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Among nonsteroidal anti-inflammatory drugs (NSAIDs), 2-arylpropionic acids exist as a racemic mixture of its enantiomeric forms, with S-enantiomers primarily responsible for inhibition of prostaglandin synthesis and of inflammatory events. The aim of this study was to compare the anti-inflammatory effects of R- and S-ketoprofen in vitro and in vivo. S-Ketoprofen efficiently inhibited carrageenan-induced edema formation, but it could also amplify the LPS-induced production of the inflammatory cytokines tumor necrosis factor (TNF) and interleukin-1 (IL-1), in close correlation with its ability to inhibit prostaglandin synthesis. Because these inflammatory cytokines are among the factors involved in carrageenan-induced inflammation and also are possibly involved in gastric damage, enhanced cytokine production could partially mask the analgesic effect of S-ketoprofen, and it can be associated with the clinical evidence of its gastric toxicity. On the other hand, R-ketoprofen contributes to the overall activity of the racemate, by playing the main role in ketoprofen-induced analgesia. Unlike the S-isomer, R-ketoprofen did not induce a significant increase of cytokine production even at cyclooxygenase-blocking concentrations. It is concluded that the R-isomer directly contributes to the anti-inflammatory effects of ketoprofen, being more analgesic, and because it does not amplify inflammatory cytokine production.

Cognitive behavioral therapy (CBT) approaches use case formulation procedures based on the diathesis–stress conceptualization model, arranged in two dimensions: emotional vulnerability (present in a patient’s consciousness in terms of core beliefs) and coping strategies. Nevertheless, despite its pivotal role, there are a limited number of validation studies for this model. Life themes and semi-adaptive plans: Implications of biased beliefs, elicitation and treatment (LIBET) is a CBT case formulation method grounded on the CBT diathesis–stress model that aims to help validate the CBT case formulation model, and, in particular, its bidimensional arrangement. In LIBET, the two classic CBT dimensions are called “life themes,” which are mental states of focused attention to emotional sensitivities represented as core beliefs in consciousness, and “semi-adaptive plans,” which are the rigid management strategies of “life themes” implemented by adopting coping strategies such as anxious safety behaviors, compulsive controls and aggressive or rewarding strategies. The study uses quantitative textual analysis to validate the LIBET procedure in a clinical sample. The investigation discusses the extent to which the results can be considered a validation of the arrangement of the general CBT diathesis–stress model in the two dimensions of core beliefs and coping strategies.

On April 18, 2007 an international meeting on Pathophysiology of Ageing, Longevity and Age-Related Diseases was held in Palermo, Italy. Several interesting topics on Cancer, Immunosenescence, Age-related inflammatory diseases and longevity were discussed. In this report we summarize the most important issues. However, ageing must be considered an unavoidable end point of the life history of each individual, nevertheless the increasing knowledge on ageing mechanisms, allows envisaging many different strategies to cope with, and delay it. So, a better understanding of pathophysiology of ageing and age-related disease is essential for giving everybody a reasonable chance for living a long and enjoyable final part of the life.

Background: Using the Self-Regulatory Executive Function model as a basis, this study explored whether, in both general population and clinical samples, metacognitive beliefs and repetitive negative thinking (i.e., rumination and worry) are associated with higher levels of emotion dysregulation. Methods: 395 participants from the general population and 388 outpatients seeking psychological treatment were recruited. Emotion dysregulation, metacognitive beliefs, rumination, worry, anxiety, depression, personality disorders were assessed. ANOVA and Welch's tests, correlation and path analyses were run. Results: Repetitive negative thinking was found to play a mediating role in the relationship between metacognitive beliefs and emotion dysregulation in both general population and clinical samples. Moreover, metacognitive beliefs were found to be directly associated to emotion dysregulation. Limitations: The cross-sectional design. Conclusions: Emotion dysregulation appears to be associated with the tendency to engage in repetitive negative thinking and metacognitive beliefs. Repetitive negative thinking and metacognitive beliefs could be a suitable therapeutic target to reduce difficulties in emotion regulation.

Background and aim: Transcranial direct current stimulation (tDCS) and metacognitive therapy (MCT) can reduce depressive symptoms as monotherapies or associated with pharmacological treatment. Here, we investigated the effectiveness of combining these treatments in a group of patients with major depressive disorder (MDD). Methods: So far, fourteen participants (10 females, Mage 43 ± 12) out of N= 54 estimated sample size were recruited at the Department of Neuroscience and Mental Health – Fondazione IRRCS Ca’ Granda Ospedale Maggiore Policlinico of Milano. All participants were under pharmacological treatment. They were randomly assigned to three groups receiving (i) real tDCS + sham MCT (n= 7); (ii) sham tDCS + MCT (n = 6) (iii) real tDCS + MCT (n= 1). The treatment lasted eight weeks, in which participants had one weekly MCT (groups ii and iii) or clinical interview session (group i) following the tDCS. TDCS was combined with attentional training (20 minutes, 1.5 mA, anode over the left dorsolateral prefrontal cortex) and took place three times a week for the first three weeks and then once a week. Clinical standardized questionnaires measuring depressive symptoms, anxiety, worry, rumination, and meta-beliefs were administered before and after the treatment, two weeks, three, six, and twelve months after treatment’s end. Results: Due to sampling distribution, mixed effects models were run, including time and only two groups as fixed factors (i and ii) and participants’ random intercept. Outcome measures revealed an effect of time, showing symptoms reduction after the treatment. Crucially, our results suggested a more robust reduction of worry and negative beliefs in the group receiving MCT compared to the one receiving only tDCS. Conclusions: despite preliminary, our results suggest that MCT can effectively reduce core symptoms contributing to the development and maintenance of MDD. Completing data collection will allow disentangling whether tDCS can boost this effect.

Glioblastoma multiforme (GBM) is the most malignant primary brain cancer. Despite aggressive treatments currently there is no cure for GBM. Many challenges should be considered for the development of new therapeutical agents for glioblastoma, including appropriate target selectivity and pharmacokinetics. Several mutations and alterations of key cellular pathways including tyrosine kinases (TKs) are involved in malignant transformation and tumor progression. Thus, the targeting of multiple pathways and the development of innovative combination drug regimens is expected to yield improved therapies. Moreover, the abilities to cross the blood-brain barrier (BBB) reaching effective concentrations in brain and to remain into this tissue avoiding the effects of efflux transporters are also critical issues in the development of new therapeutics for GBM. CR13626 is a novel brain penetrant small molecule able to potently inhibit in vitro the activity of EGFR, VEGFR2 (aka KDR), Fyn, Yes, Lck, HGK (aka MAP4K4) and RET kinases relevant for GBM development. CR13626 shows good oral bioavailability (72%) and relevant brain penetration (brain/plasma ratio of 1.4). In an orthotopic xenograft glioblastoma mouse model, oral treatment with CR13626 results in a time-dependent reduction of tumor growth, leading to a significant increase of animal survival. The unique properties of CR13626 warrant its further investigation as a potential new drug candidate in glioblastoma.

© 2019 Elsevier Ltd Research has indicated that craving is one of the strongest predictors of treatment outcome and relapse in Alcohol Use Disorders (AUD) but there is little consensus on the factors that may influence its activation and escalation. Research has also shown that desire thinking is an important cognitive process which may exacerbate craving in problem drinkers. The aim of present study was to explore, for the first time, the role of desire thinking in prospectively predicting relapse, craving and binge drinking in patients receiving treatment for AUD. One hundred and thirty-five patients admitted to two rehabilitation centres and two outpatient services for addiction and mental health problems were administered baseline, treatment completion and three months follow-up measures of anxiety and depression, AUD severity, binge drinking frequency, craving and desire thinking. Results indicated that the verbal perseveration component of desire thinking at treatment completion was the only significant predictor of relapse at follow-up over and above baseline AUD severity and binge drinking frequency. Furthermore, the imaginal prefiguration component of desire thinking and craving levels at treatment completion were found to predict craving levels at follow-up independently of AUD severity and binge drinking frequency at baseline. Finally, both the imaginal prefiguration and verbal perseveration components of desire thinking at treatment completion were found to be the only predictors of binge drinking frequency at follow-up independently of AUD severity and binge drinking frequency at baseline. Treatments for AUD should aim to reduce desire thinking in people to enhance clinical outcomes and reduce relapse risk.

Cognitive-behavioral treatments assume that the mechanisms of change depend on the assessment and questioning of biased beliefs. In contrast, recent developments have emphasized mindful acceptance interventions, in which clients allow thoughts to come and go without questioning them. In order to discuss therapeutic efficacy difference in emotional disorders, we explored the possible normalizing effects of cognitive questioning and mindful acceptance on sympathetic reactivity aroused by recall tasks. We compared the effects of different sequencing of cognitive questioning and mindful acceptance on emotional distress in two groups in which questioning either preceded (group 1) or followed (group 2) acceptance. Thirty-five non-clinical individuals (21 males, 14 females) randomly allocated to either group 1 or 2 participated in the experimental tasks (unpleasant recall, cognitive questioning, and metacognitive acceptance). Sympathetic reactivity levels were measured using galvanic skin response. Results showed that acceptance reduced sympathetic reactivity when compared to questioning. The best sequence was that in which questioning preceded acceptance. By interpreting sympathetic reactivity as a measure of emotional distress and experimental tasks as models for therapeutic approaches, this experiment suggests that acceptance is better than questioning in reducing emotional distress especially when cognitive questioning is followed by mindful acceptance.

In Albert Ellis' rational emotive behavior therapy (REBT; DiGiuseppe et al., A Practioner's guide to rational emotive behavior therapy. New York, NY: Oxford University Press, 2014; Ellis, Reason and emotion in psychotherapy. New York, NY: Stuart, 1962; Ellis and Grieger, Handbook of rational-emotive therapy. New York, NY: Springer, 1986), the therapist uses three specific steps of the basic ABC DEF procedure of REBT, namely the B-C connection, D rationale and negotiation of F, to formulate the patient's problems, regulate the therapeutic process, and manage the therapeutic alliance. The negotiation of F establishes the goals of the therapy and the specific REBT contract. The B-C connection and the rationale of D help the patient to detach from his or her irrational beliefs. The healthy attitude is not to have negative thoughts but rather to tolerate them and not take seriously their demands and awfulizing aspects. This REBT attitude anticipates metacognitive procedures. It is this unceasing sharing of the rationale of the therapy that allows the REBT therapist to show empathy and respect toward the patient.

Background The possibility of using noninvasive brain stimulation to treat mental disorders has received considerable attention recently. Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are considered to be effective treatments for depressive symptoms. However, no treatment recommendation is currently available for anxiety disorders, suggesting that evidence is still limited. We conducted a systematic review of the literature and a quantitative analysis of the effectiveness of rTMS and tDCS in the treatment of anxiety disorders. Methods Following PRISMA guidelines, we screened 3 electronic databases up to the end of February 2020 for English-language, peer-reviewed articles that included the following: a clinical sample of patients with an anxiety disorder, the use of a noninvasive brain stimulation technique, the inclusion of a control condition, and pre/post scores on a validated questionnaire that measured symptoms of anxiety. Results Eleven papers met the inclusion criteria, comprising 154 participants assigned to a stimulation condition and 164 to a sham or control group. We calculated Hedge's g for scores on disorder-specific and general anxiety questionnaires before and after treatment to determine effect size, and we conducted 2 independent random-effects meta-analyses. Considering the well-known comorbidity between anxiety and depression, we ran a third meta-analysis analyzing outcomes for depression scores. Results showed a significant effect of noninvasive brain stimulation in reducing scores on disorder-specific and general anxiety questionnaires, as well as depressive symptoms, in the real stimulation compared to the control condition. Limitations Few studies met the inclusion criteria; more evidence is needed to strengthen conclusions about the effectiveness of noninvasive brain stimulation in the treatment of anxiety disorders. Conclusion Our findings showed that noninvasive brain stimulation reduced anxiety and depression scores compared to control conditions, suggesting that it can alleviate clinical symptoms in patients with anxiety disorders.

This paper attempts to explore the cultural background for the adoption and practice of REBT by cognitive therapists in Italy since the 1980s. It is not an attempt to capture the history of Italian culture and philosophy from antiquity. Italian therapists tend to prefer the assessment phase of the ABC framework and not fully adopt REBT disputing interventions. They also attempt to link the ABC not only to the here and now but also to clients’ personal development. In our experience, they have combined REBT with constructivism and metacognition. These current features parallel the historical lack of confidence shown by many Italian philosophical thinkers—from Machiavelli to Gianni Vattimo—in the possibility of reducing reality to verification as well as the reproducible rules of logical rationality. The foregoing highlights the interest in exploring the emotional roots of politics, history, and concrete reality in the time frame following the 1980s. Some typical features of Italian social life, such as individualism, hierarchy, remote social distance, and competition can also be thought of as corresponding with the historical features of the way REBT has been adopted and functions in Italy.

BACKGROUND AND PURPOSE: CR4056 is a first‐in‐class imidazoline‐2 (I(2)) receptor ligand characterized by potent analgesic activity in different experimental animal models of pain. In a recent phase II clinical trial, CR4056 effectively reduced pain in patients with knee osteoarthritis. In the present study, we investigated the effects of CR4056 on PKCε translocation in vitro and on PKCε activation in vivo in dorsal root ganglia (DRG) neurons. EXPERIMENTAL APPROACH: Effects of CR4056 on bradykinin‐induced PKCε translocation were studied in rat sensory neurons by immunocytochemistry. PKCε activation was investigated by immunohistochemistry analysis of DRG from complete Freund's adjuvant‐treated animals developing local hyperalgesia. The analgesic activity of CR4056 was tested on the same animals. KEY RESULTS: CR4056 inhibited PKCε translocation with very rapid and long‐lasting activity. CR4056 decreased hyperalgesia and phospho‐PKCε immunoreactivity in the DRG neurons innervating the inflamed paw. The effect of CR4056 on PKCε translocation was blocked by pertussis toxin, implying that the intracellular pathways involved G(i) proteins. The inhibition of PKCε translocation by CR4056 was independent of the α(2)‐adrenoeceptor and, surprisingly, was also independent of idazoxan‐sensitive I(2) binding sites. The I(2) agonist 2BFI had no effect alone but potentiated the activity of low concentrations of CR4056. CONCLUSIONS AND IMPLICATIONS: Our results demonstrate that CR4056 shares the ability to inhibit PKCε translocation with other analgesics. Whether the inhibition of PKCε involves binding to specific subtype(s) of I(2) receptors should be further investigated. If so, this would be a new mode of action of a highly specific I(2) receptor ligand.

Erectile dysfunction (ED) and premature ejaculation (PE) are two forms of male sexual disorder with both psychological and physical features. While their cognitive, attentional, and affective components have been investigated separately, there is a lack of knowledge about the role played by cognitive attentional syndrome in their onset and maintenance. The aim of the present study was to investigate the possible contribution of perseverative thinking styles and thought control strategies to the development and maintenance of ED and PE. The authors hypothesized that such modes of processing might constitute a cognitive attentional syndrome specific to these disorders and sustained by particular metacognitive beliefs. A semistructured interview was administered to 11 participants with ED and 10 with PE in order to assess their metacognitive beliefs and cognitive attentional processes. The results suggest that individuals with ED and PE adopt a range of cognitive attentional strategies aimed at improving their sexual performance, and endorse both positive and negative metacognitive beliefs about these thinking responses. Overall, their cognitive and attentional patterns worsened negative internal states, reduced sexual excitement, detached them from their bodily sensations, and hindered sexual functioning. These preliminary findings suggest that perseverative thinking, thought control strategies, and metacognitive beliefs may play a key role in the onset and maintenance of male sexual dysfunction.

Cognitive Behavioral Therapy (CBT), Rational Emotive Behavior Therapy (REBT) and Metacognitive Therapy (MCT) models show both similarities and differences in conceptualizing anxiety. This work assumes that REBT’s irrational and MCT’s metacognitive beliefs play a mediation role while CBT’s disorder specific content beliefs act as triggers. This hypothesis is tested using a regression model in which metacognitive and irrational beliefs play a mediation role while content disorder beliefs are independent variables. This paper applied this model to generalized anxiety disorder (GAD), a psychiatric diagnosis in which anxiety is the major feature. In GAD, the specific content beliefs are negative problem orientation and intolerance of uncertainty. Therefore, 149 non clinical subjects completed 4 self-report questionnaires: the Negative Orientation to the Problems Questionnaire and the Intolerance of Uncertainty Scale as measures for content cognitive beliefs, the Attitudes and Beliefs Scale for irrational beliefs, and the Metacognitive Questionnaire 30 Items Version for metacognitive beliefs. The generalized anxiety disorder questionnaire was chosen in order to measure anxiety as dependent variable. Regression analyses confirmed that irrational and metacognitive beliefs mediate the relation between cognitive content beliefs and GAD. We clinically interpret mediation as a second level regulation.

Eleonora Comi,1,2 Marco Lanza,1 Flora Ferrari,1 Valeria Mauri,1,3 Gianfranco Caselli,1 Lucio Claudio Rovati1 1Department of Pharmacology and Toxicology, Rottapharm Biotech, 2PhD Program in Neuroscience, University of Milan-Bicocca, 3Department of Surgery and Translational Medicine, University ofMilan-Bicocca, Monza,Italy Purpose: CR4056, (2-phenyl-6-(1H-imidazol-1yl) quinazoline), an imidazoline-2 (I2) receptor ligand, is a promising analgesic drug that has been reported to be effective in several animal models of pain. The aim of this study was to evaluate the effects of CR4056 in two well-established rat models of osteoarthritis (OA), mimicking the painful and structural components of human OA.Methods: Knee OA was induced either by single intra-articular injection of monoiodoacetate (MIA) or by medial meniscal tear (MMT) in the right knee of male rats. In the MIA model, allodynia and hyperalgesia were measured as paw withdrawal threshold to mechanical stimulation. In the MMT model, pain behavior was analyzed as weight-bearing asymmetry (i.e. difference in hind paw weight distribution, HPWD) between the injured and the contralateral limbs.Results: Acute oral administration of CR4056, 14 days after MIA injection, significantly and dose-dependently reduced allodynia and hyperalgesia 90 minutes after treatment, whereas acute naproxen administration significantly reduced allodynia but not hyperalgesia. After 7days of repeated treatment, both CR4056 and naproxen showed significant anti-allodynic and anti-hyperalgesic effects in the MIA model. Rats undergoing MMT surgery developed a significant and progressive asymmetry in HPWD compared with sham-operated animals. Repeated treatment with CR4056 significantly reduced the progression of the pain behavior, whereas naproxen had no effects.Conclusion: The data presented here show that the I2 ligand CR4056 could be a new effective treatment for OA pain. The compound is currently under Phase II clinical evaluation for this indication. Keywords: osteoarthritis, pain, CR4056, imidazoline-2 receptors, MIA, MMT