Natural Polyhydroxy Flavonoids, Curcuminoids, and Synthetic Curcumin Analogs as α7 nAChRs Positive Allosteric Modulators.

The α7 nicotinic acetylcholine receptor (α7 nAChR) is a ligand-gated ion channel that is involved in cognition disorders, schizophrenia, pain, and inflammation. Allosteric modulation of this receptor might be advantageous to reduce the toxicity in comparison with full agonists. Our previous results obtained with some hydroxy-chalcones, which were identified as positive allosteric modulators (PAMs) of α7 nAChR, prompted us to evaluate the potential of some structurally related naturally occurring flavonoids and curcuminoids and some synthetic curcumin analogues, with the aim of identifying new allosteric modulators of the α7 nAChR. Biological evaluation showed that phloretin, demethoxycurcumin, and bis-demethoxicurcuming behave as PAMs of α7 nAChR. In addition, some new curcumin derivatives were able to enhance the signal evoked by ACh; the activity values found for the tetrahydrocurcuminoid analog 23 were especially promising.

Defects in memory B-cell and plasma cell subsets expressing different immunoglobulin-subclasses in patients with CVID and immunoglobulin subclass deficiencies.

BACKGROUND: Predominantly antibody deficiencies (PADs) are the most prevalent primary immunodeficiencies, but their B-cell defects and underlying genetic alterations remain largely unknown. OBJECTIVE: We investigated patients with PADs for the distribution of 41 blood B-cell and plasma cell (PC) subsets, including subsets defined by expression of distinct immunoglobulin heavy chain subclasses. METHODS: Blood samples from 139 patients with PADs, 61 patients with common variable immunodeficiency (CVID), 68 patients with selective IgA deficiency (IgAdef), 10 patients with IgG subclass deficiency with IgA deficiency, and 223 age-matched control subjects were studied by using flow cytometry with EuroFlow immunoglobulin isotype staining. Patients were classified according to their B-cell and PC immune profile, and the obtained patient clusters were correlated with clinical manifestations of PADs. RESULTS: Decreased counts of blood PCs, memory B cells (MBCs), or both expressing distinct IgA and IgG subclasses were identified in all patients with PADs. In patients with IgAdef, B-cell defects were mainly restricted to surface membrane (sm)IgA+ PCs and MBCs, with 2 clear subgroups showing strongly decreased numbers of smIgA+ PCs with mild versus severe smIgA+ MBC defects and higher frequencies of nonrespiratory tract infections, autoimmunity, and affected family members. Patients with IgG subclass deficiency with IgA deficiency and those with CVID showed defects in both smIgA+ and smIgG+ MBCs and PCs. Reduced numbers of switched PCs were systematically found in patients with CVID (absent in 98%), with 6 different defective MBC (and clinical) profiles: (1) profound decrease in MBC numbers; (2) defective CD27+ MBCs with almost normal IgG3+ MBCs; (3) absence of switched MBCs; and (4) presence of both unswitched and switched MBCs without and; (5) with IgG2+ MBCs; and (6) with IgA1+ MBCs. CONCLUSION: Distinct PAD defective B-cell patterns were identified that are associated with unique clinical profiles.

Contribution of cerebrospinal fluid sCD19 levels to the detection of CNS lymphoma and its impact on disease outcome.

Flow cytometry (FCM) is more sensitive than conventional cytology for detection of occult leptomeningeal lymphoma; however, some FCM-negative patients show central nervous system (CNS) recurrence. Here, we evaluated the cerebrospinal fluid (CSF) levels of 13 B-cell-associated markers and their contribution to the diagnosis of CNS lymphoma in 91 diffuse large B-cell lymphomas (DLBCL) and 22 Burkitt lymphomas (BLs). From all markers tested, CD19 was the most informative. Thus, higher soluble CD19 (sCD19) levels were associated with a greater frequency of neurological symptoms in DLBCL and BL and with parenchymal CNS lymphoma in DLBCL; sCD19 emerged as a powerful predictor of event-free and overall survival in DLBCL and BL, particularly when combined with FCM detection of CNS disease. These results support the utility of combined FCM detection of lymphoma cells and assessment of sCD19 levels in CSF, for more accurate identification of CNS disease in DLBCL and BL patients.

A Systematic Review on Assessing Assessments: Unveiling Psychometric Properties of Instruments for Reactive Attachment Disorder and Disinhibited Social Engagement Disorder in Minors under Protective Measures.

BACKGROUND: Reactive attachment disorder (RAD) and disinhibited social engagement disorder (DSED) manifest in individuals facing attachment system challenges, particularly observed in minors under protective measures. The lack of standardized tools for assessing these difficulties and uncertainty about the most effective instruments from a psychometric perspective prompted this study. AIM: Using the COSMIN checklist, we systematically reviewed instruments assessing RAD, adhering to PRISMA. METHODOLOGY: Examined tools included the Disturbance Attachment Interview, Preschool Age Psychiatric Assessment, Relationship Patterns Questionnaire, Assessment of RAD and DSED, Development and Well-Being Assessment, and Reactive Attachment Disorder Questionnaire. RESULTS: Of the 10 articles analyzed, the results highlight a research emphasis on internal consistency and structural and construct validity, sidelining other properties. CONCLUSION: Most articles review structural validity and internal consistency. These measures are satisfactory but insufficiently evaluated. It is necessary to evaluate these tools using other indicators such as cross-cultural validity, measurement error, or responsiveness in adolescents under protective measures.

[Objective assessment of the level of comorbidity in geriatric patients with bowel cancer: relationship between the surgical results and survival]. / Evaluación objetiva del grado de comorbilidad en pacientes geriátricos con neoplasia de colon: relación con los resultados quirúrgicos y la supervivencia.

OBJECTIVES: Bowel cancer is increasing in prevalence in geriatrics (older than 65 years). The influence of comorbidities on the post-surgical results of bowel cancer is not well known. Our aim was to assess the comorbidities using the Charlson index in a geriatric population subjected to bowel cancer surgery, and analyse their influence on the postoperative results and the mortality rate. MATERIAL AND METHODS: The study included 115 patients (over 65 years-old and with 5 years follow-up) subjected to bowel cancer surgery in the Vic General Hospital (Barcelona) between the years 2003 and 2005. Three comorbidity groups were established using the Charlson index: absent (0 points), low (1-2 points), and high (≥ 3 points). The postoperative medical and surgical complications, as well as mortality, were determined in each of the groups. RESULTS: The relative risk of a medical complication adjusted for age and stage was 2.7 (95% CI; 1.07-7) and 4.3 (95% CI; 1.3-14) times higher in the low and high comorbidity groups, respectively. There were no differences in post-surgical complications between the comorbidity groups. The length of hospital stay was higher in the in the high comorbidity group compared to the group with no comorbidity (17 days compared to 26 days, P=.02). The relative risk of mortality adjusted for age and stage was 1.7 (95% CI; 1.04-3) and 2.5 (95% CI; 1.3-4.6) in the low and high comorbidity groups, respectively. CONCLUSION: The presence of any level of comorbidity measured by the Charlson index is an independent predictive factor of medical complications and of an increase in overall mortality in geriatric patients subjected to bowel cancer surgery.

Evaluation of Psychophysical Fitness in Drivers over 65 Years of Age.

BACKGROUND: The deterioration of cognitive and psychophysical ability associated with aging has an effect on road safety, especially in the driving of vehicles. The current study's main objective is to evaluate the psychophysical aptitudes in drivers over 65 years of age in a sample of drivers in Spain. METHODS: The sample was formed of a total of 1663 drivers who attended a Driver Recognition Center. The evaluation of their psychophysical aptitudes was carried out following the Medical-Psychological Exploration Protocol for Driver Recognition Centers, edited by the Ministry of Health and the General Directorate of Traffic. RESULTS: The results show increased restrictions in the evaluation of driving ability with age, which are especially significant after 75 years of age. Regarding sex, 70.1% of women have an approved evaluation, compared to men aged between 65-69, although from 69 onwards, the percentage of approved women decreases significantly. The loss of visual capabilities and poor performance in psycho-technical tests are the main causes associated with an evaluation with restrictions, with the number of restrictive conditions increasing with age. CONCLUSIONS: There is an increase in the number of cases with age-related restrictions, especially in the case of women and ophthalmologic-related problems, although the majority of drivers over 65 years old continue driving, thus continuing with a practice that has been related to the well-being and quality of life of older adults.

Effects of Cannabis Legalization on Road Safety: A Literature Review.

BACKGROUND: Legalizing medical and recreational cannabis and decriminalizing this substance may have unanticipated effects on traffic safety. The present study aimed to assess the impact of cannabis legalization on traffic accidents. METHODS: A systematic review was carried out following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) declaration of the articles included in the Web of Science (WoS) and Scopus databases. The number of papers included in the review was 29. RESULTS: The results show that in 15 papers, there is a relationship between the legalization of medical and/or recreational cannabis and the number of traffic accidents, while in 5 papers, no such relationship is observed. In addition, nine articles indicate a greater number of risk behaviors related to driving after consumption, identifying young, male, and alcohol consumption together with cannabis as the risk profile. CONCLUSIONS: It can be concluded that the legalization of medical and/or recreational cannabis has negative effects on road safety when considering the number of jobs that affect the number of fatalities.

Reactive Attachment Disorder and Its Relationship to Psychopathology: A Systematic Review.

This study aimed to determine, through a systematic review, the relationship between Reactive Attachment Disorder (RAD) and the presence of psychopathology in children and adolescents, and to determine the existence of differences in terms of internalising and externalising psychological problems between the RAD group and groups with other disorders or with typical development. Following the PRISMA methodology, a search was carried out in the Web of Science, PubMed and Scopus databases. The search yielded 770 results, of which only 25 met the inclusion criteria. The results indicate a relationship between the presence of RAD and/or disinhibited social engagement disorder (DSED), with the presence of internalising and externalising problems. These difficulties are more present in children with RAD compared to children without personal difficulties, or children with DSED, children with autism, children with intellectual disabilities or children with hyperactivity. It can be concluded that the presence of RAD has negative consequences on the mental health of children and adolescents, with these being greater in the inhibited group than in the disinhibited group, and with respect to children with autism or hyperactivity.

Health-Related, Social and Cognitive Factors Explaining Gambling Addiction.

BACKGROUND: Gambling addiction was the first addictive behavior not related to substance use that was recognized by the DSM-5. It shares diagnostics and comorbidity with other addictions. Extensive studies have investigated the clinical variables involved, but there have been fewer studies of related cognitive and social variables. In this research, an integrative model was developed to advance the understanding of gambling addiction, and an explanatory model was created based on the concept of cognitive distortions. METHODS: The sample comprised 258 university students (59.5% women) with a mean age of 20.95 years (SD = 2.19). A series of questionnaires were administered to measure gambling addiction, depression, coping with stress, prosocial behavior, susceptibility to priming and cognitive distortions about gambling. In addition, correlations, multiple linear regressions and a simple mediation model of these variables were analyzed. RESULTS: The results indicated that gambling addiction was correlated with a variety of clinical, social and cognitive factors. These factors contributed to a model that predicted 16.8% of the variance in gambling addiction and another model using cognitive distortions as a predictor and the maximum bet as a mediator that predicted 34.5% of the variance. CONCLUSIONS: The study represents an advance by developing a theoretical model from an integrative perspective and providing a new explanatory model. The findings of this research are of great importance in the development of prevention and intervention programs for gambling addiction.

Psychosocial risk factors of technological addictions in a sample of Spanish University students: The influence of Emotional (Dys)Regulation, personality traits and Fear of Missing Out on internet addiction.

Perception of the need to be online can lead to the compulsive use of the Internet. The aim of this study is to investigate the relationships between Internet Addiction and Social Media Addiction and some psychological variables that could influence the onset of these disorders (FoMO, Emotional Dysregulation, Personality traits). The sample was composed by 598 Spanish university students aged from 18 to 35 (471 women and 118 men; average age = 21.56; standard deviation = 2.73). Participants responded to an online questionnaire regarding the use of Internet (IAT), the use of social media (BSMAS), Fear of Missing Out (FoMO), Emotional (Dys)regulation (DERS) and personality traits (BFI-15). Correlation analysis showed a positive relationship between FoMO, Social Media Addiction, Internet Addiction, Emotional (Dys)regulation and Neuroticism dimension of Big five. Also, we observed a negative relationship between Internet Addiction and Social Media Addiction, Conscientiousness dimension of Big Five, and gender. The tested mediation model highlighted that the total effect of the DERS on the IAT score was significant as well as its indirect effect via the BSMAS and FoMO scores was positive and significant. In conclusion, we proposed a new integrated model for understanding the characteristics, predictors, and risk factors of IA.

Expression and functional properties of α7 acetylcholine nicotinic receptors are modified in the presence of other receptor subunits.

Although α7 nicotinic receptors are predominantly homopentamers, previous reports have indicated that α7 and ß2 subunits are able to form heteromers. We have studied whether other nicotinic receptor subunits can also assemble with α7 subunits and the effect of this potential association. Coexpression of α7 with α2, α3, or ß4 subunits reduced to about half, surface α-bungarotoxin binding sites and acetylcholine-gated currents. This is probably because of inhibition of membrane trafficking, as the total amount of α7 subunits was similar in all cases and a significant proportion of mature α7 receptors was present inside the cell. Only ß4 subunits appeared to directly associate with α7 receptors at the membrane and these heteromeric receptors showed some kinetic and pharmacological differences when compared with homomeric α7 receptors. Finally, we emulated the situation of bovine chromaffin cells in Xenopus laevis oocytes by using the same proportion of α3, ß4, α5, and α7 mRNAs, finding that α-bungarotoxin binding was similarly reduced in spite of increased currents, apparently mediated by α3ß4(α5) receptors.

Motives for gambling, cognitive distortions, and irresponsible gambling: Proposal for an explanatory model of gambling addiction in university students.

There are many factors that appear to be directly related to the development of gambling addiction problems, and it is important to understand these relationships from a clinical perspective in order to develop prevention and intervention programs. This research seeks to analyze the relationships these problems have with gambling motives, cognitive distortions and irresponsible gambling behavior, and proposes an explanatory model of gambling addiction. The sample was made up of 258 adults residing in the province of Valencia (59.5% women), with a mean age of 20.95 years (SD = 2.19). A series of questionnaires were applied to measure the variables involved, and bivariate correlations, simple and multiple linear regressions and a structural equation model were analyzed. The results indicated that gambling motives were positively related to cognitive distortions, acting as predictors of these. Additionally, the proposed theoretical model showed goodness of fit on various indices and explained 69% of variance in cognitive distortions, 37% of that in irresponsible gambling and 43% of that in gambling addiction. The main limitation of this research is that the sample belongs to a very specific population, who did not necessarily have gambling problems. The main contributions are uncovering some of the relationships between gambling motives and cognitive distortions and the proposal of a mediating role of irresponsible gambling in the relationship between cognitive distortions and the development of gambling problems. If the proposed model replicates, it can be of help to research and health professionals.

Prospect Theory: A Bibliometric and Systematic Review in the Categories of Psychology in Web of Science.

Prospect Theory (PT) is an alternative, dynamic explanation of the phenomenon of risky decision making. This research presents an overview of PT's history in health fields, including advancements, limitations, and bibliometric data. A systematic and bibliometric review of the scientific literature included in the psychological categories of Web of Science (WoS) was performed following the PRISMA 2020 statement for systematic reviews. A total of 37 studies (10 non-empirical and 27 empirical) were included in the sample. Bibliometric results showed thematic variability and heterogeneity regarding the production, researchers, and methodologies that are used to study PT. The systematic results highlight three main fields of PT research: preventive and screening behaviors, promotion of healthy habits, and COVID-related decision making. Personal and contextual factors which alter the usual pattern specified by PT are also described. To conclude, PT currently has an interdisciplinary character suitable for health promotion, with recent studies broadening its applicability.

Sense of Coherence and Work Stress or Well-Being in Care Professionals: A Systematic Review.

Job-related stress affects the physical and psychological health of professionals dedicated to care. This work is a systematic review that aims to determine the relationships between a sense of coherence (SOC) and work stress and well-being perceived by care professionals. The review was carried out following the PRISMA guidelines, and the search was carried out using the Web of Science (WoS), PubMed, and Scopus databases, obtaining a final selection of 41 articles. The results indicate that stress, depression, burnout, and posttraumatic stress disorder (PTSD) negatively correlate with SOC; in contrast, job satisfaction, well-being, and quality of life positively correlate with SOC. It is concluded that SOC could act as a mediating variable and as a predictor variable of these health problems.

Decision Making in Addictive Behaviors Based on Prospect Theory: A Systematic Review.

Traditionally, research on addictive behaviors has been based on the study of their risk factors, with impulsivity being the main risk factor. However, this study aims to approach this topic from the analysis of decision making. According to the prospect theory, low levels of loss and risk aversion will increase the probability of showing addictive behaviors. A systematic review of the possible relationships between these behaviors and prospect theory was carried out. To this end, the works that have studied loss and risk aversion in populations with addictive behaviors to date (N = 15) were compiled. Apart from other eligibility criteria, the selection process was only performed with studies that included the prospect theory or cumulative prospect theory, in English or Spanish, since 1979. WoS, Scopus, Dialnet and PsycInfo were the information sources selected. For this purpose, PRISMA guidelines have been followed. It was found that users of addictive substances show less loss aversion than nonusers. These results cannot be transferred to pathological gamblers. The significance of this work for future research and the implementation of prevention and intervention programs is highlighted. The results show an approach to addictions from a novel perspective.

Social Support and Resilience as Predictors of Prosocial Behaviors before and during COVID-19.

The objective of this research was to analyze the relationship between social support and resilience with prosocial behavior before and during the confinement caused by COVID-19. Materials and Methods: The participants were divided into a confined group (228 women and 84 men) and an unconfined group (153 women and 105 men), all of whom were university students. Instruments were applied to measure the variables proposed. Results: Social support predicted 24.4% of the variance in prosocial behavior among women and 12% among men in the confined group; no evidence of this relationship was found in the unconfined groups. Resilience predicted 7% of the variance in prosocial behavior among confined women, 8.4% among confined men, 8.8% among unconfined women, and 5.1% in unconfined men. Discussion and Conclusion: The results show the importance of social support and resilience in prosocial behaviors, which are key elements for the proper functioning of society, especially in the face of a crisis such as COVID-19.

P2X4 activation modulates volume-sensitive outwardly rectifying chloride channels in rat hepatoma cells.

Volume-sensitive outwardly rectifying (VSOR) Cl(-) channels are critical for the regulatory volume decrease (RVD) response triggered upon cell swelling. Recent evidence indicates that H(2)O(2) plays an essential role in the activation of these channels and that H(2)O(2) per se activates the channels under isotonic isovolumic conditions. However, a significant difference in the time course for current onset between H(2)O(2)-induced and hypotonicity-mediated VSOR Cl(-) activation is observed. In several cell types, cell swelling induced by hypotonic challenges triggers the release of ATP to the extracellular medium, which in turn, activates purinergic receptors and modulates cell volume regulation. In this study, we have addressed the effect of purinergic receptor activation on H(2)O(2)-induced and hypotonicity-mediated VSOR Cl(-) current activation. Here we show that rat hepatoma cells (HTC) exposed to a 33% hypotonic solution responded by rapidly activating VSOR Cl(-) current and releasing ATP to the extracellular medium. In contrast, cells exposed to 200 microm H(2)O(2) VSOR Cl(-) current onset was significantly slower, and ATP release was not detected. In cells exposed to either 11% hypotonicity or 200 microm H(2)O(2), exogenous addition of ATP in the presence of extracellular Ca(2+) resulted in a decrease in the half-time for VSOR Cl(-) current onset. Conversely, in cells that overexpress a dominant-negative mutant of the ionotropic receptor P2X4 challenged with a 33% hypotonic solution, the half-time for VSOR Cl(-) current onset was significantly slowed down. Our results indicate that, at high hypotonic imbalances, swelling-induced ATP release activates the purinergic receptor P2X4, which in turn modulates the time course of VSOR Cl(-) current onset in a extracellular Ca(2+)-dependent manner.

Role of loop 9 on the function of neuronal nicotinic receptors.

We have studied the role of loop 9 in the function of neuronal nicotinic receptors. By systematically mutating the residues in the loop we have determined that the most important amino acids determining the coupling of binding to gating are the ones closer to the transmembrane region. Single mutations at location E173 in homomeric alpha7 receptors destroyed their function by completely abolishing the current while preserving the expression at the membrane. In contrast, heteromeric receptor alpha3beta4 with the same mutations retained some function. We conclude that loop 9 has a different role in the function of homomeric and heteromeric receptors.

Mutants of ß-strand ß3 and the loop B in the interface between α7 subunits of a homomeric acetylcholine receptor show functional and pharmacological alterations.

Activation of nicotinic acetylcholine receptors (nAChR) requires a global conformational change involving a number of domains of the protein. Structural data from Torpedo nAChR suggest that adjacent subunits might be functionally coupled at the interface between the ß-strand ß3 and the loop B through a salt bridge between α1Asp152 and γArg78. We have checked this hypothesis in homomeric α7 nAChRs by mutating residues at these (Gly152 and Arg79) and neighboring locations and analyzing the results obtained after expression of single and double mutants in Xenopus oocytes. We found that Arg79 mutants showed a decreased gating function when challenged with different agonists, being the reduction more important for dimethylphenylpiperazinium. EC(50) values in these mutants were also increased up to 30-fold. In contrast, mutating Gly152 only showed significant higher EC(50) values for ACh. However, all Gly153 mutants presented increased gating function and lower EC(50) values with no significant differences among them. When analyzing several mutant cycles it is concluded that Arg79 is functionally coupled to Gly152, but neither to Gly153 nor to Asp157. These data suggest an involvement of the minus side of homomeric α7 nAChRs in their gating function, reinforcing the significance of complementary subunits in the gating of neuronal nAChRs.

Substitutions of amino acids in the pore domain of homomeric α7 nicotinic receptors for analogous residues present in heteromeric receptors modify gating, rectification and binding properties.

We have studied the role of different amino acids in the M2 transmembrane domain of the α7 neuronal nicotinic receptor by mutating residues that differ from the ones located at the same positions in other α (α2-α10) or ß (ß2-ß4) subunits. Our aim was to investigate the contribution of these amino acids to the peculiar kinetic and inward rectification properties that differentiate the homomeric α7 receptor from other nicotinic receptors. Mutations of several residues strongly modified receptor function. We found that Thr245 had the most profound effect when mutated to serine, an amino acid present in all heteromeric receptors composed of α and ß subunits, by dramatically increasing the maximal current, decreasing the decaying rate of the currents and decreasing receptor rectification. Some mutants also showed altered agonist-binding properties as revealed by shifts in the dose-response curves for acetylcholine. We conclude that residues in the M2 segment and flanking regions contribute to the unusual properties of the α7 receptor, especially to its characteristic fast kinetic behavior and strong inward rectification and furthermore to the potency of agonists.