

Background: Rheumatoid arthritis (RA) is associated with an increased risk of morbidity and mortality, when compared with general population, largely due to enhanced atherosclerotic disease. In this work, we aimed at assessing both occurrence and predictive factors of subclinical and clinical atherosclerosis in RA., Methods: From January 1, 2015, to December 31, 2015, consecutive participants with RA, admitted to Italian Rheumatology Units, were assessed in the GIRRCS (Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale) cohort. After that, those participants were followed up in a 3-year, prospective, observational study, assessing the occurrence of subclinical and clinical atherosclerosis and possible predictive factors. McNemar test was employed to assess the changes in subclinical and clinical atherosclerosis, and regression analyses exploited the ORs for the occurrence of those comorbidities., Results: We analysed 841 participants, mostly female (82.2%) and with median age of 60 years (range 21-90). The remission was achieved and maintained by 41.8% of participants during the follow-up. We observed an increased rate of subclinical atherosclerosis at the end of follow-up (139 vs 203 participants, p < 0.0001), particularly in participants with a disease duration less than 5 years at baseline (70 participants vs 133 participants, p < 0.0001). Type 2 diabetes (T2D) (OR 4.50, 95%CI 1.74-11.62, p = 0.002), high blood pressure (OR 2.03, 95%CI 1.04-4.14, p = 0.042), ACPA (OR 2.36, 95%CI 1.19-4.69, p = 0.014) and mean values of CRP during the follow-up (OR 1.07, 95%CI 1.03-1.14, p = 0.040) were significantly associated with higher risk of subclinical atherosclerosis. We observed an increased rate of clinical atherosclerosis at the end of follow-up (48 vs 76 participants, p < 0.0001). T2D (OR 6.21, 95%CI 2.19-17.71, p = 0.001) was associated with a significant risk of clinical atherosclerosis. The achievement and the maintenance of remission reduced the risk of subclinical (OR 0.25, 95%CI 0.11-0.56, p = 0.001) and clinical atherosclerosis (OR 0.20, 95%CI 0.09-0.95, p = 0.041)., Conclusions: We reported an increased prevalence and incidence of both subclinical and clinical atherosclerosis in 3-year prospectively followed participants, mainly in the subset with a duration of disease less than 5 years. The achievement and the maintenance of remission are associated with a reduction of the risk of subclinical and clinical atherosclerosis. Among "traditional" cardiovascular risk factors, participants with T2D showed a higher risk of clinical and subclinical atherosclerosis.

Objectives: Good drug survival of tumour necrosis factor inhibitors (TNFi) has been shown in axial spondyloarthritis (axSpA) patients treated in real-life setting. However, few studies have compared drug survival of the first TNF inhibitor between radiographic axSpA (r-axSpA) and non-radiographic axSpA (nr-axSpA) patients in real-world clinical practice. The aim of this work was to evaluate the effectiveness by assessing the retention rate of first-line TNFi in r-axSpA and nr-axSpA patients. Baseline predictive factors for TNFi discontinuation were also evaluated., Methods: We retrospectively assessed axSpA patients, who underwent first line therapy with TNFi. Demographic and clinical data was obtained through structured interview, review of medical records and physical examination. Disease activity indices such as the Bath Ankylosing Spondylitis Metrology Index (BASMI), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Ankylosing Spondylitis Disease Activity Score evaluating C Reactive Protein (ASDAS-CRP), Leeds Enthesitis Index (LEI) were assessed at baseline. Moreover Health Assessment QuestionnaireDisability Index (HAQ), erythrocyte sedimentation rate (ESR, mm/h), CRP (mg/dl) and HLA-B27 were recorded as well. Data on x-ray and magnetic resonance imaging of the sacroiliac joints were also collected. Drug retention rates were analysed using Kaplan-Meier curves; log-rank test was performed to demonstrate differences in the survival functions. Cox regression models were used to estimate the inference of several disease and clinical characteristics on drug discontinuation., Results: Drug survival of first-line TNFi was significantly lower in patients who had nr-axSpA than in those with r-axSpA (p=0.005). HLA-B27 frequency was higher in patients with x-ray sacroiliitis than in those with nr-axSpA (p=0.01) as well as mean CRP serum level (p=0.0001), whereas both mean BASDAI and LEI score were higher in patients with nr-axSpA than in those with r-axSpA (p=0.018 and p=0.007, respectively). Global retention rate in our cohort was 60.34% with mean survival time (MST) of 58.68 months (95% CI 47.93-69.42). MST for patients diagnosed with r-axSpA was 66.79 months (95% CI 53.54-80.04) and 39.05 months (95% CI 24.12-53.99) for those with nr-axSpA. Moreover, nr-axSpA (HR 1.620), higher BMI (HR 1.093) and BASFI, (HR 1.192) had an impact on drug discontinuation, whereas HLA-B27 presence (HR. 0.523) had protective effect., Conclusions: Effectiveness of TNFi, seems to be lower in nr-axSpA patients than in those with r-axSpA. In addition obesity and functional disability negatively impact the persistence on first line TNFi in axSpA patients in real life setting.

Objective: This study was aimed at assessing the long-term ocular control of adalimumab (ADA) in a large real-world population with noninfectious primary or secondary uveitis, focusing on the steroid-sparing effect and on disease-modifying antirheumatic drug (DMARD) cotreatment., Methods: In this retrospective, multicenter study, the efficacy of ADA was evaluated in terms of ocular control, changes in best-corrected visual acuity (BCVA), corticosteroid-sparing effect, and drug retention rate, overall and stratified according to DMARD cotreatment., Results: 106 patients were included. 88.7% had an associated systemic disease. After 6 and 12 months, proportions of patients with effective ocular control were 83.7% and 83.3%, respectively. At last the follow-up, 94.6% of patients had satisfactory ocular control. No difference in terms of ocular control at all time points emerged among patients starting ADA for ocular vs . systemic involvements. Patients with poor baseline BCVA remained stable or improved, while those with good BCVA hardly worsened. At 6 and 12 months, the median dose of prednisone significantly reduced to 5 mg/day (0-5) and 2.5 mg/day (0-5) ( p < 0.001). Over a median follow-up of 36 months, 38 subjects discontinued ADA treatment. Mild to moderate side effects were reported in 7 patients (6.6%). ADA ocular control, corticosteroid-sparing effect, and drug retention rate were not influenced by the concomitant use of DMARDs., Conclusion: The long-term ocular control of ADA in noninfectious primary or secondary uveitis is confirmed, also for BCVA preservation. Concomitant use of DMARDs does not provide additional benefits to ADA alone in terms of ocular control, steroid spare, and drug retention rate.

Objective: Since Behçet's syndrome (BS) is the prototype of inflammation-induced thrombosis, immunosuppressants are recommended in place of anticoagulants. We undertook this study to assess the clinical efficacy and the corticosteroid-sparing effect of adalimumab (ADA)-based treatment versus disease-modifying antirheumatic drug (DMARD) therapy in a large retrospective cohort of patients with BS-related venous thrombosis., Methods: We retrospectively collected data on 70 BS patients treated with DMARDs or ADA-based regimens (ADA with or without DMARDs) because of venous complications. Clinical and imaging evaluations were performed to define vascular response. We explored differences in outcomes between ADA-based regimens and DMARDs with respect to efficacy, corticosteroid-sparing role, and time on treatment. We also evaluated the role of anticoagulants as concomitant treatment., Results: After a mean ± SD follow-up period of 25.7 ± 23.2 months, ADA-based regimens induced clinical and imaging improvement of venous thrombosis more frequently (P = 0.001) and rapidly (P < 0.0001) than did DMARDs. The mean dose of corticosteroids administered at the last follow-up visit was significantly lower with ADA-based regimens than with DMARDs (P < 0.0001). The time on treatment was significantly longer with ADA plus DMARDs than with DMARDs alone (P = 0.002). No differences were found in terms of efficacy and time on treatment between DMARDs or ADA-based regimens among patients who received anticoagulants and those who did not., Conclusion: In this large retrospective study, we have shown that ADA-based regimens are more effective and rapid than DMARDs in inducing resolution of venous thrombosis in BS patients, allowing reduction of steroid exposure. Moreover, our findings suggest that anticoagulation does not modify the efficacy of either ADA-based regimens or DMARDs for venous complications., (© 2018, American College of Rheumatology.)

Whereas some previous data on carriers with isolated antiphospholipid antibodies positivity (APP) suggested an increased risk of arterial events in this clinical setting, no data are available on subclinical atherosclerosis in this clinical setting. This article reports data on intima-media thickness of the common carotid artery (CCA-IMT) and of the Bulb (Bulb-IMT) and on the prevalence of carotid plaques in APP carriers and in subjects with antiphospholipid syndrome (APS) specifically stratifying for the presence of thrombotic manifestations, cardiovascular risk factors, antibody isotype and concomitant Systemic Lupus Erythematosus (SLE) or other autoimmune diseases.

Background: Medication Overuse Headache (MOH) can be related in some patients to dependence-related behaviour characterised by craving, a deficit in controlling substance intake, which is associated to orbitofrontal cortex (OFC) dysfunction. The aim of this study was to explore the psychological correlates in MOH patients and the functioning of the OFC through neuropsychological assessment (Iowa Gambling Task: IGT) and to relate it to prognosis at a one year follow-up point., Findings: Seventeen subjects suffering from probable MOH were included and compared to 19 migraineurs and to 17 controls. The results show significant between group differences for behavioural dependence, depression, anxiety, catastrophizing. There were no between group differences for impulsivity. Mean IGT score did not allow differentiation of MOH patients from the other groups, whereas the score was significantly different between opiate abusers and other medication abusers (45 +/-5.7 versus 57.1 +/-8.2, p = 0.019). Among the clinical variables rated at inclusion, the amount of acute headache medication taken per month was the only one predicting the prognosis (RR = 1.05, 95% CI = 1-1.06, p = 0.04). A slight increase in risk of relapse at 1 year was observed in patients with poorer IGT scores (RR = 0.92, 95% CI = 0.85-1, p = 0.05) and higher behavioural-dependence scores (RR = 1.07, 95% CI = 1-1.14, p = 0.05). None of the other psychological variables predicted relapse risk., Conclusions: These results must be interpreted with caution due to the low number of subjects. They showed a deficit in decision making processes in MOH patients who overuse medications containing psychoactive substances like opiates. Moreover dependence-related variables are related to the prognosis.

Adolescence is a crucial developmental period characterized by specific behaviors reflecting the immaturity of decision-making abilities. However, the maturation of precise cognitive processes and their neurobiological correlates at this period remain poorly understood. Here, we investigate whether a differential developmental time course of dopamine (DA) pathways during late adolescence could explain the emergence of particular executive and motivational components of goal-directed behavior. First, using a contingency degradation protocol, we demonstrate that adolescent rats display a specific deficit when the causal relationship between their actions and their consequences is changed. When the rats become adults, this deficit disappears. In contrast, actions of adolescents remain sensitive to outcome devaluation or to the influence of a pavlovian-conditioned stimulus. This aspect of cognitive maturation parallels a delayed development of the DA system, especially the mesocortical pathway involved in action adaptation to rule changes. Unlike in striatal and nucleus accumbens regions, DA fibers and DA tissue content continue to increase in the medial prefrontal cortex from juvenile to adult age. Moreover, a sustained overexpression of DA receptors is observed in the prefrontal region until the end of adolescence. These findings highlight the relationship between the emergence of specific cognitive processes, in particular the adaptation to changes in action consequences, and the delayed maturation of the mesocortical DA pathway. Similar developmental processes in humans could contribute to the adolescent vulnerability to the emergence of several psychiatric disorders characterized by decision-making deficits.

In order to select actions appropriate to current needs, a subject must identify relationships between actions and events. Control over the environment is determined by the degree to which action consequences can be predicted, as described by action-outcome contingencies--i.e. performing an action should affect the probability of the outcome. We evaluated in a first experiment adaptation to contingency changes in rats with neurotoxic lesions of the medial prefrontal cortex. Results indicate that this brain region is not critical to adjust instrumental responding to a negative contingency where the rats must refrain from pressing a lever, as this action prevents reward delivery. By contrast, this brain region is required to reduce responding in a non-contingent situation where the same number of rewards is freely delivered and actions do not affect the outcome any more. In a second experiment, we determined that this effect does not result from a different perception of temporal relationships between actions and outcomes since lesioned rats adapted normally to gradually increasing delays in reward delivery. These data indicate that the medial prefrontal cortex is not directly involved in evaluating the correlation between action--and reward--rates or in the perception of reward delays. The deficit in lesioned rats appears to consist of an abnormal response to the balance between contingent and non-contingent rewards. By highlighting the role of prefrontal regions in adapting to the causal status of actions, these data contribute to our understanding of the neural basis of choice tasks.

To investigate the involvement of dopaminergic projections to the prelimbic and infralimbic cortex in the control of goal-directed responses, a first experiment examined the effect of pretraining 6-OHDA lesions of these cortices. We used outcome devaluation and contingency degradation procedures to separately assess the representation of the outcome as a goal or the encoding of the contingency between the action and its outcome. All groups acquired the instrumental response at a normal rate, indicating that dopaminergic activity in the medial prefrontal cortex is not necessary for the acquisition of instrumental learning. Sham-operated animals showed sensitivity to both outcome devaluation and contingency degradation. Animals with dopaminergic lesions of the prelimbic cortex, but not the infralimbic cortex, failed to adapt their instrumental response to changes in contingency, whereas their response remained sensitive to outcome devaluation. In a second experiment, aimed at determining whether dopamine was specifically needed during contingency changes, we performed microinfusions of the dopamine D(1)/D(2) receptor antagonist flupenthixol in the prelimbic cortex only before contingency degradation sessions. Animals with infusions of flupenthixol failed to adapt their response to changes in contingency, thus replicating the deficit of animals with dopaminergic lesions in Experiment 1. These results demonstrate that dissociable neurobiological mechanisms support action-outcome relationships and goal representation, dopamine signaling in the prelimbic cortex being necessary for the former but not the latter.

Background: The effect of propofol on anxiety has not been well studied. In humans, such investigations are confused by the fact that sedation often coexists with anxiolysis. Therefore, the authors evaluated the effects of minimal sedation with propofol in rats placed in an innate anxiogenic situation, the elevated plus-shaped maze., Methods: In experiment 1, spontaneous locomotor activity was determined in rats as a measure of sedative effect induced by propofol (0-9 mg/kg administered intraperitoneally). In experiment 2, groups of rats received propofol (0-9 mg/kg) or diazepam (0-2 mg/kg) and then were placed on a plus-shaped maze elevated above the ground that was composed of two opposite closed arms and two opposite open arms. On an initial exposure to the maze, undrugged rats avoid the open arms, with the number of entries into and time spent within the open arms constituting approximately 20% of their total activity. This reflects normal anxiety in a rodent for any elevated open platform., Results: In experiment 1, 0-9 mg/kg propofol did not alter spontaneous activity in rats. In experiment 2, propofol and diazepam significantly increased the number of entries into and the time spent within the open arms. Propofol at a dose of 9 mg/kg significantly increased the rats' level of exploration of the open arms to about 50% of all exploratory activity, and a similar observation was made with 2 mg/kg diazepam., Conclusions: In a standard animal model, propofol has anxiolytic properties at doses that do not produce sedation.

Background: The effect of either midazolam or the combination of midazolam and propofol on the affective state was assessed in rats at subanesthetic doses and at recovery from anesthesia., Methods: The putative drug(s)-induced affective states were repeatedly paired with one of two distinguishable compartments of an experimental cage, whereas the vehicle(s)-induced effect was repeatedly paired with the other compartment. During a subsequent choice test for one compartment over the other, the rats' preference for the drug(s)-paired compartment over the vehicle(s)-paired compartment is indicative of a pleasant state induced by the drug(s). In experiment 1, rats were conditioned with different doses of midazolam either at subanesthetic states or at recovery from anesthesia. In experiment 2, groups of rats were conditioned with different combinations of midazolam and propofol either at subanesthetic states or at recovery from anesthesia induced jointly by midazolam (10 mg/kg) and propofol (60 mg/kg). Experiment 3 was conducted in the same way as experiment 2, except that midazolam was paired with both compartments. In addition, these groups were tested not only in an undrugged state but also in a drugged (with midazolam) state., Results: In experiment 1, rats exhibited a place preference for the environment previously associated with midazolam, at subanesthetic and anesthetic doses. Experiment 2 showed that a propofol-induced place preference was found to be dose-dependently suppressed by midazolam. Experiment 3 replicated the findings of experiment 2 and extended them to the mechanism by which midazolam blocked a propofol-induced place preference., Conclusions: Midazolam administered before propofol blocked the expression of a propofol-induced pleasant state.