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Salvatore Settineri,1 Fabio Frisone,2 Emanuele Maria Merlo,2 Daniele Geraci,3 Gabriella Martino31Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina, Italy; 2Department of Cognitive Sciences, Psychology, Educational and Cultural Studies (COSPECS), University of Messina, Messina, Italy; 3Department of Clinical and Experimental Medicine, University of Messina, ItalyBackground: The pathological reality of diabetes and the incidents in following the prescribed therapies have been considered and are still a serious and relevant problem in the health sector.Objective: This review aims at highlighting the importance of clinical psychological phenomena that underlie the notion of therapies.Methods: The review was conducted through search engines such as PubMed, Medline, Web of Science and Google Scholar. The articles related to compliance, adherence, concordance, empowerment and the self-management of diabetes were included, in order to highlight the possible similarities and differences that these terms bring with them in them management of diabetes.Results: Starting from 252 initial publications, 101 articles were selected that highlighted the practical implications that each term has compared to the others.Conclusion: The review can represent a bridge between the medical approach and clinical psychology, in which integration can suggest paths aiming at improving patients’ existential conditions and adaptation.Keywords: compliance, adherence, concordance, empowerment, self-management, diabetes

Background: The literature consistently highlights the significant burden faced by healthcare professionals, often describing caregivers as "invisible patients." Resilience is a critical factor in their well-being and quality of life. This study aimed to examine the presence of variables such as resilience and burden in caregivers, along with factors like age, gender, education, and work commitment, to understand the correlations among these independent and clinical variables., Methods: The sample consisted of 126 carers aged 18-30 years old (M: 26.15; SD: 3.21) with a 77.8% of the sample being female. The variables included the socio-demographic (age, sex, education, hours/days of speech per week and years of service) and clinical status, therefore burden (time dependence, development, physical, social and emotional burden) and resilience (self-perception, planned future, social competence, structured style, family cohesion and social resources)., Results: Regarding the correlational analyses involving socio-demographic variables and resilience, only a few significant correlations were found. However, significant positive correlations were identified between socio-demographic variables and burden, specifically with age, hours and days of work per week, and years of service. Conversely, education showed a significant negative correlation with burden, highlighting its protective role. Significant correlations between resilience and burden variables were generally positive, except for self-perception and developmental burden. Multivariate linear regression analyses revealed numerous dependencies, with predictors such as age, sex, education, hours/days of work per week, and years of service influencing the dependent variables related to burden and resilience., Conclusions: This study examined fundamental socio-demographic, occupational, and psychological variables in the lives of caregivers. It highlights not only the presence of factors that negatively impact caregivers' quality of life but also important relationships between personal variables, resilience, and burden risk. Therefore, it is crucial to consider the findings of this study, along with existing literature, to design interventions aimed at reducing burdens and improving the quality of life for caregivers.

Objective: Euthymia is a transdiagnostic construct characterized by the presence of positive mood states, psychological flexibility and resilience. These components contribute to psychological wellbeing and support mental functioning. Exposure to suffering and high levels of stress can lead to the onset of burnout and secondary traumatic stress, but also lack of compassion satisfaction. The study aimed to test the existing relationships between euthymia, psychological well-being, and factors associated with quality of life of healthy participants involved in medical settings., Method: The sample was composed of 177 healthy participants involved in medical settings, 118 women (66.7%) and 59 men (33.3%) aged between 19 and 69 years old (mean = 27.16; SD = 8.47). Standardized psychodiagnostics instruments were used to assess euthymia (Euthymia Scale-ES), psychological well-being (The Well-Being Index scale-WHO-5) and the quality of life of the involved participants (Professional Quality of Life Measure-ProQOL-5)., Results: The results showed that gender, well-being and psychological well-being were predictors of compassion satisfaction and secondary traumatic stress. Specifically, female gender predicted higher levels of compassion satisfaction. Well-being and psychological flexibility predicted higher levels of compassion satisfaction and lower secondary traumatic stress. Psychological well-being predicted higher levels of compassion satisfaction., Conclusions: Promoting euthymia and well-being helps individuals to preserve psychological well-being and increase tolerance to stressful life situations. Results highlighted the need for promoting health care professionals' euthymia and well-being. In line with evidence, encouraging interventions based on evidence appears relevant., Competing Interests: Competing interests: None., (© 2024 Giovanni Fioriti Editore s.r.l.)

Background: Type 1 Diabetes Mellitus (T1DM) represents a serious chronic condition affecting a wide number of people. Discussion of the physical issues associated with T1DM pervades the literature, however, there is less discussion of the psychological consequences. Mental health difficulties, alexithymia and uncertainty are present in this population, and known to be harmful for the onset, maintenance and worsening of T1DM. This study aimed to evaluate the presence of these phenomena in people with T1DM., Methods: 105 participants aged between 11 and 17 years old (M: 13.88; SD: 2.16) affected by T1DM were included in the sample. To assess the presence of mental health difficulties, SAFA scales (Depression, Anxiety and Somatic symptoms) were included in the protocol together with TAS-20 and IUS-12, which evaluate the presence and role of alexithymia and intolerance to uncertainty in the sample, respectively., Results: A concerning presence of anxiety, depression and somatic symptoms was found in the sample. Mental health difficulties appeared to be consistently present in the sample, often overcoming pathological thesholds. Alexithymia and uncertainty were also common, highlighting their role in T1DM., Conclusions: Active mental health difficulties together with high rates of alexithymia and intolerance to uncertainty were prevalent in the sample of adolescents with diabetes., (© 2024. The Author(s).)

Type 1 diabetes mellitus (T1DM) represents a complex pathology affecting a large number of people. Research suggests that psychological factors influence coping with T1DM. This study aimed to investigate the presence and role of psychopathology, alexithymia and uncertainty in people affected by T1DM. The sample consisted of 137 patients (88 females, 49 males) affected by T1DM aged from 11 to 19 years old (Mean: 13.87; SD: 2.40). The diagnostic protocol consisted of a sociodemographic questionnaire, Self-administration Psychiatric Scales for Children and Adolescents (SAFA), Toronto Alexithymia Scale-20 (TAS-20) and Intolerance to Uncertainty Scale-12 (IUS-12). Descriptive, differential, correlational and regression analyses were performed in order to examine the relationships between these variables. The results suggested the sample had high levels of psychopathological indexes, alexithymia and intolerance of uncertainty. Also, there were significant differences between TAS-20 and IUS-12 distributions with respect to psychopathology. Correlations and multivariate linear regressions indicated age, gender and education significantly predicted alexithymia and intolerance of uncertainty. This data suggest the presence of elevated psychopathology, alexithymia and uncertainty in people with diabetes.

Background: Body image and psychosocial functioning represent central challenges during adolescence and early adulthood. Malocclusion, defined as an irregularity in the alignment of the teeth, is known to negatively influence psychological outcomes. The current study aimed to elucidate the role of malocclusion, together with age, gender, and dental class, in body image and psychological functioning., Methods: A total of 126 participants aged from 12 to 19 years old (mean: 15.87, SD: 2.35, female participants: 52.4%, male participants: 47.6%) were recruited. Participants were visited at the University Hospital of Messina, Italy, and completed a sociodemographic questionnaire, the Body Image Concern Inventory (I-BICI), and the Psychosocial Impact of Dental Aesthetics Questionnaire (PIDAQ)., Results: Significant correlations were found between age, dental class, the BICI, and the PIDAQ. In particular, age showed a positive and significant correlation with PIDAQ-total score. The correlations between occlusal status and the BICI variables were all significant and positive. All correlations between occlusal status and the PIDAQ variables were all significant and positive, except for dental self-confidence. The correlations between the variables of the PIDAQ and BICI instruments were all significant and positive, except for dental self-confidence, where the directions were significant and negative. Moreover, age, gender, and occlusal status predicted BICI and PIDAQ scores. Age was a positive predictor for PIDAQ self-confidence, gender for BICI and PIDAQ total scores, along with dysmorphic symptoms, social impact, psychological impact, and aesthetic concerns. Several significant gender differences were highlighted by the analyses, with higher scores in the female group on all the BICI variables, except symptom interference, and all the PIDAQ variables, except dental self-confidence., Conclusions: Malocclusion appeared to play a central role in the psychological, representational, and psychosocial life of the participants. This research suggests that malocclusion and dental issues influence the psychological, representational, and psychosocial life of adolescents. Further research is required to examine the psychological impact of dental problems.

In patients with Parkinson's disease (PD), constipation is common, and it appears in a prodromal stage before the hallmark motor symptoms. The present study aimed to investigate whether Velusetrag, a selective 5‑HT4 receptor agonist, may be a suitable candidate to improve intestinal motility in a mouse model of PD. Five months old PrP human A53T alpha-synuclein transgenic (Tg) mice, which display severe constipation along with decreased colonic cholinergic transmission already at 3 months, were treated daily with the drug for 4 weeks. Velusetrag treatment reduced constipation by significantly stimulating both the longitudinal and circular-driven contractions and improved inflammation by reducing the level of serum and colonic IL1β and TNF-α and by decreasing the number of GFAP-positive glia cells in the colon of treated mice. No significant downregulation of the 5-HT4 receptor was observed but instead Velusetrag seemed to improve axonal degeneration in Tgs as shown by an increase in NF-H and VAChT staining. Ultimately, Velusetrag restored a well-balanced intestinal microbial composition comparable to non-Tg mice. Based on these promising data, we are confident that Velusetrag is potentially eligible for clinical studies to treat constipation in PD patients., (© 2023. Springer Nature Limited.)

Delay discounting refers to the depreciation of the value of a reward as a function of the time it takes to obtain it. Growing evidence shows altered delay discounting in several pathological conditions, including neurological disorders. Here, we conducted a systematic review and meta-analysis of the published literature on delay discounting (DD) in Parkinson's Disease (PD). We found steeper DD in patients with PD, compared to healthy controls, both in "on" and "off" dopaminergic medication. These results confirm altered DD in PD and suggest an independent influence of the dopaminergic medication and the clinical condition itself on it. Also the effect of impulse control disorder and of pharmacological treatments are analysed., Competing Interests: Declaration of interest None., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Over the last few decades, studies on the oral microbiome have increased awareness that the balance between the host and the microbial species that coexist in it is essential for oral health at all stages of life. However, this balance is extremely difficult to maintain, and many factors can disrupt it: general eating habits, sugar consumption, tobacco smoking, oral hygiene, and use of antibiotics and other antimicrobials. It is now known that alterations in the oral microbiota are responsible for developing and promoting many oral diseases, including periodontal disease. In this context, diet is an area for further investigation as it has been observed that the intake of particular foods, such as farmed animal meat, dairy products, refined vegetable oils, and processed cereals, affects the composition of the microbiota, leading to an increased representation of acid-producing and acid-tolerant organisms and periodontal pathogens. However, little is known about the influence of diet on the oral microbiome and the creation of a suitable microenvironment for the development of periodontal disease. The aim of the present study is to evaluate current knowledge on the role of diet in the oral dysbiosis underlying periodontal disease.

Although it is well known that lifestyle changes can affect plasma glucose levels, there is little formal evidence for the sustained effectiveness of exercise and diet in diabetes mellitus (DM) management. Self-care in DM refers to the real-life application of the knowledge that the patient gained during the education programmes. The goals are to bring about changes in the patient's behaviour, thus improving glycaemic control. We evaluated the influence of DM self-care activities (SCA) on glycaemic control in a total of 159 patients with DM. Plasma glycated haemoglobin (HbA1c) levels were used to monitor glycaemic control, while SCA were assessed using the standardised Diabetes Self-Management Questionnaire (DSMQ). In our study, 53% of the patients had a HbA1c ≥ 7%. In univariate linear regression models, a statistically significant inverse association was observed between the HbA1c (the dependent variable) and both the DSMQ Dietary Control Score (R2 = 0.037, p = 0.0145) and the DSMQ Sum Score (R2 = 0.06, p = 0.0014). The mean absolute change in the HbA1c% associated with one standard deviation (SD) change in the DSMQ Sum Score, independent of the other significant variables retained in the compacted multivariate regression model, was -0.419% (confidence interval: 95%: from -0.18 to -0.65). Although the impact of the DSMQ Score was modest when compared to the other independent variables in the multivariate model, the findings emphasise the importance of maintaining optimal lifestyle changes to avoid hyperglycaemia and its complications. In conclusion, enhanced self-management of DM is associated with improved glucose control. In patients with chronic diseases such as DM, the role of streamlining SCA encompassing physical activity and proper dietary choices is imperative because of a significantly reduced access to healthcare globally as a result of the COVID-19 pandemic.

Background: Is well known that oral health and dental aesthetic have significant effects on the sociality of human beings. The aim of the present study was to assess some aspects of oral health with possible repercussions in adolescent and youth, with particular reference to gender differences., Methods: A total of 190 subjects with female prevalence (F = 62.6%, M = 37%) and ages between 14 and 29 years old (Mean = 23.8; SD = 3.27) participated. Evaluation was carried using standardized instruments to assess quality of oral life (PIDAQ), negative impact of oral conditions (OHIP-14), and self-esteem (Rosenberg Self Esteem Scale). Correlational and difference analyses and linear regressions were performed., Results: Significant gender differences were found in terms of gender, in reference to variables such as self-confidence and convictions. Positive correlations emerged between psychological impact and social impact, aesthetic concern and social impact, convictions and self-confidence, oral health with psycho-social impact, and aesthetic concern, self-esteem with oral health. Inverse correlations emerged between psycho-social impact and self-confidence, aesthetic concern and self-confidence, oral health, and self-confidence. Multivariate linear regression indicated relations between age and psychological impact, sex and self-confidence, crooked teeth and conviction., Conclusions: The impact of oral health on the psychological well-being of young people is relevant. These factors, if considered within clinical practice, can improve the quality of life of the subject.

Background: Defense mechanisms serve as mediators referred to the subjects' attempt to manage stressors capable of threatening their integrity. Mature defense mechanisms represent the high adaptive group, including suppression, which allows the subject to distance disturbing contents from consciousness. In line with general defensive intents, suppression would preserve stable mood states, as in the case of euthymia. Clinical issues usually disturb homeorhesis , so that the study of subjects' suppressive tendencies would suggest possible existing relations among defense mechanisms, mood states, and clinical issues. The study highlighted the significant existing relations among factors such as suppression, euthymia, mood states, and clinical psychological phenomena. Methods: The observation group was composed of 150 participants, 51 males (34%) and 99 females (66%), aged from 25 to 30 years old, with a mean age of 26.63 years old (SD = 1.51). The study was conducted through the use of measures related to subjects' characteristics, euthymia, psychological flexibility and psychological well-being (Euthymia Scale), suppression (Suppression Mental Questionnaire), well-being (Who-5), and compassion (ProQol-5). Results: The performed analyses consisted of descriptive statistics, correlations, differences, and regressions among the considered variables. Starting from the first hypothesis, SMQ factors appeared to be significantly and positively correlated with Euthymia factors, rather than Regression in the Ego service (-). In line with the previous result, significant and positive correlations emerged among SMQ and Well-being (WHO-5) variables, maintaining an inverse relation with Regression in the Ego service. Significant differences emerged between male and female groups concerning SMQ total score and rationalization, with higher male group scores. Finally, significant dependencies emerged among the selected predictors (SMQ variables) and Compassion satisfaction. Conclusion: The emerged results highlighted significant relations among the considered variables so that it was possible to highlight the common directions assumed by suppression variables, well-being, and euthymia. Moreover, suppression appeared as a significant predictor with a causal role in clinical satisfaction. The results that have emerged allow us to consider defenses through an empirical perspective, useful to suggest an extension to other groups, phenomena, and conditions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Merlo, Stoian, Motofei and Settineri.)

Background: Alzheimer's Disease (AD) impairs the ability to carry out daily activities, reduces independence and quality of life and increases caregiver burden. Our understanding of functional decline has traditionally relied on reports by family and caregivers, which are subjective and vulnerable to recall bias. The Internet of Things (IoT) and wearable sensor technologies promise to provide objective, affordable, and reliable means for monitoring and understanding function. However, human factors for its acceptance are relatively unexplored. Objective: The Public Involvement (PI) activity presented in this paper aims to capture the preferences, priorities and concerns of people with AD and their caregivers for using monitoring wearables. Their feedback will drive device selection for clinical research, starting with the study of the RADAR-AD project. Method: The PI activity involved the Patient Advisory Board (PAB) of the RADAR-AD project, comprised of people with dementia across Europe and their caregivers (11 and 10, respectively). A set of four devices that optimally represent various combinations of aspects and features from the variety of currently available wearables (e.g., weight, size, comfort, battery life, screen types, water-resistance, and metrics) was presented and experienced hands-on. Afterwards, sets of cards were used to rate and rank devices and features and freely discuss preferences. Results: Overall, the PAB was willing to accept and incorporate devices into their daily lives. For the presented devices, the aspects most important to them included comfort, convenience and affordability. For devices in general, the features they prioritized were appearance/style, battery life and water resistance, followed by price, having an emergency button and a screen with metrics. The metrics valuable to them included activity levels and heart rate, followed by respiration rate, sleep quality and distance. Some concerns were the potential complexity, forgetting to charge the device, the potential stigma and data privacy. Conclusions: The PI activity explored the preferences, priorities and concerns of the PAB, a group of people with dementia and caregivers across Europe, regarding devices for monitoring function and decline, after a hands-on experience and explanation. They highlighted some expected aspects, metrics and features (e.g., comfort and convenience), but also some less expected (e.g., screen with metrics)., Competing Interests: EP was employed by company Alfasigma Schweiz AG. NM is an employee of Janssen Research and Development, LLC and holds equity. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Stavropoulos, Lazarou, Diaz, Gove, Georges, Manyakov, Pich, Hinds, Tsolaki, Nikolopoulos, Kompatsiaris and the RADAR-AD Consortium.)

Objective: Work-related stress typically occurs due to particularly challenging dynamics, risks and pressure. Prolonged exposure to stress may cause serious consequences on psychophysical well-being. The current study was conducted to reexamine the clinical instruments useful for evaluating the risk factors and to examine two closely linked dimensions, which may constitute protective factors such as coping strategies and satisfaction., Method: Through a narrative review of the scientific literature of the last 5 years, carried out through the PubMed, Web of Science and Scopus databases, the most relevant clinical instruments used in the evaluation of stress, job satisfaction and coping strategies were examined., Results: Based on the considered inclusion criteria, 142 articles were selected, and 10 of the most used psycho-diagnostic instruments were identified for the evaluation of the three dimensions. The selected assessment instruments were deeply discussed in order to highlight strengths and limitations., Conclusions: A variety of studies used a range of psycho-diagnostic tools in order to measure stress, coping strategies and job satisfaction. However, their integration is necessary to guarantee a complete evaluation protocol., (© 2021 Giovanni Fioriti Editore s.r.l.)

Background: The COVID-19 pandemic has expanded to reach many countries, involving healthcare systems facing high numbers of infected patients. The repercussions concern every segment of the population; therefore it is necessary to understand the extent of psychopathological variations., Participants and Procedure: 355 subjects aged from 18 to 78 years old ( M = 36.51, SD = 13.08) with a prevalence of female subjects (70.3%) were involved in completing the protocol during the early 10 days of lockdown. The module provided for the collection of personal information, such as age, gender, and years of study. The variables considered concerned the administration of the IUS-12, the TAS-20, the PVDQ-15 and the SMQ. Descriptive statistics, correlational and linear regressions analyses were performed in order to highlight significant relationships and dependences among the variables., Results: Several relationships emerged with reference to the included variables. In particular, uncertainty and alexithymia proved to be indices with an important predictive role in developing psychopathology. The suppression of disturbing and unknown contents represented a defense for overcoming representations, whose impact proved to be negative in terms of adaptation. The results clarified the general tendencies of the population to cope with anguish due to the lack of knowledge in the first 10 days of lockdown., Conclusions: The impact of the COVID-19 pandemic on the population is evident. The decision to analyze uncertainty, alexithymia and contamination as relevant issues brought the need to analyze a dynamic of conscious suppression of disturbing contents. The results may represent key points to establish interventions., (Copyright © Institute of Psychology, University of Gdansk.)

Kabuki syndrome (KS) is a rare cause of intellectual disability primarily caused by loss-of-function mutations in lysine-specific methyltransferase 2D ( KMT2D ), which normally adds methyl marks to lysine 4 on histone 3. Previous studies have shown that a mouse model of KS ( Kmt2d +/βGeo ) demonstrates disruption of adult neurogenesis and hippocampal memory. Proof-of-principle studies have shown postnatal rescue of neurological dysfunction following treatments that promote chromatin opening; however, these strategies are non-specific and do not directly address the primary defect of histone methylation. Since lysine-specific demethylase 1A (LSD1/KDM1A) normally removes the H3K4 methyl marks added by KMT2D, we hypothesized that inhibition of KDM1A demethylase activity may ameliorate molecular and phenotypic defects stemming from KMT2D loss. To test this hypothesis, we evaluated a recently developed KDM1A inhibitor (TAK-418) in Kmt2d +/βGeo mice. We found that orally administered TAK-418 increases the numbers of newly born doublecortin (DCX) + cells and processes in the hippocampus in a dose-dependent manner. We also observed TAK-418-dependent rescue of histone modification defects in hippocampus both by western blot and chromatin immunoprecipitation sequencing (ChIP-seq). Treatment rescues gene expression abnormalities including those of immediate early genes such as FBJ osteosarcoma oncogene ( Fos ) and FBJ osteosarcoma oncogene homolog B ( Fosb) . After 2 weeks of TAK-418, Kmt2d +/βGeo mice demonstrated normalization of hippocampal memory defects. In summary, our data suggest that KDM1A inhibition is a plausible treatment strategy for KS and support the hypothesis that the epigenetic dysregulation secondary to KMT2D dysfunction plays a major role in the postnatal neurological disease phenotype in KS., Competing Interests: This work was partially supported with a grant from Takeda Pharmaceutical Company, who owns rights to TAK-418. E.M.P., J.D., A.N., R.B., S.M., M.D., Y.H., S.M., M.I., and H.K. are employees of Takeda Pharmaceutical Company., (© 2021 The Author(s).)

Background: The health professionals are involved in the paths of care for patients with different medical conditions. Their life is frequently characterized by psychopathological outcomes so that it is possible to identify consistent burdens. Besides the possibility to develop pathological outcomes, some protective factors such as resilience play a fundamental role in facilitating the adaptation process and the management of maladaptive patterns. Personal characteristics and specific indexes such as burdens and resilience are essential variables useful to study in-depth ongoing conditions and possible interventions. The study was aimed at highlighting the presence and the relations among factors as personal variables, burdens, and resilience, to understand health professionals' specific structure and functions. Methods: The observation group was composed of 210 participants, 55 males (26.2%), and 155 females (73.8%), aged from 18 to 30 years old with a mean age of 25.92 years old ( SD = 3.33). The study considered personal characteristics of the subjects, such as age, gender, years of study, days of work per week, hours of work per week, and years of work. Our study had been conducted with the use of measures related to burdens (Caregivers Burden Inventory) and resilience (Resilience Scale for Adults). Results: The performed analyses consisted of descriptive statistics, correlations, and regressions among the considered variables. Several significant correlations emerged among personal characteristics, CBI, and RSA variables. Specifically, age and work commitment indexes appeared to be significantly related to the development of burdens, differently from the years of study. Significant correlations emerged among personal and RSA variables, indicating precise directions for both domains. Age and gender were identified as predictors to perform multivariate regression analyses concerning CBI factors. Significant dependence relations emerged with reference to all CBI variables. Conclusion: Pathological outcomes and resilience factors represent two sides of the health professionals' experiences, also known as "invisible patients." Greater knowledge about present conditions and future possibilities is a well-known need in literature so that the current analyses considered fundamental factors. In line with state of the art, future studies are needed in order to deepen elusive phenomena underlying maladjustment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Merlo, Stoian, Motofei and Settineri.)

Background: Gambling has increasingly become a problem in adolescence over the last 20 years. Previous research has failed to identify exactly the level of involvement of adolescents in gambling, yet a relevant presence of addictive behaviors was noticed., Objective: This narrative review highlights the implications of adolescent gambling, taking into consideration the main risk and protection factors aimed at limiting gambling activity, as well as the main links with the impulse-control disorder, addiction, and behavioral addiction., Methods: The review process was conducted through Medline, Scopus, Web of Science and Google Scholar search engines. The considered keywords were "Gambling" AND "Adolescence," "Behavioral addiction," AND "Adolescence." The articles related to gambling and adolescence in the last 20 years were included in compliance with inclusion and exclusion criteria, to perform a consistent analysis of the phenomenon and the related maintenance factors., Results: Starting from 1067 articles, 107 were selected to denote the main thematic areas involved in the gambling problem. The online search was completed on December 13, 2019., Conclusions: The narrative review of literature can facilitate the analysis of gambling problems in adolescence, as the main studies in the last 20 years showed the complexity of the problem, the links between addiction, and the most effective methods of prevention and treatment.

Canine oral melanoma (COM) is the most frequent tumour with oral localization in dogs. Copy number gains and amplifications of CCND1, a gene coding for Cyclin D1, are the most frequent chromosomal aberrations described in human non-UV induced melanomas. Twenty-eight cases of COM were retrieved from paraffin-blocks archives. A total of 4 μm thick sections were immunostained with an antibody against human Cyclin D1 and Ki-67. Cyclin D1 and Ki-67 expressions were scored through two counting methods. DNA was extracted from 20 μm thick sections of formalin-fixed paraffin-embedded blocks. Pathological and surrounding healthy tissue was extracted independently. Cyclin D1 immunolabelling was detected in 69% (18/26) while Ki-67 was present in 88.5% (23/26) of cases. Statistical analysis revealed correlation between two counting methods for Cyclin D1 (r = 0.54; P = .004) and Ki-67 (r = 0.56; P = .003). The correlation found between Ki-67 and Cyclin D1 indexes in 16/26 cases labelled by both antibodies (r = 0.7947; P = .0002) suggests a possible use of Cyclin D1 index as prognostic marker. Polymerase chain reaction analysis on CCND1 coding sequence revealed the presence of nine somatic mutations in seven samples producing synonymous, missense and stop codons. Since none of the single-nucleotide polymorphisms was found to be recurrent, it is suggested that overexpression of Cyclin D1 may be the consequence of alterations of CCND1 upstream regions or other genetic aberrations not detectable with the methodology used in this study. Future studies are needed to verify the potential use of Cyclin D1 index as prognostic indicator and to highlight the molecular events responsible for Cyclin D1 overexpression in COMs., (© 2019 John Wiley & Sons Ltd.)

Human Mucosal Melanoma (hMM) is an aggressive neoplasm of neuroectodermal origin with distinctive features from the more common cutaneous form of malignant melanoma (cMM). At the molecular level, hMMs are characterized by large chromosomal aberrations rather than single-nucleotide mutations, typically observed in cMM. Given the scarcity of available cases, there have been many attempts to establish a reliable animal model. In pet dogs, Canine Oral Melanoma (COM) is the most common malignant tumor of the oral cavity, sharing clinical and histological aspects with hMM. To improve the knowledge about COM's genomic DNA alterations, in the present work, formalin-fixed, paraffin-embedded (FFPE) samples of COM from different European archives were collected to set up an array Comparative Genomic Hybridization (aCGH) analysis to estimate recurrent Copy Number Aberrations (CNAs). DNA was extracted in parallel from tumor and healthy fractions and 19 specimens were successfully submitted to labeling and competitive hybridization. Data were statistically analyzed through GISTIC2.0 and a pathway-enrichment analysis was performed with ClueGO. Recurrent gained regions were detected, affecting chromosomes CFA 10, 13 and 30, while lost regions involved chromosomes CFA 10, 11, 22, and 30. In particular, CFA 13 showed a whole-chromosome gain in 37% of the samples, while CFA 22 showed a whole-chromosome loss in 25%. A distinctive sigmoidal trend was observed in CFA 10 and 30 in 25 and 30% of the samples, respectively. Comparative analysis revealed that COM and hMM share common chromosomal changes in 32 regions. MAPK- and PI3K-related genes were the most frequently involved, while pathway analysis revealed statistically significant perturbation of cancer-related biological processes such as immune response, drug metabolism, melanocytes homeostasis, and neo-angiogenesis. The latter is a new evidence of a significant involvement of neovascularization-related pathways in COMs and can provide the rationale for future application in anti-cancer targeted therapies., (Copyright © 2019 Brocca, Ferraresso, Zamboni, Martinez-Merlo, Ferro, Goldschmidt and Castagnaro.)

Background: The function of emotions, beginning from the proto-emotions, is the adaptation to the environment. This is based on the Homeorhesis , the equilibrium due to the adaptive operation of excitement and the dissipation of emotions. The object relations of the participants foresee the practice of defense mechanisms in a continuum that goes from the consciousness to the oneiric activities. The predominant and maladaptive use of defense mechanisms in the psychosomatic phenomenology, can be identified with deficits in emotional awareness, with the impossibility to manage excitement and dissipation of emotions foreseen by the oneiric phenomena., Methods: The observation group is composed by 140 participants, 56 males (43%) and 84 females (57%),with pathological-functional disorders of psychosomatic domain. The study had been conducted with the use of measures related to the conscious defense of suppression (Suppression Mental Questionnaire), to the emotional awareness linked to the psychosomatic phenomena (Diagnostic Criteria for Psychosomatic Research Structured Interview-DCPR-SI) and to the states of perturbation and conservation of oneiric activities (The Manheim Dream Questionnaire-MADRE)., Results: Significant inverse correlations emerged among rationalization, repressive function and illness Denial, as for the suppression mental questionnaire factors and irritable mood, but for Regression in the service of the Ego; inverse and significant correlations emerged among suppression, repressive function, rationalization and gastrointestinal psychosomatic outcomes and among suppression, repression and cardiological psychosomatic outcomes. Regarding alexithymia, a positive correlation emerged with rationalization and inverse with Regression in the service of the Ego. Positive correlations emerged between illness denial and overall emotional tone, for disease phobia and meaningfulness and for cardiological psychosomatic outcomes and nightmare distress and recurring nightmares., Conclusion: The study of such outcomes due to a prevalent defensive style based on suppression, suggest the identification of a key phenomenon, which translates into maladjustment that goes from functional disorders to parasomnia. The bridge established by the obfuscation of conscious contents until the manifestations of disturbance of ancient activities such as oneiric ones, expresses the need to transform an emotional maladaptive style, in line with classic literature and the current state of art.

Limited veterinary literature is available regarding prognostic markers for canine renal cell carcinoma (CRCC). We retrospectively evaluated COX-2 expression, histological and clinical features associated with prognosis of CRCC. Sixty-four cases post-nephrectomy were included, 54 had histopathological assessment and 30 had COX-2 immunostaining performed. Eight dogs (13%) had metastatic disease at initial diagnosis. Twenty-seven dogs (42%) received adjuvant therapy after nephrectomy. On univariate analysis, COX-2 expression, mitotic index (MI), histologic type, vascular invasion, neoplastic invasiveness and metastasis at diagnosis were significantly associated with overall median survival time (MST). COX-2 score (COX-2 score > 3 MST 420 days versus 1176 days if COX-2 score <3; P = 0.011) and MI (MI > 30 MST 120 days versus 540 days for MI < 30; P = 0.003) were the only variables associated with CRCC outcome on multivariate analysis. The addition of MI and COX-2 immunostaining to standard histopathological evaluation would help predicting outcome in CRCC patients., (© 2016 John Wiley & Sons Ltd.)

Composite material structures are commonly used in many industrial sectors (aerospace, automotive, transportation), and can operate in harsh environments where impacts with other parts or debris may cause critical safety and functionality issues. This work presents a method for improving the accuracy of impact position determination using acoustic source triangulation schemes based on the data collected by piezoelectric sensors attached to the structure. A novel approach is used to estimate the Differential Time-of-Arrival (DToA) between the impact response signals collected by a triplet of sensors, overcoming the limitations of classical methods that rely on amplitude thresholds calibrated for a specific sensor type. An experimental evaluation of the proposed technique was performed with specially made circular piezopolymer (PVDF) sensors designed for Structural Health Monitoring (SHM) applications, and compared with commercial piezoelectric SHM sensors of similar dimensions. Test impacts at low energies from 35 mJ to 600 mJ were generated in a laboratory by free-falling metal spheres on a 500 mm × 500 mm × 1.25 mm quasi-isotropic Carbon Fiber Reinforced Polymer (CFRP) laminate plate. From the analysis of many impact signals, the resulting localization error was improved for all types of sensors and, in particular, for the circular PVDF sensor an average error of 20.3 mm and a standard deviation of 8.9 mm was obtained., Competing Interests: The authors declare no conflict of interest.

Connectivity studies using resting-state functional magnetic resonance imaging are increasingly pooling data acquired at multiple sites. While this may allow investigators to speed up recruitment or increase sample size, multisite studies also potentially introduce systematic biases in connectivity measures across sites. In this work, we measure the inter-site effect in connectivity and its impact on our ability to detect individual and group differences. Our study was based on real, as opposed to simulated, multisite fMRI datasets collected in N=345 young, healthy subjects across 8 scanning sites with 3T scanners and heterogeneous scanning protocols, drawn from the 1000 functional connectome project. We first empirically show that typical functional networks were reliably found at the group level in all sites, and that the amplitude of the inter-site effects was small to moderate, with a Cohen's effect size below 0.5 on average across brain connections. We then implemented a series of Monte-Carlo simulations, based on real data, to evaluate the impact of the multisite effects on detection power in statistical tests comparing two groups (with and without the effect) using a general linear model, as well as on the prediction of group labels with a support-vector machine. As a reference, we also implemented the same simulations with fMRI data collected at a single site using an identical sample size. Simulations revealed that using data from heterogeneous sites only slightly decreased our ability to detect changes compared to a monosite study with the GLM, and had a greater impact on prediction accuracy. However, the deleterious effect of multisite data pooling tended to decrease as the total sample size increased, to a point where differences between monosite and multisite simulations were small with N=120 subjects. Taken together, our results support the feasibility of multisite studies in rs-fMRI provided the sample size is large enough., (Copyright © 2017. Published by Elsevier Inc.)

Cryptococcosis is a worldwide and potentially fatal mycosis documented in wild and captive koalas ( Phascolarctos cinereus ) caused by Cryptococcus neoformans . Though mainly a subclinical disease, when the nasal cavity is affected, epistaxis, mucopurulent nasal discharge, dyspnea, and facial distortion may occur. This report describes a case of cryptococcosis in a koala where unilateral exophthalmos was the only evident clinical sign and magnetic resonance imaging and computed tomography findings are described. Both advanced imaging techniques should be considered as standard and complementary techniques for nasal cavity evaluation in koalas.

Blockade of corticotropin-releasing factor receptor 1 (CRF1) suppresses stress-induced alcohol seeking in rodents, but clinical translation remains. Here, we first showed that the CRF1 antagonist verucerfont potently blocks hypothalamic-pituitary adrenal (HPA) axis activation in adrenalectomized rats. We then evaluated verucerfont for its ability to block HPA axis activation and reduce stress-induced alcohol craving in alcohol-dependent patients. Anxious, alcohol-dependent women (age 21-65 years, n=39) were admitted to the NIH Clinical Center and completed withdrawal treatment before enrollment if needed. One-week single-blind placebo was followed by randomized double-blind verucerfont (350 mg per day) or placebo for 3 weeks. Verucerfont effects on the HPA axis were evaluated using the dexamethasone-CRF test. Craving was evaluated using two established protocols, one that combines a social stressor with physical alcohol cue exposure, and one that uses guided imagery to present personalized stress, alcohol, or neutral stimuli. An fMRI session examined brain responses to negative affective stimuli and alcohol cues. In contrast to our recent observations with another CRF1 antagonist, pexacerfont, verucerfont potently blocked the HPA axis response to the dexamethasone-CRF test, but left alcohol craving unaffected. Right amygdala responses to negative affective stimuli were significantly attenuated by verucerfont, but responses to alcohol-associated stimuli were increased in some brain regions, including left insula. Discontinuation rates were significantly higher in the verucerfont group. Our findings provide the first translational evidence that CRF1 antagonists with slow receptor dissociation kinetics may have increased efficacy to dampen HPA axis responses. The findings do not support a clinical efficacy of CRF1 blockade in stress-induced alcohol craving and relapse.

A mathematical model is proposed to describe a diesel-polluted clayey soil bioremediation process. The reaction system under study was considered a completely mixed closed batch reactor, which initially contacted a soil matrix polluted with diesel hydrocarbons, an aqueous liquid-specific culture medium and a microbial inoculation. The model coupled the mass transfer phenomena and the distribution of hydrocarbons among four phases (solid, S; water, A; non-aqueous liquid, NAPL; and air, V) with Monod kinetics. In the first step, the model simulating abiotic conditions was used to estimate only the mass transfer coefficients. In the second step, the model including both mass transfer and biodegradation phenomena was used to estimate the biological kinetic and stoichiometric parameters. In both situations, the model predictions were validated with experimental data that corresponded to previous research by the same authors. A correct fit between the model predictions and the experimental data was observed because the modelling curves captured the major trends for the diesel distribution in each phase. The model parameters were compared to different previously reported values found in the literature. Pearson correlation coefficients were used to show the reproducibility level of the model., (Copyright © 2016. Published by Elsevier B.V.)

Dopamine D3 receptors have been pharmacologically engaged in humans since the development of the first antipsychotics and ergot-derivative dopamine (DA) agonists, even without knowing it. These agents were generally non-selective, developed primarily to target D2 receptors. In the last 10 years the understanding of the clinical implication of D3 receptors has been progressing also due to the identification of D3 gene polymorphisms, the use of more selective PET ligands such as [(11)C]-(+)-PHNO and the learning regarding the clinical use of the D3-preferential D2/D3 agonists ropinirole and pramipexole. A new specific neuroplasticity role of D3 receptor regarding dendrite arborisation outgrowth in dopaminergic neurons was also proposed to support, at least in part, the slowing of disease observed in subjects with Parkinson׳s Disease treated with DA agonists. Similar mechanisms could be at the basis of the antidepressant-like effects observed with DA agonists when co-administered with standard of care. Severe adverse event occurring with the use of anti-parkinsonian DA agonists in predisposed subjects, i.e., impulse control disorders, are now suggested to be putatively related to overactive D3 receptors. Not surprisingly, blockade of D3 receptors was proposed as treatment for addictive disorders, a goal that could be potentially achieved by repositioning buspirone, an anxiolytic drug with D3-preferential antagonistic features, or with novel selective D3 antagonists or partial agonists currently in development for schizophrenia. At the moment ABT-925 is the only selective D3 antagonist tested in schizophrenic patients in Phase II, showing an intriguing cognitive enhancing effects supported by preclinical data. Finally, exploratory pharmacogenetic analysis suggested that ABT-925 could be effective in a subpopulation of patients with a polymorphism on the D3 receptor, opening to a possible personalised medicine approach., (Copyright © 2015. Published by Elsevier B.V.)

Unlabelled: In patients with social anxiety disorder (SAD) it has been reported that selective serotonin reuptake inhibitors (SSRIs) and placebo induce anxiolytic effects by attenuating neural activity in overlapping amygdala subregions, i.e. left basolateral and right ventrolateral amygdala. However, it is not known whether these treatments inhibit amygdala subregions via similar or distinct brain pathways. As anxiolytic treatments may alter amygdala-frontal couplings we investigated differences and similarities in amygdala-frontal functional co-activation patterns between responders and nonresponders to SSRIs and placebo in patients with SAD. Positron emission tomography (PET) with oxygen-15-labeled water was used to measure anxiety-related regional cerebral blood flow in 72 patients with SAD before and after 6-8 wk of treatment under double-blind conditions. Functional couplings were evaluated with a seed region approach using voxel values from the left basolateral and right ventrolateral amygdala. Responders and nonresponders to SSRIs and placebo showed different treatment-induced co-activations between the left amygdala and the dorsolateral prefrontal cortex (dlPFC) as well as the rostral anterior cingulate cortex (ACC). Conjunction analysis suggested shared anxiolysis-dependent inverse co-activations in SSRI and placebo responders between the left amygdala-dlPFC and left amygdala-rostral ACC, and a shared positive co-activation between left amygdala-dorsal ACC. We demonstrate that amygdala-frontal co-activation patterns differentiate effective from ineffective anxiolytic treatments and that SSRI and placebo responders share overlapping neuromodulatory paths that may underlie improved emotion regulation and reduced expression of anxiety., Trial Registration: clinicaltrials.gov Identifier: NCT00343707.

Pharmacological stimulation of N-methyl-D-aspartate receptors (NMDAr) could enhance the outcome of cue-exposure therapy for smoking cessation. NMDAr stimulation can be achieved by increasing pharmacologically the synaptic levels of glycine, a necessary co-agonist. Here, we evaluate the effects of SSR504734, a selective inhibitor of glycine type I transporter (GlyT1) in an extinction-reinstatement procedure inducing robust and lasting nicotine-seeking behavior in rats. Male Wistar rats were trained to associate discriminative stimuli (S(D)s) with the availability of nicotine (0.03 mg/kg/65 μL/2 second/infusion) or sucrose (45-mg pellet) versus non-reward in two-lever operant cages. Reinforced response was followed by cue signaling 20-second time-out (CSs). Once the training criterion was met, rats underwent extinction of lever presses, in the absence of reinforcers, S(D) s and CSs. Re-exposure to nicotine or sucrose S(D+)/CS(+), but not non-reward S(D-)/CS(-), revived responding at the previously reinforced lever. Acute pre-treatment with SSR504734 (10 mg/kg i.p.) reduced nicotine-seeking but not sucrose-seeking behavior without influencing rats' locomotor activity. Sub-chronic treatment (10 mg/kg i.p. for 5 days) during daily exposure to S(D+)/CS(+) reduced nicotine-seeking; however, this effect was transient, with return to S(D+)/CS(+) responding at 72 hours. Full recovery to S(D+)/CS(+) responding was observed after 1 month suggesting that SSR504734 sub-acute treatment did not engage the long-term plasticity mechanisms probably involved in nicotine-seeking. In conclusion, GlyT1-inhibitors might offer a therapeutic opportunity for acute cue-controlled nicotine-seeking, but the lack of persistent effects of the sub-chronic treatment associated with nicotine cues exposure suggests that short-term administration of GlyT1-inhibitor SSR504734 is not sufficient to promote extinction of nicotine-cue conditioned responding., (© 2013 The Authors, Addiction Biology © 2013 Society for the Study of Addiction.)

An 8-year-old female adult reindeer (Rangifer tarandus tarandus) was referred to the Veterinary Hospital of Madrid for evaluation of a conjunctival mass on the left eye which had been present for about 2 months. A surgical excision was performed and biopsy material submitted for light microscopic evaluation which confirmed the diagnosis of conjuctival squamous cell carcinoma. Nuclear p53 immunolabeling was found in 52% of the neoplastic cells. Follow-up examination at 12 months postsurgery did not reveal recurrence of this neoplasm. Conjunctival squamous cell carcinoma has not been reported previously in reindeer and seems to have similar characteristics to the one existing in bovine species., (© 2012 American College of Veterinary Ophthalmologists.)

Molecular biomarkers for antipsychotic treatments have been conceptually linked to the measurements of dopamine functions, mostly D(2) receptor occupancy, either by imaging using selective PET/SPECT radioactive tracers or by assessing plasma prolactin levels. A quest for novel biomarkers was recently proposed by various academic, health service, and industrial institutions driven by the need for better treatments of psychoses. In this review we conceptualize biomarkers within the Translational Medicine paradigm whose goal was to provide support to critical decision-making in drug discovery. At first we focused on biomarkers as outcome measure of clinical studies by searching into the database clinicaltrial.gov. The results were somewhat disappointing, showing that out of 1,659 antipsychotic trials only 18 used a biomarker as an outcome measure. Several of these trials targeted plasma lipids as sentinel marker for metabolic adverse effects associated with the use of atypical antipsychotics, while only few studies were aimed to new disease specific biological markers. As an example of a mechanistic biomarker, we described the work done to progress the novel class of glycine transporter inhibitors as putative treatment for negative symptoms of schizophrenia. We also review how large-scale multiplex biological assays were applied to samples from tissues of psychiatric patients, so to learn from changes of numerous analytes (metabolic products, lipids, proteins, RNA transcripts) about the substrates involved in the disease. We concluded that a stringent implementation of these techniques could contribute to the endophenotypic characterization of patients, helping in the identification of key biomarkers to drive personalized medicine and new treatment development.

What Is Already Known About This Subject: • Several lines of evidence suggest a possible role of 5-HT(6) receptor antagonists in dementia or cognitive dysfunction of schizophrenia. SB-742457 is a potent 5-HT(6) antagonist and has shown efficacy in different animal models of cognitive impairment. It is currently in development as a cognitive enhancer. Risperidone, commonly used to control agitation and psychotic features in both schizophrenia and Alzheimer's disease, is a D(2)/5-HT(2A ) antagonist with low affinity for 5-HT(6) receptors and limited effects on cognitive parameters., What This Study Adds: • As the combination of risperidone and SB-742457 may constitute a reasonable combination in cognitively impaired patients, pharmacodynamic interaction effects were investigated in this study. The only significant drug-drug interaction was a small increase of electroencephalogram (EEG) alpha and beta bands, which might suggest mild arousing activity of SB-742457 on the central nervous system-depressant effects of risperidone. The clinical relevance of these findings in patients remains to be established. Additionally, this study provided an extensive multidimensional pharmacodynamic profile of risperidone in healthy volunteers, showing that this antipsychotic suppresses motor performance (eye-hand coordination, finger tapping and postural stability), alertness, memory and neurophysiological functions (saccadic eye movements and EEG power spectrum)., Aim: Several lines of evidence suggest a possible role of 5-HT(6 ) receptor antagonists in cognitive dysfunction of schizophrenia. Atypical antipsychotics, such as risperidone, are currently used in these disorders. Therefore, the pharmacological interactions between the 5-HT(6) antagonist SB-742457 and risperidone were investigated in the light of possible co-medication., Methods: A randomized, double-blind, two-way crossover design was used to study the interaction between multiple doses SB-742457 50 mg and a single dose risperidone 2 mg in 18 healthy subjects., Results: Treatment was well tolerated. The most common adverse event was somnolence in 83% during the combination vs. 50% of subjects after risperidone, 32% after placebo and 11% after SB-742457. Combination treatment produced a statistically significant increase in the maximum plasma concentration of risperidone and had no effect on SB-742457 pharmacokinetics. Risperidone decreased saccadic peak velocity, finger tapping, adaptive tracking, subjective alertness, delayed word recognition and body sway and increased electroencephalogram (EEG) theta power and prolactin. The only pharmacodynamic interaction of risperidone and SB-742457 was an increase of absolute EEG alpha (ratio = 1.25, 95% CI = 1.11, 1.40, P= 0.0004) and beta power (ratio = 1.14, 95% CI = 1.03, 1.27, P= 0.016). No significant effects of SB-742457 alone were found., Conclusion: The pharmacokinetic interactions between SB-742457 and risperidone detected in this study were not clinically relevant. The increase in EEG alpha and beta power is incompatible with enhanced risperidone activity, but could point to mild arousing effects of the combination. Most pharmacodynamic changes of risperidone are consistent with previously reported data. The potential cognitive effects of SB-742457 remain to be established., (© 2011 Centre for Human Drug Research. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.)

Ghrelin is a 28-amino-acid polypeptide expressed in the stomach and hypothalamus that stimulates GH secretion, increases food intake (FI) and promotes body weight (BW) gain most likely via activation of the growth hormone secretagogue receptor type 1a (GHSR1a). GSK1614343 is a novel selective and potent GHSR antagonist with no partial agonist properties, recently characterized as GH secretion inhibitor by Sabbatini et al. [Chem Med Chem 2010;5:1450-1455]. In the present study, GSK1614343 (10 mg/kg) was not able to antagonize ghrelin-induced food consumption in rat, but unexpectedly stimulated FI and BW gain in both rats and dogs, a profile associated with decreased ghrelin plasma level. Interestingly, GSK1614343 selectively reduced the pro-opiomelanocortin mRNA levels in rat hypothalami chronically treated with the compound. To better understand the observed effects, we administered GSK1614343 (30 mg/kg) to Ghsr null mice and measured body mass components (fat, lean and free fluid) by using a NMR spectrometer. The increases of FI and BW were abolished in Ghsr null mice, while fat and lean masses increased in wild-type mice. Taken together, these results indicate that the orexigenic effect of GSK1614343 is mediated by GHSR1a and that the weight gain could be attributed to the increase of both adiposity and muscle mass, but not to fluid retention. The observed dissociation between effects on GH secretion and effects on FI/BW is inconsistent with a simple hormone-receptor model, suggesting unknown underlying regulations of the ghrelin system whose understanding require further investigation., (Copyright © 2011 S. Karger AG, Basel.)

In vitro and in vivo studies demonstrated that nociceptin/orphanin FQ inhibits norepinephrine release, while the effects of norepinephrine on nociceptin/orphanin FQ release remain unknown. Previous studies in healthy and hypertensive subjects showed that prolonged and forced hyperventilation induces different blood pressure (BP) responses depending on changes in plasma catecholamine levels. We investigated whether the effects of hyperventilation on the sympatho-adrenergic system involve nociceptin/orphanin FQ release. Fifty-six healthy subjects (26 females, mean age 63+/-2 and 30 males, mean age 63+/-3) underwent the hyperventilation test. A hierarchical cluster analysis based on BP response to hyperventilation identified three groups of subjects: group 1 (n=20) with a decrease in BP, norepinephrine (1311.1+/-45.5 fmol/ml versus 900.0+/-55.3 fmol/ml, P<0.01) and nociceptin/orphanin FQ (13.0+/-0.7 pg/ml versus 7.9+/-0.8 pg/ml, P<0.01), group 2 (n=18) without any change in BP and norepinephrine (1133.0+/-31.5 fmol/ml versus 1176.0+/-44.6 fmol/ml), with a decrease in nociceptin/orphanin FQ (12.5+/-3.2 pg/ml versus 7.4+/-0.6 pg/ml, P<0.01) and group 3 (n=18) with an increase in BP, norepinephrine (1216.7+/-50.9 fmol/ml versus 1666.7+/-44.9 fmol/ml, P<0.01) and nociceptin/orphanin FQ values (11.5+/-1.6 pg/ml versus 19.9+/-1.5 pg/ml, P<0.01). Norepinephrine changes in response to hyperventilation in groups 1 and 3 were directly (P<0.01) correlated with those of nociceptin/orphanin FQ. Our results showed that vigorous and prolonged hyperventilation changes plasma nociceptin/orphanin FQ levels due to the direct effects of hypocapnic alkalosis or to different sympatho-adrenergic system responses., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

The aim of our study was to evaluate the effects of repeated episodes of angina and induced myocardial ischemia on plasma nociceptin/orphanin FQ (N/OFQ) levels. Patients with unstable angina (23 with new onset severe angina or accelerated angina and 18 with subacute angina at rest) who had had repeated spontaneous episodes of chest pain in the last week before the study underwent myocardial perfusion single-photon emission computed tomography using adenosine infusion. Twenty subjects without clinical symptoms of angina matched for age, sex and cardiac risk factors served as a control group. N/OFQ levels were significantly (P<0.01) higher in the patients (15.2+/-2.1 pg/ml) than in the control group (8.5+/-2.6 pg/ml). Blood pressure and heart rate did not significantly differ. All patients showed transient adenosine infusion myocardial ischemia that did not induce chest pain or significantly modify plasma N/OFQ levels or hemodynamic parameters. Our findings show that unstable angina is associated with a significant increase in circulating N/OFQ levels unrelated to intervening transient myocardial ischemia or hemodynamic changes. This increase is probably related to the chest pain repeatedly occurring in the course of coronary artery disease, but absent during transient adenosine-induced myocardial ischemia.

Background: Although the amygdala is thought to be a crucial brain region for negative affect, neuroimaging studies do not always show enhanced amygdala response to aversive stimuli in patients with anxiety disorders. Serotonin (5-HT)-related genotypes may contribute to interindividual variability in amygdala responsiveness. The short (s) allele of the 5-HT transporter linked polymorphic region (5-HTTLPR) and the T variant of the G-703T polymorphism in the tryptophan hydroxylase-2 (TPH2) gene have previously been associated with amygdala hyperresponsivity to negative faces in healthy controls. We investigated the influence of these polymorphisms on amygdala responsiveness to angry faces in patients with social anxiety disorder (SAD) compared with healthy controls., Methods: We used positron emission tomography with oxygen 15-labelled water to assess regional cerebral blood flow in 34 patients with SAD and 18 controls who viewed photographs of angry and neutral faces presented in counterbalanced order. We genotyped all participants with respect to the 5-HTTLPR and TPH2 polymorphisms., Results: Patients with SAD and controls had increased left amygdala activation in response to angry compared with neutral faces. Genotype but not diagnosis explained a significant portion of the variance in amygdala responsiveness, the response being more pronounced in carriers of s and/or T alleles., Limitations: Our analyses were limited owing to the small sample and the fact that we were unable to match participants on genotype before enrollment. In addition, other imaging techniques not used in our study may have revealed additional effects of emotional stimuli., Conclusion: Amygdala responsiveness to angry faces was more strongly related to serotonergic polymorphisms than to diagnosis of SAD. Emotion activation studies comparing amygdala excitability in patient and control groups could benefit from taking variation in 5-HT-related genes into account.

Placebo may yield beneficial effects that are indistinguishable from those of active medication, but the factors underlying proneness to respond to placebo are widely unknown. Here, we used functional neuroimaging to examine neural correlates of anxiety reduction resulting from sustained placebo treatment under randomized double-blind conditions, in patients with social anxiety disorder. Brain activity was assessed during a stressful public speaking task by means of positron emission tomography before and after an 8 week treatment period. Patients were genotyped with respect to the serotonin transporter-linked polymorphic region (5-HTTLPR) and the G-703T polymorphism in the tryptophan hydroxylase-2 (TPH2) gene promoter. Results showed that placebo response was accompanied by reduced stress-related activity in the amygdala, a brain region crucial for emotional processing. However, attenuated amygdala activity was demonstrable only in subjects who were homozygous for the long allele of the 5-HTTLPR or the G variant of the TPH2 G-703T polymorphism, and not in carriers of short or T alleles. Moreover, the TPH2 polymorphism was a significant predictor of clinical placebo response, homozygosity for the G allele being associated with greater improvement in anxiety symptoms. Path analysis supported that the genetic effect on symptomatic improvement with placebo is mediated by its effect on amygdala activity. Hence, our study shows, for the first time, evidence of a link between genetically controlled serotonergic modulation of amygdala activity and placebo-induced anxiety relief.

The amygdala plays a central role in various aspects of affect processing and mood regulation by its rich anatomical connections to other limbic and cortical regions. It is plausible that depressive disorders, and response to antidepressant drugs, may reflect changes in the physiological coupling between the amygdala and other components of affect-related large-scale brain systems. We explored this hypothesis by mapping the functional coupling of right and left amygdalae in functional magnetic resonance imaging data acquired from 19 patients with major depressive disorder and 19 healthy volunteers, each scanned twice (at baseline and 8 weeks later) during performance of an implicit facial affect processing task. Between scanning sessions, the patients received treatment with an antidepressant drug, fluoxetine 20 mg/day. We found that the amygdala was positively coupled bilaterally with medial temporal and ventral occipital regions, and negatively coupled with the anterior cingulate cortex. Antidepressant treatment was associated with significantly increased coupling between the amygdala and right frontal and cingulate cortex, striatum, and thalamus. Treatment-related increases in functional coupling to frontal and other regions were greater for the left amygdala than for the right amygdala. These results indicate that antidepressant drug effects can be measured in terms of altered coupling between components of cortico-limbic systems and that these effects were most clearly demonstrated by enhanced functional coupling of the left amygdala.

Background: Impairments in the neural circuitry of verbal working memory are evident in depression. Factors of task demand and depressive state might have significant effects on its functional neuroanatomy., Methods: Two groups underwent functional magnetic resonance imaging while performing a verbal working memory task of varying cognitive load (n-back). The patient group comprised 20 medication-free individuals in an acute episode of unipolar major depression and the control group comprised 20 healthy individuals. Scans were acquired at weeks 0 (baseline), 2, and 8. Patients received treatment with fluoxetine after the baseline scan. Cerebral activations were measured for mean overall activation as well as the linear and quadratic load-response activity with increasing task demand (1-, 2-, 3-back)., Results: There were no significant differences in performance accuracy between groups. However, a main effect of group was observed in the load-response activity in frontal and posterior cortical regions within the verbal working memory network in which patients showed a greater load-response relative to control subjects. Group by time effects were revealed in the load-response activity in the caudate and thalamus. As a marker of treatment response, a lower linear load-response at baseline in the dorsal anterior cingulate, left middle frontal, and lateral temporal cortices was associated with an improved clinical outcome., Conclusions: Maintenance of performance accuracy in patients was accompanied by a significant increase in the load-response activity in frontal and posterior cortical regions within the verbal working memory network. These data also provide further support for resilience of activity in the anterior cingulate as a predictor of treatment response in depression.

Objective: Processing affective facial expressions is an important component of interpersonal relationships. However, depressed patients show impairments in this system. The present study investigated the neural correlates of implicit processing of happy facial expressions in depression and identified regions affected by antidepressant therapy., Method: Two groups of subjects participated in a prospective study with functional magnetic resonance imaging (fMRI). The patients were 19 medication-free subjects (mean age, 43.2 years) with major depression, acute depressive episode, unipolar subtype. The comparison group contained 19 matched healthy volunteers (mean age, 42.8 years). Both groups underwent fMRI scans at baseline (week 0) and at 8 weeks. Following the baseline scan, the patients received treatment with fluoxetine, 20 mg daily. The fMRI task was implicit affect recognition with standard facial stimuli morphed to display varying intensities of happiness. The fMRI data were analyzed to estimate the average activation (overall capacity) and differential response to variable intensity (dynamic range) in brain systems involved in processing facial affect., Results: An attenuated dynamic range of response in limbic-subcortical and extrastriate visual regions was evident in the depressed patients, relative to the comparison subjects. The attenuated extrastriate cortical activation at baseline was increased following antidepressant treatment, and symptomatic improvement was associated with greater overall capacity in the hippocampal and extrastriate regions., Conclusions: Impairments in the neural processing of happy facial expressions in depression were evident in the core regions of affective facial processing, which were reversed following treatment. These data complement the neural effects observed with negative affective stimuli.

Background: Evidence is accumulating that pharmacological blockade of the substance P preferring neurokinin-1 (NK1) receptor reduces anxiety. This study compared the effects of an NK1 receptor antagonist, citalopram, and placebo on brain activity and anxiety symptoms in social phobia., Methods: Thirty-six patients diagnosed with social phobia were treated for 6 weeks with the NK1 antagonist GR205171 (5 mg), citalopram (40 mg), or matching placebo under randomized double-blind conditions. GR205171 was administered for 4 weeks preceded by 2 weeks of placebo. Before and after treatment, regional cerebral blood flow (rCBF) during a stressful public speaking task was assessed using oxygen-15 positron emission tomography. Response rate was determined by the Clinical Global Impression Improvement Scale., Results: Patients improved to a larger extent with the NK1 antagonist (41.7% responders) and citalopram (50% responders), compared with placebo (8.3% responders). Within- and between-group comparisons showed that symptom improvement was paralleled by a significantly reduced rCBF response to public speaking in the rhinal cortex, amygdala, and parahippocampal-hippocampal regions. The rCBF pattern was corroborated in follow-up analyses of responders and subjects showing large state anxiety reduction., Conclusions: Short-term administration of GR205171 and citalopram alleviated social anxiety. Neurokinin-1 antagonists may act like serotonin reuptake inhibitors by attenuating neural activity in a medial temporal lobe network.

Background: Depression is associated with interpersonal difficulties related to abnormalities in affective facial processing., Objectives: To map brain systems activated by sad facial affect processing in patients with depression and to identify brain functional correlates of antidepressant treatment and symptomatic response., Design: Two groups underwent scanning twice using functional magnetic resonance imaging (fMRI) during an 8-week period. The event-related fMRI paradigm entailed incidental affect recognition of facial stimuli morphed to express discriminable intensities of sadness., Setting: Participants were recruited by advertisement from the local population; depressed subjects were treated as outpatients., Patients and Other Participants: We matched 19 medication-free, acutely symptomatic patients satisfying DSM-IV criteria for unipolar major depressive disorder by age, sex, and IQ with 19 healthy volunteers. Intervention After the baseline assessment, patients received fluoxetine hydrochloride, 20 mg/d, for 8 weeks., Main Outcome Measures: Average activation (capacity) and differential response to variable affective intensity (dynamic range) were estimated in each fMRI time series. We used analysis of variance to identify brain regions that demonstrated a main effect of group (depressed vs healthy subjects) and a group x time interaction (attributable to antidepressant treatment). Change in brain activation associated with reduction of depressive symptoms in the patient group was identified by means of regression analysis. Permutation tests were used for inference., Results: Over time, depressed subjects showed reduced capacity for activation in the left amygdala, ventral striatum, and frontoparietal cortex and a negatively correlated increase of dynamic range in the prefrontal cortex. Symptomatic improvement was associated with reduction of dynamic range in the pregenual cingulate cortex, ventral striatum, and cerebellum., Conclusions: Antidepressant treatment reduces left limbic, subcortical, and neocortical capacity for activation in depressed subjects and increases the dynamic range of the left prefrontal cortex. Changes in anterior cingulate function associated with symptomatic improvement indicate that fMRI may be a useful surrogate marker of antidepressant treatment response.

Prenatal stress strongly affects sexual dimorphism of male rats. Much less information is instead available on the effects of postnatal stress on sexual maturation during the so-called stress hyporesponsive period (SHRP). For this reason, we compared corticosterone-treated (CS; 10 mg/kg sc, suspended in sesame oil) or maternally separated pups (MS; 5 h/day in the first week of life) with control rats. Control and MS pups also received sesame oil injections. The effects of these procedures on physical development (body weight and eye opening), sexual maturation [anogenital distance, testis weight, 3beta-hydroxysteroid dehydrogenase/(Delta5-4) (3betaHSD) isomerase activity and time to testis descent] and glucocorticoid receptor (GR) immunoreactivity in the testis were examined. Corticosterone treatment significantly (P<.05) advanced testis descent and increased testis weight and 3betaHSD activity at puberty. In addition, adult CS rats presented higher levels of GR immunoreactivity in testicular tubules when compared to control and MS rats. No differences were found between control and MS rats. On this basis, we propose that the silencing of adrenocortical function during the SHRP could be finalized to preserve sexual maturation from the influence of glucocorticoid effects. As SHRP is unique to rodents, this phenomenon could be related to their successful reproductive strategy.

We report the case of a 64 year old male patient with a history of ischemic heart disease who underwent surgery for an abdominal mass. The histological diagnosis was highly malignant non-Hodgkin's lymphoma. After surgery the patient was admitted to our Department and received 6 courses of chemotherapy according to the COP schedule, followed by radiotherapy to the left upper abdominal region and ipsilateral lung base. The patient achieved partial remission. One month later he began to complain of left axillary lymphadenomegaly, polydipsia and polyuria. A NMR brain scan showed a hypophyseal mass. The patient was treated with DDAVP and chemotherapy with the PRO-MACE protocol; the polyuria and lymphadenomegaly disappeared and the size of the hypophyseal mass reduced markedly. The clinical picture was, therefore, attributed to a hypophyseal localization of the non-Hodgkin's lymphoma, which is a very rare manifestation of lymphomatous spread to the central nervous system. Our case is also interesting because it shows that a favorable outcome can be obtained with chemotherapy, provided that the latter is sufficiently aggressive. This is not necessarily the case with radiotherapy which may also be followed by late and severe neurologic sequelae.

Platelet derived growth factor (PDGF) was identified as a powerful mitogenic growth factor which is released from activated platelets and has a marked activity as vasoconstrictor agent. In the present study we have measured cisternal cerebrospinal fluid (CSF) levels of PDGF in 72 patients operated on for intracranial aneurysm in order to verify whether it might be related to the clinical aspects of SAH with special regard to symptomatic vasospasm. CSF samples were obtained at surgery by cisternal puncture of the subarachnoid cistern the nearest to the aneurysm before aneurysm isolation and exclusion. The specimen were frozen in liquid nitrogen and stored at -80 degrees C until analysis. PDGF was measured using a commercially available reagent. Values are expressed as pg/ml of CSF. In 18 cases no radiological and clinical signs of SAH were detected and the mean cisternal CSF level of PDGF was 885.0 +/- 104.5 pg/ml; 20 patients were operated on between day 1 and 3 from the last SAH episode: mean cisternal CSF level of PDGF was 1917.5 +/- 459.4 pg/ml. In 34 patients treated with delayed surgery protocol, mean cisternal CSF level of PDGF was 995.3 +/- 73.8 pg/ml. Statistical analysis showed significant differences between groups (P: 0.011). In the subgroup of patients operated on within day 3 after SAH, 6 presented vasospasm and had mean cisternal CSF PDGF level which was significantly higher (P < 0.01) than in 14 patients without vasospasm. In the delayed "surgical" patients there was no significant difference in cisternal CSF levels of PDGF considering the occurrence of vasospasm. The results of the present study suggest that (a) after SAH there is a significant release of PDGF early after SAH and (b) higher levels of PDGF found in cisternal CSF of patients operated on within 72 hours after SAH may be predictive of symptomatic vasospasm.

The case is reported of a 44 year old male patient admitted to our Department for left pyramidal hemisyndrome. Familial anamnesis was positive for premature cardiovascular complications and the patient, who was a heavy smoker, had suffered from arterial hypertension and claudicatio intermittens for 10 years. Laboratory investigations showed increased plasma levels of triglycerides, cholesterol and apolipoprotein B, with a sharp decrease in apo A/apo B ratio. Ultrasound and angiographic scans showed severe and diffuse atherosclerotic lesions. A diagnosis was made of familial combined hyperlipidemia and treatment was begun with simvastatin, which produced a progressive normalization of lipidic picture, without any effect of the symptoms related to lower limb occlusive arteriopathy. Two apparently healthy sisters of the patient have also been studied. The first was found to be affected by familial combined hyperlipidemia with isolated increase in cholesterol plasma levels, the second was perfectly normal. This case demonstrates that subjects with similar alterations in lipidic metabolism may present with completely different clinical pictures, even within the same inherited disorder. Different hypotheses are discussed to explain the particularly severe and precocious atherosclerotic lesions of our patient: sex, smoking habit and arterial hypertension, which would have been caused, at least in part, by the observed congenital malformation of renal circulation.

In order to verify the utility of the captopril test (CT) in diagnosing renal artery stenosis we performed a prospective study in 94 consecutive patients (40 females, 54 males, mean age 52.4 +/- 12.3 years) suspected of having renovascular hypertension and with a serum level of creatinine < 2 mg/dl. Antihypertensive drugs were withdrawn one week before the CT or, if this was considered unsafe, patients were treated with nifedipine or diltiazem (53 subjects; 56.4%). We used renal angiography and the Muller criteria to interpret the CT. Our results were as follows: sensitivity, 92%; specificity, 96%; positive predictive value, 88%; and negative predictive value, 97%. In our study a simplified criterion for positive CT-postcaptopril plasma renin activity > 10 ng/mL/h-provided a similar diagnostic value. We conclude that the captopril test is a useful screening test for the detection of renal artery stenosis in selected hypertensive patients and that it can also be reliably performed in patients who are taking calcium antagonists.