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Funder: Cranfield University; Id: http://dx.doi.org/10.13039/501100000859, Funder: European Association of Cooperative Banks, Funder: Centre for Social and Sustainable Innovation, University of Victoria, Funder: Santander Universities; Id: http://dx.doi.org/10.13039/501100019904, This paper examines how ownership structure interacts with monetary policy in shaping financial intermediaries' appetite for risk. By constructing a large panel of banks across Western Europe, we provide evidence that differences in bank ownership influence the transmission of monetary policy via the risk-taking channel. While shareholder banks actively adjust the riskiness of their portfolios to changes in interest rates, stakeholder banks appear to be less responsive to such changes. These findings call for greater attention to the nature of bank ownership when setting monetary policy.

Over the last decade, interest in the clinical field regarding the emotional area of the child has grown. Several studies have confirmed the efficacy of cognitive-behavioural treatment in childhood and adolescence (Sukhodolsky, Kassinove, & Gorman, 2004; Compton et al., 2004), and programmes for the prevention of emotional disorders, such as Rational Emotive Education (Educazione Razionale Emotiva) (Di Pietro, Morosini, & Agostini 1999), have been disseminated in schools. This is a preventive psychoeducational intervention, which derives from the principles of Ellis’s Rational Emotional Behavioural Therapy (1989) and was brought to Italy in 1991 by Mario di Pietro (1992), following its adaptation at the Institute for Rational-Emotive Therapy in New York. In recent years the Italian version has been updated and integrated with the principles of Acceptance and Commitment Therapy, making the intervention more innovative. The purpose of this article is to provide an analysis of the application of Rational Emotional Behavioural Therapy in childhood and adolescence and to deepen the practical aspects of Rational Emotive Education, providing some useful ideas for the realisation of a psychoeducational project in primary schools.

It is widely accepted that the famous Tartini's third tone, i.e., the appearance of an additional third tone of lower frequency when playing a dyad on the violin, is a subjective phenomenon generated by the listener's cochlear nonlinearity. However, the recent demonstration that additional tones of audible amplitude can also be generated by the violin itself during playing of a dyad (violin combination tones), raises the question if these tones might have influenced Tartini's third sound perception. The experiments reported here were made to ascertain this possibility. To this end, following Tartini experiments, several dyads played by either one violin or two violins playing one note of the dyad each, were recorded. The analysis of the spectra shows that violin combination tones are present in all the dyads investigated, but exclusively when the dyad is played by a single violin and not when the same dyad is played by two violins. Tartini found the third tones to be the same in both conditions, which means that violin combination tones in his experiments were either absent or too small to affect the perception of the subjective third tones arising from cochlear distortion.

Background/Purpose: CR6086, a selective EP4 antagonist, dose-dependently improves disease features in rheumatoid arthritis (RA) models in rodents. Indeed, recent studies highlight the role of the EP4 receptor in modulating autoimmunity and in counteracting bone erosion. Aim of the present study was to test CR6086 as an add-on medication with methotrexate (MTX). Methods: DBA/1 male mice were immunized with bovine type II collagen (BCII) in CFA. On arthritis onset, animals were assigned to the following experimental groups: vehicle, oral CR6086 30 mg/kg/day, MTX 1 or 3 mg/kg/three times a week alone or in combination with daily CR6086 30 mg/kg. Edema measurement and clinical scores were blindly determined daily before drug administration. After 2 weeks of treatment, mice were sacrificed and serum BCII antibodies measured. Paw joints were blindly scored for histological features. Data were analyzed by ANOVA or by Kruskal-Wallis test followed by appropriate post-hoc comparison test. Results: CR6086 strongly and significantly reduced score and edema within the first week of treatment compared to vehicle. MTX 3 mg/kg modestly reduced clinical signs over the second week of treatment, while MTX 1 mg/kg was inactive. CR6086/MTX combined treatments significantly reduced clinical score and edema within the first week of treatment. Figure 1 reports the AUC analysis of the whole treatment. Post-hoc pairwise comparisons showed that combined treatments were significantly superior to each single treatment (P

Alcohol Use Disorder (AUD) is a debilitating condition with serious adverse effects on health and psycho-social functioning. The most effective psychological treatments for AUD show moderate efficacy and return to dysregulated alcohol use after treatment is still common. The aim of the present study was to evaluate Metacognitive Therapy (MCT) as applied to AUD. Five patients were treated using a non-concurrent multiple baseline design with follow-up at 3- and 6-months time points. Each patient received 12 one-hour sessions of MCT. Following MCT all patients demonstrated large and clinically meaningful reductions in weekly alcohol use and number of binge drinking episodes that were upheld at follow-up in almost all cases. Metacognitive beliefs, as secondary outcome, also changed substantially. The findings from this study offer preliminary evidence of positive effects associated with MCT in AUD and support the need for a definitive trial of MCT in addictive behaviors.

"It is physically certain that given two simultaneous loud and prolonged tones one can hear a third tone, different from the played sounds": with these words taken from his essay Trattato di musica secondo la vera scienza dell'armonia published in 1754 Giuseppe Tartini (1692-1770), celebrated violinist, and researcher of musical theory and "physicomathematical harmonist" (Barbieri, 1990) introduces his discovery, made some years before (in 1713), of the socalled third tone. As explained by Tartini himself, if a listener stands halfway between two violin or oboe players some steps apart, he can hear another tone, in addition to the played notes (principal or primary notes), called by Tartini the "third tone"

Introduction The present study investigated two male sexual dysfunctions: male erectile disorder (ED) and premature ejaculation (PE), respectively defined as “persistent or recurrent inability to attain, or to maintain an adequate erection until completion of the sexual activity” and “persistent or recurrent ejaculation with minimal sexual stimulation before, on, or shortly after penetration and before the person wishes it” or within two minutes of penetration. The metacognitive model is based on the idea that “it is not merely what a person thinks but how he or she thinks, that determines emotions and the control one has over them.” (Wells, 2008). In the metacognitive theory of psychological dysfunction, Wells and Matthews (1994) propose that a set of metacognitive beliefs are responsible for psychological disturbance by maintaining maladaptive attentive and cognitive coping strategies. This array of factors constitutes a Cognitive Attentional Syndrome (CAS; Wells, 2000), sustained by the presence of some metacognitive plans and beliefs that control the use of thought and attention. Some of the CAS components have been investigated in relation to male sexual dysfunctions, even if they have not been conceptualized in a specific metacognitive frame. For example, Hartmann and colleagues (2005) reported that, if compared to normal controls, “during sexual intercourse PE patients were totally preoccupied with thoughts about controlling their orgasm, while this was not a strong cognitive factor for the functional men. Other prevailing cognitions in PE patients referred to the anticipation of a possible failure and the embarrassing situation following a rapid ejaculation”. Objectives To our knowledge, no study has investigated the presence of CAS and metacognitive beliefs in the maintenance of Sexual Dysfunctions. The central aim of this study was to explore the specific role of CAS components and related metacognitive beliefs in affecting sexual performances of men with PE and ED. In line with a metacognitive conceptualization, it was hypothesized that ED and PE could be triggered, maintained or even worsened by CAS. In addition, it was hypothesized that this mode of processing would be roamed by specific positive and negative metacognitive beliefs. Sample A purposive convenience sample consisted of 11 ED and 10 PE participants. The diagnosis was done in accordance with the DSM-IV (APA, 1994). For the purpose of the present study, only primary diagnosis was considered, defined as the first and more impairing disease for which men had asked an andrology consulting. The mean age of the sample was 40 years (SD=7.4) and age ranged from 27 to 49 years. The sample was entirely Caucasian. Materials All participants were interviewed using the metacognitive profiling template adapted to specifically focus on cognitive aspects of sexual dysfunctional experiences. The interview schedule attempted to elicit data from four main preordained categories (1) The cognitive style during a negative sexual experience: participants were asked to describe a recent episode of sexual negative experience and to identify what triggered their perception of failure (2) Attentional focus during sexual approach: participants were asked about the focus of their attention while approaching sexual activity, and to explain the advantages and disadvantages they found in using their attention in that way (3) Pursued goal: participants were asked about the purpose of their cognitive and attentional response, whether they reached it, how they knew when their goal had been achieved and when the process of achieving the goal was interrupted (4) Metacognitive beliefs: in order to examine positive and negative metacognitive beliefs, participants were asked to identify advantages and disadvantages they perceived in their cognitiveattentional response or in giving up the process Procedure All participants were enrolled among those who had asked for an andrology counselling and none of them presented a lifelong disease. The data were collected over a period of six months. Interviews were audio recorded, transcribed, and anonymized. A top-down thematic content analysis, using a deductive method of analysis was carried-out to screen the interviews. Specifically, the developing analysis was influenced by both primary material (the transcripts of the patients) and secondary sources related to theory and therapeutic approaches (Metacognitive Theory). Transcripts were preliminarily analysed by an independent researcher who was not trained to the metacognitive protocol using a descriptive thematic approach (Braun & Clarke, 2006), which involves identifying codes and themes inductively (data driven approach) from the raw data. Once the initial descriptive thematic analysis was performed, it emerged that there was a strong relation between the categories derived from the raw data and the four categories belonging to the metacognitive profile template. Subsequently, the analytical process was extended and the emerging themes were grouped according with the metacognitive profile template categories. Triangulation strategies (Morse, Barrett, Mayan, Olson, and Spiers, 2002) were employed to ensure methodological coherence, appropriateness of the sampling procedures, and negative case analysis. A number of five debriefing sessions between the first author and the wider research team were set-out in order to discuss data collection procedures, analytical steps, and interpretations issues.Results Cognitive style during a negative sexual experience Participants, regardless of the type of dysfunction, identified two types of trigger: negative bodily sensations (18) and negative anticipatory thoughts about their sexual performance (14). For what concerns the cognitive style, it is possible to identify 4 different strategies that participants reported to use when trigger occurred: (1) they ruminated about the trigger and its consequences; (2) they worried about negative outcomes; (3) they tried to motivate themselves through self-imposed statements; (4) they tried to suppress and to distract from negative thoughts or bodily sensations. Attentional focus during sexual approach Participants reported that their attentive focus during sexual approach was mostly focused on monitoring (1) their partner’s reactions and sensations or (2) their own thoughts and bodily sensations. Pursued goal Participants reported using their strategy with the aim of achieving a better sexual performance or understand the causes of their problem. Metacognitive beliefs Participants identified positive metacognitive beliefs about the usefulness of their cognitive-attentional response in: (1) enhancing sexual performance, (2) controlling negative thoughts and emotions, (3) understanding the causes of their sexual problem. Participants identified negative metacognitive beliefs that concerned: (1) the direct damage on sexual functioning, (2) increase in negative thoughts and emotions, (3) uncontrollability of their cognitive-attentional response. Discussion The findings of this study suggest that metacognitive beliefs and CAS components may play a role in the maintenance of sexual dysfunctions and in the exacerbation of negative emotional states. Findings show both similarities and differences in CAS among individuals with ED and PE. Similarities refer to triggers, goals and attentional focus: • All individuals activated CAS components in response to negative sensations or thoughts associated with their sexual functioning, aiming most of all to improve their sexual performance or, only few men with ED, to better understand their sexual dysfunction. • Attentional focus is almost equally distributed between internal bodily sensations and external partner reactions. Both of these attentional strategies may have been applied in order to monitor what individuals considered signals of (1) threat and (2) goal progress. • The goal seems partially related to cognitive style: all the men with PE referred to aim at reaching a better performance, and consistently with this aim, none of them engaged in deeper and perseverative thinking styles such as worry or rumination. On the other hand, few men with ED were committed to reach a better understanding of their dysfunction, and it is possible that they tried to reach this goal by worrying or ruminating, as indicated by six of them. Differences between ED and PE refer mainly to cognitive styles. • ED mostly activated a perserverative thinking style in the form of self-imposed statements, rumination or worry. PE showed higher negative appraisal associated with triggers, and reported the activation of thought control strategies (e.g. distraction) in order to suppress them: this aligns PE patients with patients with a body dysmorphic disorder (Cooper & Osman, 2007). • PE also showed a greater proportion of partial goal achievement compared with ED, despite admitting that they are unable to solve their problem. This could suggest that even if in the short-term period thought control strategies may lead to a reduction in excitement and anxiety, in the longer term they may become a coping strategy employed to achieve cognitive and emotional avoidance, that may also interfere with emotional processes and increase the number of target-related intrusive thoughts through the well-established rebound effect (Davies & Clark, 1998). Positive metacognitive beliefs concern the usefulness of CAS response to improve sexual functioning and to understand and control negative sensations and thoughts. Such beliefs may be involved in the activation of perseverative thinking and thought control strategies and are coherent with what was identified about chronic fatigue syndrome (Maher-Edwards et al., 2012). Negative metacognitive beliefs concern the uncontrollability of perseverative thinking styles and the negative impact of CAS components on emotional states and sexual functioning. These beliefs may play a role in propagating negative affect and loss of excitement that may lead to an escalation of CAS process. Consistently with this hypothesis, men with ED, that referred more negative metacognitive beliefs about uncontrollability, were also more inclined to use perseverative thinking styles such as worry and rumination. On the other hand, no men with PE reported negative metacognitive beliefs about uncontrollability, and none of them used to worry or ruminate in front of a trigger. This is consistent with the metacognitive formulation of GAD (Wells, 2008). This research has some limitations, with respect to the small size of the sample and the possibility that participants present simultaneously different aspects of sexual disease. Even considering these limitations, from a therapeutic perspective the findings suggest that techniques and principles of metacognitive therapy (e.g. Attentional Training; Wells, 2008) might be beneficial with some patients suffering from ED or PE. In particular, men with ED should gain a more flexible control over their perseverative thinking style, while men with PE should reduce their need to control negative thoughts and to monitor the negative implications of their sexual functioning they usually associate with them. Future studies investigating the role of CAS components and related metacognitive beliefs will require the use of specific psychometric measures of all variables to support preliminary findings and should enroll a major number of participants in order to confirm or disconfirm the trend that has been identified. Despite the small sample of individuals and the retrospective nature of the measures employed, present findings provide preliminary evidence that CAS and metacognitive beliefs may play a key role in sexual dysfunctions, coherently with previous research about body dysmorphic disorder (Cooper & Osman, 2007), primary insomnia (Waine, Broomfield, Banham, & Espie, 2009), desire thinking (Caselli & Spada, 2010), smoking (Nikčević & Spada, 2010), chronic fatigue syndrome (Maher-Edwards et al., 2012) and gambling disorder (Spada et al., 2015).

Objective: Research has found that the prevalence of psychological distress is substantially higher in transgender compared to cisgender populations. This study explored the role of metacognitions as mediators of anxiety in a sample comprising of cisgender and transgender individuals. Method: 125 individuals (19 trans-male; 24 male; 25 trans-female; 57 female) completed a series of measures that assessed metacognitions, worry, and anxiety. Results: Correlation analyses were used to identify potential mediators of the relationship between gender identity and anxiety. A mediation model indicated that beliefs about thoughts concerning uncontrollability and danger entirely mediated the relationship between gender identity and anxiety (b= 2.00, BCa CI [0.68, 3.49]). Conclusions: Metacognitions play an important role in anxiety in transgender individuals.

Introduction and aim: Osteoarthritis (OA) is a degenerative chronic joint condition. Joint pain is the earliest symptom of OA and is driven by both nociceptive and neuropathic mechanisms. CR4056, an I2 ligand, was previously reported to be effective in several animal models of inflammatory, neuropathic and postoperative pain. Aim of this study was to evaluate the effect of CR4056 in the model of OA pain obtained by the injection of monosodium iodoacetate (MIA) into the knee joint of rats, which produces cartilage degeneration, mimicking the painful and structural components of human OA. Besides, MIA model is associated with an early phase neuropathy. Methods: OA was induced by a single intra-articular injection of 1 mg/50 μl MIA in the infrapatellar area of the right knee of male Wistar rats. Pain thresholds were evaluated as mechanical allodynia (automatic Von Frey tester) and mechanical hyperalgesia (PAM device) on day 1 before MIA injection and on day 7, 14 and 21 after MIA injection. CR4056 (2, 6, 20 mg/kg) and 10 mg/kg naproxen were administered orally, as single treatment on day 7 and as sub-chronic treatment from day 14 to day 21, once a day. Results and conclusion: 6 and 20 mg/kg CR4056 induced a statistically significant anti-allodynic effect on T14 and T21, and a statistically significant anti-hyperalgesic effect at each time point (T7, T14, T21). The analgesic efficacy of naproxen was statistically significant after the sub-chronic treatment only. CR4056 could, therefore, represent a new highly effective treatment option for OA pain.

Bortezomib (BTZ) is an antineoplastic drug mainly used for the treatment of multiple myeloma and some types of solid tumors. Despite its effectiveness, BTZ clinical use is frequently limited by the onset of painful peripheral neuropathy, generally associated with alterations of A delta and C type primary afferent fibers. The neurotoxic mechanisms of BTZ remain poorly understood, although proteotoxic stress and mitochondrial impairment may contribute to the pathogenesis of the sensory distal neuropathy. To evaluate these aspects, spinal cord electrophysiological recordings and behavioral test alterations for neuropathic pain and immunohistochemistry studies of pain-related sensory biomarkers were performed in a Wistar rat model of BTZ-induced painful peripheral neuropathy. Then, three different analgesic drugs (CR4056, Gabapentin and Buprenorphine) were tested against BTZ-painful neuropathy. The animals were intravenously treated with BTZ 0.20 mg/kg, 3 times a week for 8 weeks, followed by 2 weeks of analgesic administrations. Bortezomib induced both mechanical allodynia and peripheral neuropathy in rats after 8 weeks of treatment. CR4056 was able to recover the painful condition without changing the nerve structural damage. Moreover, BTZ- induced changes both in the electrical activity of wide dynamic range neurons, and in the transient receptor potential vanilloid type 1 receptor (TRPV1) and neuropeptides calcitonin gene-related peptide (CGRP) immunolabeling expression in the spinal cord. In conclusion, the results of the study suggest that the alteration in the spinal cord electrophysiological recordings and CGRP/TRPV1 levels modulation are involved in the persistence pain symptoms in BTZ-induced peripheral neuropathy. Therefore, this model will enable us to test promising analgesic drugs designed to ameliorate or restore painful condition, and to compare it with standard compounds.

The Metacognitions about Smoking Questionnaire was shown to possess good psychometric properties, as well as predictive and divergent validity within the populations that were tested. The metacognition factors explained incremental variance in smoking behaviour above smoking outcome expectancies.

Bortezomib (BTZ), a selective proteasome inhibitor, is an antitumor drug used to treat multiple myeloma. As a side effect, BTZ determines a painful peripheral neuropathy (PPN), often refractory to management. Chronic BTZ administration in female Wistar rats induced a PPN in which the development of mechanical allodynia is associated to an increase in the expression of TRPV1 and CGRP in the dorsal root ganglia (DRG) and spinal cord dorsal horn. In this study we examine the possible role of two standard analgesics, Gabapentin (Gaba) and buprenorfin (Bupre), in modulating the expression of TRPV1 and CGRP in the DRG and spinal cord of rats chronically treated with BTZ. To this aim, female Wistar rats were treated with BTZ 0.20 mg/kg, 3 times a week for 8 weeks (i.v.). Then Gaba (100 mg/kg, daily, p.o.) and Bupre (28,8 µg/kg, daily, s.c.) were orally administered in a curative schedule for 2 weeks. The expression of TRPV1 and CGRP, a neuropeptide involved in nociceptive neurotransmission, was examined in L4-L5 DRG and spinal cord segments by means of western blot (WB) and immunohistochemistry. WB analysis did not show any statistically significant change of protein levels in DRG and spinal cord. Instead, chronic BTZ treatment followed by a 2 weeks follow-up period affected TRPV1 expression by inducing an increase in the proportion of TRPV1-like immunoreactive (LI) DRG neurons, whereas did not affect the percentage of CGRP-LI neurons. Labeled perikarya were mostly of small- and medium-size. No BTZ-induced changes in immunolabeling were appreciable in the dorsal horn of the spinal cord. Treatment with Gaba and Bupre reduced levels of TRPV1 protein in spinal cord homogenates, whereas had no effect on DRG protein levels. None of the analgesics appeared to reverse in a statistically significant way the BTZ-induced increase of labelled DRG neurons nor induced any change in the detectability of positive innervation in the spinal cord dorsal horn.

Bortezomib (BTZ), a selective proteasome inhibitor, is a potent antineoplastic drug to treat multiple myeloma. In clinical practice, the most significant side effect of its administration, is a peripheral painful sensory neuropathy (PN), characterized by numbness and tingling in a distal stocking-glove distribution as well as distal paresthesia and generally associated with impairment of Adelta and C type primary afferent fibers. At the moment the therapies for PN are not really effective and almost only symptomatic. To evaluate if BTZ-induced sensory deficits are associated to loss of epidermal nerve fibers as is observed in other PN conditions, here we examine the effect of a well-established chronic BTZ-treatment schedule on the number of intraepidermal nerve fibers (IENF) in a rat model of BTZ-induced PN and compared the outcome of chronic BTZ-treatment followed by two-weeks of follow up with that of animals that received a 2-weeks treatment period with two analgesic drugs commonly used in clinical practice such as Gabapentin (Gaba) and buprenorphine (Bupre). To these aims, female Wistar rats were treated with BTZ 0.20 mg/kg, 3 times a week for 8 weeks (i.v.). Then analgesic were orally administered according to the following curative schedule: Gaba (100 mg/kg, daily, p.o.), Bupre (28,8 μg/kg, daily, s.c.). At the end of treatments, the hindlimb footpad skin was examined by immunohistochemistry for the pan-neuronal marker PGP9.5 and the neuropeptide calcitonin gene-related peptide (CGRP), a neuropeptide involved in pain perception and neurotransmission. Labelled nerve fibers were distributed in the reticular and papillary dermis and within the epidermal lining. Quantitative evaluation of IENF showed that, according to the painful symptoms induced by BTZ, the mean linear density of CGRP-labelled IENF normalized by that of the PGP9.5-labelled ones shows a statistically significant decrease in BTZ-treated rats. None of the analgesics used in this study appeared to reverse the BTZ-induced loss of IENF. Results obtained suggest that the CGRP-positive innervation is likely involved in the persistence of BTZ-induced pain and that detectability of CGRP-positive IENF appears not to be related to the effectiveness of the selected analgesics.

Bortezomib (BTZ) is a proteasome inhibitor used as first-line therapy for multiple myeloma. However, its administration induces the development of severe painful peripheral neuropathy (PPN). This painful condition is an important medical need since the available treatments are actually ineffective. We recently described a mice model of PPN that shares most of the conditions found in patients treated chronically with BTZ (Carozzi et al., 2013). In fact, BTZ determines dysfunction of all fiber types in sensory nerves and, at least in mice, alters the electrical activity of the spinal dorsal horn neurons. This alteration of the basal electrophysiological activity induces also relevant changes in the central nociceptive transmission. In this work we characterize the neuroprotective effects of an imidazoline receptor 2 ligand (CR4056) able to allosterically inhibit the activity of monoamine oxidase-A, a key enzyme in the regulation of neuropathic pain. Wistar rats were treated with BTZ 0.20 mg/kg, 3 times a week for 8 weeks (i.v). Then CR4056 was orally administered in a curative schedule at 6 mg/kg, once a day, for 2 weeks. Gabapentin (100 mg/kg, daily, p.o.) and buprenorphine (28,8µg/kg, daily, s.c.) were used as internal analgesic standards. At the end of both BTZ and analgesic treatments, we measured the caudal and sciatic nerve conduction velocity (NCV), the morphological/morphometrical alterations in the caudal nerve and the neuropathic pain development. BTZ treatment induced a significant impairment of sensory, but not motor NCV, slight hyperalgesia, significant mechanical allodynia and clearing of myelinated fibers in the caudal nerves. After two weeks of follow up animals did not spontaneously recover functional, morphological and behavioral abnormalities while the 2 weeks-treatment with CR4056 (but not with gabapentine and buprenorphine) significantly resolved BTZ-induced mechanical allodynia. Results obtained show that CR4056 produces a marked analgesic effects against BTZ-induced neuropathic pain without signs of tolerance. Carozzi VA, Renn CL, Bardini M. et al. PLoS One. 2013; 8(9):e72995.

Objective: Bortezomib, a potent and selective proteasome inhibitor, is the first line treatment of relapsed, refractory multiple myeloma. One of the most commonly reported adverse reactions induced by this drug, is a peripheral neurotoxicity characterized by sensory and often painful neuropathy representing the major reason for a dose reduction and discontinuation of life-saving therapy. The use of currently available drugs for the treatment of neuropathic pain is largely empirical, and their mechanisms of action are not completely understood. CR4056 is a promising analgesic drug that interacts with imidazoline-2 receptors, and inhibits the activity of monoamine oxidases. Aim of this study was to evaluate if the new analgesic compound CR4056 could prevent (preventive schedule) or reverse (curative schedule) the neuropathic pain elicited by bortezomib in a rat model of chronic painful peripheral neuropathy . Methods: Neuropathy was induced in female Wistar rats by intravenous administration of Bortezomib (0.20 mg/kg, 3 times a week). CR4056 was orally administered at 6 mg/kg, once a day, in both preventive and curative schedules. In the preventive schedule animals were dosed with bortezomib and CR4056 starting from day 1 till week 8 or 10. In the curative schedule, established neuropathic animals were treated with CR4056 either from week 6 or week 8 till week 10. The sensory neuropathy was evaluated by tail nerve conduction velocity (NCV) at week 6, 8 and 10 after the first challenge with bortezomib. The development of neuropathic pain behaviour (mechanical allodynia) was followed by mechanical testing on day 1, at week 6, 8, 9 and 10. General toxicity, evaluated as body weight changes, was monitored twice a week Results: Bortezomib induced a severe reduction in NCV and a significant mechanical allodynia at all the indicated time points. Administration of CR4056, neither in preventive nor in curatives schedules, affected the NCV impairment. Conversely, CR4056 treatment significantly and completely prevented the development of mechanical allodynia in bortezomib treated-rats, in the preventive schedule, and totally reverted the established neuropathic pain in the curative schedule. The analgesic effect persisted until the last time point of observation without signs of tolerance. No remarkable effect induced by bortezomib or CR4056, alone or in co-treatment, was observed on body weight changes. Conclusions: The present study evidences a significant and long lasting analgesic effect of CR4056, which could represent a new therapeutic option for the treatment of bortezomib-induced chronic neuropathic pain.

Bortezomib (Btz) is a highly effective and widely used antineoplastic drug for the treatment of many tumors, primarily multiple myeloma. Despite its effectiveness, the use of this proteasome inhibitor is limited by its toxicity. Among Btz side effects, peripheral neurotoxicity is a major and clinically relevant problem. In fact, since the earliest Phase I and Phase II studies, sensory peripheral neuropathy emerged as a dose-limiting side effect. Moreover, a significant proportion of Btz-treated patients developed severe neuropathic pain. The treatment of Btz-induced neuropathic pain is extremely difficult with the currently available drugs and still remains a major challenge for oncologists and neurologists. Aim of this study was to demonstrate if the new analgesic compound CR4056 could reverse the neuropathic pain induced by a chronic treatment with Btz in the rat. The anti-nociceptive and dose-dependent effect of CR4056 was assessed in a well-established experimental rat model in which Btz was administered to Wistar rats (0.20 mg/kg three times/week for 8 weeks) followed by treatment with CR4056 (6, 20 or 60 mg/kg daily p.o.) or buprenorphine administered 28,8 µg/kg/day p.o. for 2 weeks. Body weight change, hematological and histopathological parameters, nerve conduction velocity (NCV) and sensory behavioral tests were evaluated during the experiment. No remarkable effect of Btz administration or of any dose of CR4056 was observed in the hematological parameters and blood chemistry. After 8 weeks of treatment, Btz induced a severe reduction in NCV; this impairment was not reversed by CR4056 or by buprenorphine. The behavioral assessment showed a significant mechanical allodynia in rats treated with Btz for 8 weeks (delta vs. controls -6 g). Buprenorphine significantly reduced Btz-induced allodynia during the fist day by about 63%. However, this effect was lost during the following days of treatment (i.e 20% reduction on the 3rd day).The mid and high dose of CR4056 (20 and 60 mg/kg) showed a significant (i.e > 80 %) reduction of allodynia till the 3rd day of administration, afterwards a slight reduction in efficacy was recorded. On the contrary, the oral daily administration of 6 mg/kg CR4056 persistently counteracted Btz-induced allodynia, showing an even complete reversion after 2 weeks of treatment. The present study gives evidence for a relevant and persistent anti-allodynic effect of CR4056, suggesting a role for CR4056 in the management of neuropathic pain in patients treated with Btz.

Introduction: CR4056 is a novel imidazoline-2 receptor ligand endowed with low affinity MAO inhibition properties. Objectives: Aims of this study was to test with different methods the anti-nociceptive effect of CR4056 in rat models of neuropathic pain, i.e. Bortezomib(Btz)-induced neuropathic pain, streptozotocin-induced diabetes and chronic constriction injury (CCI). Methods: In the Btz model (0.20mg/kg 3qwx8 iv) and in the experimental diabetes model CR4056 was administered at 6-60mg/kg po. In the CCI mononeuropathy model CR4056 was administered at 10-80 mg/kg po. Nerve conduction velocity (NCV), dynamic, Randall-Selitto, plantar and von Frey tests were used to assess the effect of CR4056. Results: After 8 weeks of treatment, Btz induced a severe reduction in NCV and this impairment was not reversed by CR4056. The behavioral assessment showed a significant mechanical allodynia in rats treated wit Btz for 8 wks and the daily administration of CR4056 significantly reduced this condition. This effect was persistent along the entire period of administration after Btz withdrawal (2 weeks). In the models of streptozotocin-induced diabetes and CCI, treatment with CR4056 significantly attenuated mechanical and thermal hyperalgesia, while CR4056 had no effect on mechanical allodynia in both experimental models. Conclusions: These results promote the use of CR4056 as a potential treatment in the chronic neuropathic pain therapy.

AIM:The purpose of our study was to determine the efficacy of percutaneous thrombin treatment for iatrogenic femoral artery pseudoaneurysms (FAP) and to identify those criteria that may help to predict increased treatment failure risk and complications. METHODS: A number of 32 iatrogenic femoral pseudoaneurysms were treated with US-guided thrombin injection (group A), while four elderly patient with complex femoral pseudoaneurysm underwent compression assisted by removable "guidewire" (group B). Twenty-five were classified as simple (single lobe) and 11 as complex (at least two lobes with a single neck to the native vessel). Pseudoaneurysm volume, classification, thrombin dose, anticoagulation therapy status, and sheath size were considered independent prognostic factors. RESULTS: All the 36 patients (pts) had initial complete femoral pseudoaneurysms thrombosis. The aneurysm was thrombosed on a Doppler ultrasound (US) follow-up in all the cases but four (group A), those who required the additional thrombin injection. A fatal complication occurred in one patient with complex FAP (group A). CONCLUSION: Preliminary data suggest that US-guided percutaneous thrombin injection is a safe and effective method to treat iatrogenic pseudoaneurysms. Simple iatrogenic femoral pseudoaneurysms benefit a single injection of up to 500 units of topical thrombin. We recommend more caution in complex pseudoaneurysms treatment; it is preferable to perform thrombin injection first into the lobe which is not directly joined to the femoral artery. A longer bed rest and closer observation are mandatory during the subsequent 24 hours. If the lobe communicating with the femoral artery is still patent, it can be retreated. Alternatively, we propose a new strategy approach through compression assisted removable "guidewire".

Most peripheral artery emboli originate in the heart, and systemic neoplastic emboli are infrequently associated with bronchogenic carcinoma. To our knowledge, there have been no reports of pulmonary vein infiltration by small cell lung cancer.We describe a highly unusual case of multiple instances of peripheral embolism as the first overt sign of occult primary small cell lung cancer. Tumor emboli infiltrated the pulmonary veins of a 62-year-old man who presented first with a transient ischemic attack and then with other ischemic symptoms. The uncommonly wide distribution of tumor emboli over a short time resulted in death.Improvements in diagnostic imaging have led to the early identification of relatively isolated small cell lung cancers. This patient's case underscores the importance of transesophageal echocardiography in detecting cardiac emboli when the cause of cerebral ischemic attack is unknown or if there might be multiple instances of arterial embolism. Computed tomography also has a role in the investigation of possible sources of emboli and unrecognized, asymptomatic embolization.

Twenty-five medical centers and the Prader–Willi Syndrome (PWS) Association collaborated on a study which attempted to identify all people with genetically confirmed diagnosis of PWS living in Italy. Investigators of the participating centers contacted PWS subjects and/or their family, filled in a specially developed form with the required data and forwarded this information by email. The study identified 425 subjects (209 males and 216 females, between the ages of 0.4–46.7). Two hundred thirty-eight patients had del15, 104 had UPD15, 4 demonstrated a translocation affecting chromosome 15 and 79 showed a positive methylation test. There were fewer subjects found over the age of 35, probably due to the low rate of identification of older PWS patients as well as the high mortality rate. There were a greater number of male children and adolescents with PWS whilst, amongst adults, there were more females. As expected, the majority of subjects with PWS were obese, especially in adult life. Nevertheless, it is noteworthy that 26% of patients aged between 6 and 17 were normal weight. A total of 212 subjects had received GH treatment, of which 141 were still receiving therapy, while the remaining 71 had stopped. In children and adolescents (233 cases), 89 subjects had never undergone GH therapy. Eighteen PWS patients had died in the past 20 years. Obesity-related cardiovascular and respiratory diseases were the cause of death, both during childhood and after 18 years of age. Three children died suddenly whilst undergoing GH therapy. Respiratory infection and cardiac illness were the causes of death in two cases. There was no definitive cause of death found in the third case. Overall, there was no increase in number of deaths during GH treatment, suggesting that GH administration in patients with PWS, as a group, does not increase the risk of death. © 2008 Wiley-Liss, Inc.

Background Multi-element interventions for first-episode psychosis (FEP) are promising, but have mostly been conducted in non-epidemiologically representative samples, thereby raising the risk of underestimating the complexities involved in treating FEP in ‘real-world’ services. Methods/Design The Psychosis early Intervention and Assessment of Needs and Outcome (PIANO) trial is part of a larger research program (Genetics, Endophenotypes and Treatment: Understanding early Psychosis - GET UP) which aims to compare, at 9 months, the effectiveness of a multi-component psychosocial intervention versus treatment as usual (TAU) in a large epidemiologically based cohort of patients with FEP and their family members recruited from all public community mental health centers (CMHCs) located in two entire regions of Italy (Veneto and Emilia Romagna), and in the cities of Florence, Milan and Bolzano. The GET UP PIANO trial has a pragmatic cluster randomized controlled design. The randomized units (clusters) are the CMHCs, and the units of observation are the centers’ patients and their family members. Patients in the experimental group will receive TAU plus: 1) cognitive behavioral therapy sessions, 2) psycho-educational sessions for family members, and 3) case management. Patient enrolment will take place over a 1-year period. Several psychopathological, psychological, functioning, and service use variables will be assessed at baseline and follow-up. The primary outcomes are: 1) change from baseline to follow-up in positive and negative symptoms’ severity and subjective appraisal; 2) relapse occurrences between baseline and follow-up, that is, episodes resulting in admission and/or any case-note records of re-emergence of positive psychotic symptoms. The expected number of recruited patients is about 400, and that of relatives about 300. Owing to the implementation of the intervention at the CMHC level, the blinding of patients, clinicians, and raters is not possible, but every effort will be made to preserve the independency of the raters. We expect that this study will generate evidence on the best treatments for FEP, and will identify barriers that may hinder its feasibility in ‘real-world’ clinical settings, patient/family conditions that may render this intervention ineffective or inappropriate, and clinical, psychological, environmental, and service organization predictors of treatment effectiveness, compliance, and service satisfaction. Trial registration ClinicalTrials.gov Identifier NCT01436331