Cognitive emotion regulation plays a crucial role in psychopathology, resilience and well-being by regulating response to stress situations. However, the relationship between personality and adaptive and maladaptive regulation has not been sufficiently examined.Adaptive and maladaptive cognitive emotion regulation strategies of 247 university students were measured using the Cognitive Emotion Regulation Questionnaire (CERQ) and their temperament and character characteristics were analyzed with the Temperament and Character Inventory—Revised Short (TCI-RS). Two-step hierarchical multiple regression analyses were used to analyze whether TCI-RS explains the use of adaptive and maladaptive cognitive emotion regulation strategies. The latent classes of cognitive emotion regulation strategies were extracted with Latent Class Analysis (LCA) and significant differences in the subscales of CERQ and TCI-RS were examined with Analysis of Covariance (ANCOVA) and Profile Analysis after controlling for sex and age.The two-step hierarchical multiple regression model using the seven TCI-RS subscales explained 32.30% of the adaptive and 41.70% of the maladaptive CERQ subscale scores when sex and age were introduced in the first step as covariates. As for temperament, Novelty Seeking (NS) and Persistence (PS) were pivotal for adaptive and Harm Avoidance (HA) and PS for maladaptive CERQ total scores. In addition, the character traits Self-Directedness (SD) and Cooperativeness (CO) were critical for high adaptive and low maladaptive CERQ scores. Four latent emotion regulation classes were confirmed through LCA, and distinct TCI-RS profiles were found. The temperament trait HA and character trait SD were significantly different among the four latent emotion regulation classes.This study demonstrated that SD and CO are related to cognitive emotion regulation strategies along with psychological health and well-being, and that PS exhibits dualistic effects when combined with NS or HA on response to stressful situations. The importance of developing mature character represented by higher SD and CO in regard to mental health and its clinical implementation was discussed. We deal with a variety of situations in everyday life, which leads to various emotional responses. Such emotional responses appear immediate and unchangeable at first. However, biological, social, and cognitive behavioral self-regulatory processes become activated internally. These processes are responsible for monitoring, evaluating and modifying emotional reactions in order to accomplish one’s goals in the context of human life, and such a process has been termed emotion regulation . SuccessTwo separate strategies can be broadly defined as (1) mature, adaptive and positive vs. (2) immature, maladaptive and negative, and they are the product of predisposed tendencies based on individual differences .These two types of strategies, adaptive (adaptive cognitive emotion regulation questionnaire: aCERQ) and maladaptive , can be measured using the CERQ . The CERIn this context, personality has been suggested to predict the use of emotion regulation strategies of a given person . PreviouCloninger’s biopsychosocial model of personality  consistsThe temperament domain is composed of NS, HA, Reward Dependence (RD), and PS. NS is a personality trait associated with exploratory excitability in response to novel stimuli, and HA is associated with behavioral inhibition in reaction to dangerous or abhorrent stimuli. RD is a tendency to respond particularly to signals of social reward, and PS is a tendency to maintain behavior with intermittent reinforcement . The chaIn addition, higher score in SD is a critical protective factor in psychopathology and also a factor in the promotion of mental health . MeanwhiHowever, previous studies were primarily dedicated to examining the strong association between maladaptive emotion regulation strategies, psychopathology and well-being . TherefoFor these reasons, the aim of this study was to explore the association between personality and adaptive and maladaptive cognitive emotion regulation by (1) assessing how much variance in emotion regulation scores can be explained by personality scores and by (2) identifying groups of emotion regulation style and assessing differences in personality scores between these groups . This wiThe CERQ and TCI-RS were used to measure cognitive emotional regulation strategies and personality of 313 college students who enrolled in an elective course of a metropolitan university. A total of 247 (89 men and 158 women) out of 313 students chose to participate (78.9%) voluntarily after a researcher introduced and completed the questionnaires. The participants were also asked about their age, sex, and education level as the part of their survey. This study was approved by the institutional ethics board of Pusan National University (PNU IRB/2015_59_HR) and all of the participants provided the active and written informed consent.The CERQ measures the cognitive style or emotional regulation strategies when overcoming stress from negative life events and it has been frequently used to examine its relationship to psychopathology . EmotionCERQ is composed of 36 questions using a 5-point scale . The CERQ consists of two scales, aCERQ and mCERQ, along with nine subscales. The aCERQ  is composed of five subscales, namely PIP , REP , PRF , PRA  and ACC , and the mCERQ  consists of four subscales, namely RUM , CAT , BLO  and BLS .α) were reported as .66 for PIP, .80 for REP, .85 for PRF, .80 for PRA, .53 for ACC, .68 for RUM, .78 for CAT, .83 for BLO, and .76 for BLS , NS , RD , and PS  .The character dimension consists of SD , CO , and ST .α) of HA, NS, RD, PS, SD, CO, and ST were shown as .86, .83, .81, .82, .87, .76, and .90, respectively (The Korean version of the Temperament and Character Inventory-Revised-Short (TCI-RS) is a 140-item self-report questionnaire validated for use in Korea based on the original TCI . Respondectively .χ2 and t-tests. The correlations between subscales of CERQ and TCI-RS were examined with Pearson’s correlation analysis. Two-step hierarchical multiple regression analyses were conducted to examine how TCI-RS temperament and character explains adaptive and maladaptive strategy scores on the CERQ. Sex and age were introduced in the first step as covariates (model 1) and all seven TCI-RS subscales were added in the second step (model 2).The significant differences in age, school year, college major and subscales of CERQ and TCI-RS between male and female participants were examined using Latent Class Analysis (LCA) was used to explore the latent classes of all nine subscales of CERQ using Mplus 5.21 . LCA is The criteria of model fit were as follows : (1) theAfter determining the number of latent classes, ANCOVA was performed to compare aCERQ and mCERQ total scores among extracted latent CERQ classes. Following ANCOVA, Bonferroni post-hoc analysis was performed to confirm where the differences among the classes occurred. Profile Analysis was also conducted to analyze significant differences in the TCI-RS subscales between the extracted latent CERQ classes with sex and age as covariates . To calcThe data are presented as means and standard deviations or as frequencies with percentages, and estimated values for sex and age are shown as means and standard errors. All analysis was performed using IBM SPSS Statistics 20.0  and Mplus 5.21 .t = 4.92, p < .001), but not in university year  or college major  between male and female participants. The higher age of male participants most likely resulted from the fact that male students in Korea have to take a two-year leave of absence during their university enrollment to complete their mandatory military service. Since demographic features showed distinctive sex and age differences, we performed all further statistical analyses with sex and age as covariates.The demographic features of the participants are shown in t = 3.47, p < .001), PIP , ROP , PRF  and PRA  scores than female participants. However, there was no significant difference in mCERQ . For the TCI-RS subscales, male participants demonstrated significantly higher PS  and SD  scores, while female participants showed significantly higher scores in HA  than male participants.The male participants showed significantly higher aCERQ total . The aCERQ total score was significantly correlated with HA , PS , SD  and CO , and the mCERQ total score was significantly correlated with HA  and SD . For the TCI-RS subscales, HA showed a significant negative correlation with PS  and SD , and there was a significant positive correlation  between PS and SD.Correlations between CERQ and TCI-RS subscales were examined using Pearson’s correlation analysis . The aCEA two-step hierarchical multiple regression analysis  examinedF = 18.84, p < .001, 2R = .42 (2adj.R = .40)] explained 41.70% of the total variance in aCERQ total score, and it was found that age, NS, PS, SD, CO and ST were predictors of aCERQ total score. The regression model  explained 32.30% of the variance in mCERQ total score, and it was found that HA, PS, SD and CO were predictors of mCERQ total score.The regression model [p value of VLMR (p = .009), LMR (p = .010), and BLRT ( p = .000), and a greater than .8 Entropy index (.82)  .n = 78, 32.58%), MALM or Middle Adaptive and Low Maladaptive , MAHM or Middle Adaptive and High Maladaptive  and LAHM or Low Adaptive and High Maladaptive  classes based on aCERQ and mCERQ scores. aCERQ and mCERQ total score of HALM , MALM , LAHM , MAHM  classes were significantly different from each other according to ANCOVA .The four latent CERQ classes were labeled as HALM or High Adaptive and Low Maladaptive  and PRA  scores. REP score was significantly different  across the classes except between LAHM and MALM, and LAHM and MAHM. PRF score was significantly different  across the classes except between MALM and MAHM. ACC score was significantly different  across the classes except between MALM and LAHM. In aCERQ subscales, the four latent classes were significantly different from each other in PIP and PRA scores. REP score was significantly different across the classes except between LAHM and MALM, and LAHM and MAHM. PRF score was significantly different across the classes except between MALM and MAHM. ACC score was significantly different across the classes except between MALM and LAHM.Significant differences in all nine CERQ subscales among the four latent classes were found when ANCOVA and Bonferroni post-hoc analysis were performed. In aCERQ subscales, the four latent classes were significantly different from each other in regard to PIP  and the interaction between the four latent classes was significantly different in regard to parallelism , meaning that the four classes were significantly different from each other in terms of all the seven trait mean scores of TCI-RS.Profile Analysis was used to examine significant differences in TCI-RS subscales among the four latent CERQ classes . The TCISignificant differences in all seven TCI-RS subscales among the four latent classes were found when ANCOVA and Bonferroni post-hoc analysis were performed. In the temperament domain, NS score was significantly different between MALM and MAHM, and HA scores were significantly different from each other except between HALM and MALM. RD scores were significantly different only between MALM and MAHM, and between MALM and HALM. PS scores were significantly different between MALM and the other three latent classes.In the character domain, SD scores were significantly different across the classes except between MALM and HALM, and CO scores were significantly different from each other except between MALM and MAHM. ST scores were significantly different across the classes except between MALM and LAHM, and between MAHM and HALM.This study investigated the effects of personality as individual traits as well as complex profiles on cognitive emotion regulation strategies using the TCI-RS and CERQ in a sample of Korean university students. Based on an exploration of latent classes depending on adaptive and maladaptive cognitive emotion regulation, we provide further support that character traits of higher scores in both SD and CO play a pivotal role in predicting psychological adaptation and adjustment.First, as for the individual personality traits, the temperament trait HA was associated with maladaptive emotion regulation as measured by the CERQ (mCERQ) as in previous studies . That isIn addition, the temperament trait NS was found to be associated with adaptive strategies in this study. This may be expected given that an individual with a high score in NS typically seeks out and enjoys new or novel experiences, ideas and innovative activities. Extraversion and Openness of the five factor model  which shSecond, the temperament trait PS showed a dualistic effect , concurrPS is a tendency to maintain one’s behavior even in the face of punishment or compensation, and individuals with higher PS can be characterized as industrious, determined, ambitious and perfectionistic . An indiThird, it was also found that a high score in the character trait of SD promotes the use of adaptive emotion regulation and suppresses the use of maladaptive emotion regulation strategy in addition to the temperament traits such as higher HA and PS. According to Cloninger , SD is tWhen person-centered analyses were performed on the complex nature of temperament and character using LCA and Profile Analysis, there were four latent CERQ classes showing distinct personality classes. Individuals with a highly adaptive emotion regulation style/profile  exhibited the highest levels of responsibility, resourcefulness, and self-acceptance  and also the highest levels of optimism and energy levels . In contrast, individuals with a maladaptive emotion regulation style/profile  were characterized by low self-esteem, feelings of victimization, and lack of goals  and also by pessimism, low energy, and propensity for anxiety  . Indeed,Fourth, another important new finding in our study was that high scores in SD and high scores in CO and/or low scores in ST may play an important role in fast and adaptive emotional response or in the choice of cognitive emotion regulation strategy in stress situations which has not been previously reported. The importance of SD and CO in our stress response has been consistently reported , and theWhile extant studies primarily focused on the role of temperament, the present study implicates the significant role of character in emotion regulation. The character domain of TCI-RS measures psychological maturity and is reported to be a protective factor in the development of psychopathology and is also related to resilience to stress and biopsychological well-being . This stAs such, temperament and character, which play a pivotal role in well-being and mental health, affect long-term development and continuation of emotion regulation style to everyday life stressors , not onlThere are a number of limitations of this study. First, this study was conducted with a relatively small sample of Korean university students. The findings should be supported using a bigger sample balanced in sex and age. Second, the sex differences of Korean university students in personality and cognitive emotion regulation strategy should be further examined to determine whether cross-cultural differences  exist inThis study examined maladaptive and adaptive cognitive emotion regulation strategies using the two perspectives of individual traits with two-step hierarchical regression analyses and the complex interaction across the classes simultaneously through LCA. The temperament domain guided the direction of emotion regulation such that high scores in HA and PS predicted maladaptive cognitive emotion regulation strategy and high scores in NS and PS predicted adaptive strategy. As for the character domain, SD and CO were correlated positively with adaptive and negatively with maladaptive cognitive emotion regulation strategy which may explain the significance of resilience to stress and promotion of well-being.Specific combination of temperament and character traits appears to be particularly influential in predicting adaptive and maladaptive emotion regulation strategies and is also associated with both mental health and well-being. Mature personality as represented by character traits such as SD and CO rather than temperament traits was found again to account for temperamental vulnerability as well as specific cognitive emotion regulation. In particular, the effect of PS was once again found to be dualistic, supporting the concept of a non-linear model. In other words, the same high score in PS may exert an opposite tendency. It may be associated with adaptive emotion regulation when combined with high scores in NS but with maladaptive emotion regulation when combined with high scores in HA. Since adaptive emotion regulation is pivotal for psychological health, structured education and persistent interest on character development in Korean university students should be emphasized. This study provides a foundation for a potential psychological mechanism in stress response as well as existing psychopathological studies.10.7717/peerj.7958/supp-1Data S1Click here for additional data file.10.7717/peerj.7958/supp-2Data S2Click here for additional data file.


Indigoferasuffruticosa Mill. (Fabaceae) is known as anil or anileira and also with other names, due to the production of a blue pigment, which is commonly used for yarn dyeing. It is distributed in some states of Brazil  and is used in the popular medicine as a febrifuge, antispasmodic, diuretic, abortive, analgesic, purgative, or soothing agent against stomach and urinary problems, jaundice, and ulcers and also as an insecticide. In addition, I. suffruticosa can be used as animal feed. This review aimed at providing important data on the botanical, distribution, ethnopharmacology, phytochemical, pharmacological, and toxicity of I. suffruticosa based on the scientific literature. Information on I. suffruticosa was gathered via the Internet  and libraries in the period from February to March 2016. More than 40 chemical compounds have been identified and a few compounds isolated, and the main origins are the essential oils, organic extracts, and aqueous extracts of different parts of the plant. I. suffruticosa and its active compounds possess wide pharmacological actions in the literature, such as anti-inflammatory, antibacterial, antifungal, antioxidative, antitumor, antimutagenic, anticonvulsant, gastroprotective, and hepatoprotective activities. Therefore, as an important traditional popular medicine, further studies on I. suffruticosa are required for the development of new drugs and therapeutics for various diseases. Indigofera species is taxonomically present , quercetin 3-O-[α-l-rhamnopyranosyl-(1⟶6)-β-d-glucopyranoside], and quercetin 3-O-tetradec-11-en-1-ol acetate, oleic acid, 9-octadecenoic acid[z]-, 2-hydroxy-1-[hydroxyl methyl], heptanoic acid, docosyl ester, octadecanoic acid, 7-hydroxy-, 6-octadecenoic acid[z]-, and 8-octadecenoic acid [Pentadecanoic acid, 14-methyl-, oic acid  were alsI. suffruticosa identified the following different phenolic compounds: syringic acid, p-coumaric acid, vanillin, syringaldehyde, salicylic acid, quercetin, isoliquiritigenin, and formononetin.Chen et al.  using aqI. suffruticosa, (z)-3-hexenyl benzoate, methyl hexadecanoate, phytol, linoleic acid, methyl linoleate, n-docosane, n-tricosane, was also found [The presence of such compounds in the leaf oil of so found .I. suffruticosa in mouse embryos and found that, at high concentrations of the extract, the growth of the embryos was inhibited, preventing them reaching the final stage of embryogenesis, indicating that their use in high doses in humans can be harmful.Leite et al.  investigI. suffruticosa by infusion and maceration in different concentrations (from 6.25 to 50 µg/ml) tested in cell lines of HEp-2 by the MTT method did not produce any cytotoxic effect (>30 µg/ml) when compared with the control and DMEM (Dulbecco's Modified Eagle Medium).Vieira et al.  realizedI. suffruticosa showed a potent cytotoxic agent, showing the value of 0.89 for the breast tumor cell line (LM2) and lung tumor cell line (LP07), clarifying that the extract has cellular responses such as inducing apoptosis [In another study, the indigo ethanol extract purifier of poptosis .50) of 200 μg/ml.Carli et al.  also obsBioactive compounds of natural origin are essential in antineoplastic therapy, since they show promising effects on carcinogenesis and contribute to new medicinal interests. Therefore, such information has great relevance in understanding the use of this species and its promising future.I. suffruticosa extracts at varying doses (250–1000 mg/ml) in models for embryotoxicity in the development and oviposition of Aedes aegypti. In the study, a significant repellent effect was found on oviposition and an embryotoxicity was also observed, slowing the normal growth of the larvae of Aedes aegypti.Vieira et al.  used aquThe use of plant extracts is an alternative method for insect control, which can minimize the harmful effects of some insecticides on nontarget insect species, humans, and the environment, leading to new opportunities for the development of commercial products of natural origin and of great importance.I. suffruticosa processed by maceration and infusion at a dose of 50 mg/kg on sarcoma 180 and found that both forms had significant effect on reducing the tumor (62.6 and 64.5%), respectively.Vieira et al.  evaluateI. suffruticosa is still poorly studied, and new studies should investigate the possibility of using as an antitumor drug.Cancer is still the leading cause of death in the world, and plants used in traditional medicines may be a potential source of powerful chemopreventive agents because they are enriching source of beneficial secondary components. There are many plant species that have relevant biological data in the scientific literature and even commercial use for this purpose. However, the use of I. suffruticosa to 5% in the population reduction of Pediculosis capitis and observed the population reduction of lice mainly in cases of persistence in patients of 55 years. After 2 days of application, the results confirmed the insecticidal activity of I. suffruticosa tincture; this treatment seems to be a valuable and effective alternative to existing treatments.García et al.  used tinI. suffruticosa in trials on Salmonella, which showed mutagenic activity, suggesting that such an action is due to the presence of indigo pigment. Since plants are primary food sources and cure, the natural products need to be evaluated with regard to their toxicity and dosage because the indiscriminate use of homemade preparations of plants can be dangerous to health.Calvo et al.  evaluateI. suffruticosa stand out with potent antioxidant activity in an experimental model in vitro with the free radical 2,2-diphenyl-1-picrilidrazil (DPPH), and this method is a rapid way to measure the antioxidant capacity of compounds, it is based on the reduction of DPPH in solution, and this action is attributed to the presence of high concentrations of gallic acid in the extract [Ethanolic extracts of leaves of  extract . Plants I. suffruticosa  showed the protective effect on liver tissue of mice bearing sarcoma 180 [I. suffruticosa, did not observe a reduction in sarcoma 180 tumor but found that liver cells remained preserved, emphasizing its hepatoprotective effect.The aqueous extract of coma 180 . Lima etcoma 180 , using tI. suffruticosa, on mice bearing sarcoma 180 cell lines and found that such a compound did not promote a reduction in tumor growth; however, it is found that treatment with indica does not allow to alter the architecture of the liver cells, suggesting a hepatoprotective effect.Lima et al.  investigSuch an effect is considered of extreme importance since liver diseases have become a global public health problem, and much of them are a consequence of the prolonged use of chemicals and drugs.I. suffruticosa against nine strains of Staphylococcus aureus, with minimal inhibitory concentration (MIC) ranging from 0.78 to 6.25 mg/ml. The methanol extract of the aerial parts of I. suffruticosa showed a significant effect against Mycobacterium tuberculosis with an MIC of 125 μg/mL, suggesting the presence of an important bactericidal agent [Santos et al.  evaluateal agent .I. suffruticosa also showed activity against different bacteria such as B. subtilis, S. aureus, E. coli, K. pneumoniae, and P. aeruginosa, with an MIC ranging from 0.39 to 6.25 mg/ml, emphasizing that this species has a potential to inhibit bacterial growth [The endophytic fungi isolated from I. suffruticosa displays significant results against two strains of Trichophyton rubrum and Microsporum canis, with concentrations of 5 and 10 mg/ml with variation in MIC between 20 and 15 mm, with a similar effect to the standard drug ketoconazole (MIC −20 mm) [The aqueous extract of the leaves of  −20 mm) .The results obtained in these studies suggest that the extracts used had bioactive compounds responsible for the efficacy of the organic material studied. Not only the plant extracts but also those produced by microorganisms can be a source for the industrial manufacture of drugs and useful in the therapy of some microbial infections.I. suffruticosa fluid extract (0.06 g/kg for 10 days) in experimental models of shock promotes protective effect in both doses administered orally or intraperitoneally on seizures induced by this model, highlighting the antiepileptic potential of such an extract [The  extract .I. suffruticosa was tested in models of chronic epilepsy, which reduced the concentration of inhibitory amino acids (glycine and tannin) and increased the excitatory amino acid (glutamic acid) [At the concentration of 0.06 g/kg, the fluid extract of ic acid) .I. suffruticosa showed significant activities, and its action is due to the presence of secondary metabolites such as flavonoids and linalool having an action on the GABAergic system [In models of seizures, the methanol extract of the leaves of c system .I. suffruticosa was confirmed following behavior and electrophysiological analyses in rats. The systematic analysis of seizure behavior and its potentials was also recorded [The anticonvulsant effect of the aqueous extract of recorded .The findings of these studies stimulate the continuity of research in the search for new treatments for epilepsy. Although traditional therapy has good efficacy, it has high toxicity, and about 20–30% of patients who use this therapy are unable to control their seizures appropriately and have severe side effects. Therefore, new alternatives that reduce clinical manifestations and chronic conditions become essential.I. suffruticosa, partitioned with ethyl acetate and administered at a dose of 100 mg/kg, which significantly inhibited the gastric mucosal lesions induced by ethanol and nonsteroidal drugs in rats.Luiz-Ferreira et al.  exploredI. suffruticosa are interesting sources for the development of a phytotherapeutic formulation to treat gastric ulcer.In traditional medicine, several plants are used in the treatment of gastric disorders, and from the evidence presented here, it could be stated that extracts obtained from the aerial parts of I. suffruticosa on immune activity in vitro and observed that the extract triggered a high nitric oxide production and stimulated the synthesis and release of TNF-α, thus triggering the activation of macrophages and promoting the production of other molecules that improve or restore the responsiveness of the innate immune system reaction against infections.Carli et al.  investigI. suffruticosa, the indigo, also in experimental models in vitro, showed an increase in the production and release of nitric oxide and TNF-α [In another study, using a purified compound of nd TNF-α .The immune system is of fundamental importance to every living being, and its malfunction can cause various biological damages. Drugs that stimulate the production and action of the components of this system are of great biological relevance, primarily in immunodeficient individuals who are more susceptible to infections. In this way, the good results obtained for this species favor even more effective use in several diseases.I. suffruticosa (250 mg/kg) in inflammation experimental models of mice showed significant anti-inflammatory effect, with similar action to the commercial standard drug, acetyl salicylic acid [Aqueous extracts of lic acid .I. suffruticosa were used in experimental models of inflammation induced by lipopolysaccharides (LPS) in macrophages, and it was possible to observe a significant anti-inflammatory effect [In another study, aqueous and ethanolic extracts of leaves of y effect .I. suffruticosa is a strong candidate to be applied in this activity.The prolonged use of anti-inflammatories promotes several biological damages and the search for new drug therapies that reversibly abuse the harmful effect, and the low cost is still incessant. The studies already published show that I. suffruticosa have been commonly used to prepare tea for inflammatory diseases of the gynecological tract, mainly organs such as ovaries and/or uterus.Yazbek et al.  reportedIn many places, the main therapeutic resource for the treatment of discomforts and diseases of gynecological origin is still commonly represented by medicinal plants. However, few studies, such as , show thI. suffruticosa in acute toxicity in mice demonstrated the presence of deaths in the tested groups. Some signs of toxicity were noted after a few hours of intraperitoneal administration from a lower concentration to a higher concentration tested dose (2400 mg·kg−1): agitation, piloerection, exhaustion, sleepiness, irritability, and spasms. Also, it was found that the LD50 of the acute toxicity of the aqueous extract of leaves of I. suffruticosa made by infusion administered in different doses in mice showed no mortality during 72 h of observation [Studies using aqueous extracts obtained by infusing leaves of ervation .I. suffruticosa showed a low toxicity with an LD50 of 1600 mg/kg (ip) in mice. The results exhibit a lower significant change in individual behavioral and parameters that slight decrease in spontaneous locomotor activity and an increase in breathing frequency [The methanol extract of leaves of requency .Plants since ancient times have been used as medicine and have been daily providing inspiration for new research, aiming to highlight the diverse potential and expand the library of biologically active molecules.I. suffruticosa has attracted the attention of many researchers because of its high therapeutic value in the population. Different extracts of this species have presented significant results in several pharmacological activities, such as antitumor, antioxidant, anti-inflammatory, antimicrobial, antiepileptic, antifungal, anticonvulsant, gastroprotective, and hepatoprotective.In recent years, in vivo in laboratory animals, and the results presented are not enough for humans to use. Based on the low toxicity presented by the statement and little research of their phytochemicals, new clinical trials should be conducted to fill the gaps in research to establish baseline data for medicinal use, eliminating potential harmful risks and promoting beneficial effects.These studies were tested


The main objective of the present study was to evaluate the presence of overactive bladder (OAB) syndrome, nocturia, urgency, and urge incontinence in patients with obstructive sleep apnea syndrome (OSAS), and measure bladder wall thickness (BWT) in these patients.The patient group was composed of 38 patients with OSAS. The control group was composed of 15 healthy individuals. All patients were evaluated using the Epworth Sleepiness Scale (ESS) and Overactive Bladder Symptom Score (OABSS). The bladder wall thickness was measured by transabdominal ultrasound (US). The presence of nocturia, urinary urgency, and urge incontinence were also evaluated.2) of patients with urgency was found to be significantly lower (p=0.014). The time spent below 90% of oxygen saturation (SO2) was significantly longer in patients with urinary urgency (p=0.009). There was no difference in BWT measurements between the patient group and the control group. There was a significant relationship between BWT values and OABSS in patients with OSAS (p=0.002).The mean OABSS was significantly higher in the patient group compared with the control group (p=0.048). The minimum oxygen saturation (Min.SOThe results of the present study suggest that OSAS is associated with OAB syndrome. As a key symptom of OAB, urgency correlates with hypoxia in cases with OSAS. Although the present study did not observe any difference in BWT measurements between the patients and the control group, there was a correlation between BWT measurements and OABSS in patients with OSAS. Obstructive sleep apnea syndrome (OSAS) is a common disorder characterized by instability of the upper airway during sleep, resulting in reduction or elimination of the airflow, oxygen desaturation, and sleep disturbances . ApproxiOveractive bladder syndrome is defined as a symptom-based clinical diagnosis of urinary urgency with or without urgency incontinence (UI), usually with urinary frequency and nocturia, in the absence of infections or other evident pathological features . The keyNocturia is the main symptom of lower urinary tract problems, which are often attributable to an underlying benign prostatic hyperplasia (BPH) in men. However, nocturia can represent several possible systematic health-related disorders, including OSAS. Definitions of nocturia have been previously published by the Standardization Committee of the International Continence Society (ICS) as the need to awake at night one or more times to void. Nocturia represents the number of voids recorded during a night's sleep .As a diagnostic marker, potential use of bladder wall thickness (BWT) values in patients with OAB has been a current issue. In patients with OAB syndrome, BWT measurements are usually performed with transvaginal ultrasound (US) in women, and consistent results have been reported . CompareThe aim of the present study was to evaluate the presence of OAB syndrome, nocturia, urgency, and urge incontinence in patients with mild, moderate and severe OSAS, and measure BWT in these patients.After obtaining an informed consent from each participant, the patients who were diagnosed with OSAS using full-night polysomnography (PSG) at the sleep disorder laboratory of Kocaeli University, Health Sciences Institute, Derince Training and Research Hospital between December 2015 and December 2016 were screened. Patients with neurological disorders , metabolic disorders , congestive heart failure, and those with a history of hypnotic, diuretic and anticholinergic drug use or who underwent urogenital operations  were excluded from the study. A total of 38 patients with OSAS were included in the study. The control group was composed of 15 individuals who were suspected of having a sleep disorder, but found to be normal on full-night PSG results. Exclusion criteria were also evaluated in the control group. The study protocol was approved by the local Ethics Committee. The study was conducted in accordance with the principles of the Declaration of Helsinki.A full-night PSG was performed in all patients and controls at the sleep disorder laboratory (Embla N 7000). The PSG examination included electroencephalogram, electro-oculogram, chin and leg electromyogram, electrocardiogram, snoring, thermistor, nasal pressure transducer, finger pulse oximetry, thoracic and abdominal respiratory movements, and body position. The scores were determined according to the 2010 American Academy of Sleep Medicine criteria. Patients with an apnea/hypopnea index (AHI) of ≥5/hour were considered to have OSAS. An AHI value between ≥5/hour and <15/hour was defined as mild; an AHI value ≥15/hour and less than 30/hour was defined as moderate; and an AHI value >30/hour was defined as severe OSAS.2), and the percentage of sleep time spent below 90% of oxygen saturation (time SO2<90%) were noted.Age, sex, body mass index (BMI), and Epworth Sleepiness Scale (ESS) scores of all patients were recorded. During PSG, the rate of sleep periods, AHI values, minimum oxygen saturation (Min.SOAll patients were administered Turkish version of Overactive Bladder Symptom Score (OABSS-V8) and the IPSS-QoL; and BWT measurements were carried out under US guidance. In addition, the presence of nocturia, urgency, and UI was examined. The Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI) were also administered.The present study used the Turkish version of OABSS-V8. Tarcan et al.  analyzedInternational Prostate Symptoms Score (IPSS-QoL) usually provides objective assessment of the questionnaire. IPSS-QoL was used only in men. This scale contains seven questions related to prostatic symptoms and one question related to quality of life. Using IPSS-QoL, values between 0 and 7 were considered to indicate mild obstruction, values between 8 and 19 to indicate moderate obstruction, and values between 20 and 35 indicate severe obstruction.All patients underwent suprapubic transabdominal US . The 4C-RC Convex ultrasound probe was used. BWT was measured with approximately 250-300cc of urine in the bladder (pre-voiding). Bladder measurement was made from the thickest point of the right or left wall.The NCSS  2007  program was used for statistical analysis. In addition to the descriptive statistical methods  used in the evaluation of the study data, Student's-t test was used for two-group comparisons of variables with normal distribution, and Mann-Whitney U-test was used for two-group comparisons of variables without normal distribution for the quantitative data. Kruskal-Wallis test was used to compare variables without normal distribution between more than two groups. Spearman's Correlation Analysis was used for evaluating the relationship between variables. Intragroup comparison of parameters without normal distribution was made using Wilcoxon Signed Ranks test. The Fisher-Freeman--Halton exact test, Fisher's exact test and the Yates’ Continuity Correction test (Yates’ correction Chi-square test) were used for the comparison of the qualitative data. Logistic regression analysis was performed in order to evaluate all factors affecting nocturia, urgency, and UI. Linear regression analysis was performed in order to evaluate all the factors affecting BWT and OABSS. A p value <0.05 was considered statistically significant.2 and the time spent <90% oxygen saturation were found to be significantly lower in the patient group . However, no significant difference was found in the ESS scores between the two groups, although higher scores were observed in the patient group . The OABSS values of severe cases were significantly higher than the OABSS values of cases with no OSAS (p=0.049). In the model obtained as a result of the multivariate analysis , gender variable was found significant. It was found that the OABSS value increases to 5.584 if the case is female  .Individual effects of age, gender, BMI and group on BWT were not significant. There was no significant difference in BWT measurements between the groups .There was no significant difference between IPSS-QoL scores of the groups.A positive statistically significant relationship was reported between the ESS scores and OABSS, as evidenced by that ESS increased, OABSS increased, at the 32.8% level . There was a positive statistically significant relationship between the ESS scores and IPSS-QoL as evidenced by that ESS increased, IPSS-QoL increased, at the 48.3% level .There was a significant positive relationship between BWT values and OABSS as evidenced by increased BWT and increased OABSS at the level of 48.1%  in the patient group .2=19.491, p=0.003). It was found that the rate of UI was 11.969-fold higher in female cases .Multivariate analysis evaluating the effects of age, gender, BMI and groups on nocturia and urgency showed no significant difference. In multivariate analysis, effects of each variable including age, gender, and BMI on UI were significant . The time spent <90% SO2 was significantly longer in patients with urgency .The Min.SOIn our study, the OABSS of OSAS patients were found to be significantly higher than those of the control group. Overactive bladder syndrome is defined as a symptom-based clinical diagnosis of urinary urgency, with or without urge incontinence, usually with urinary frequency and nocturia, in the absence of infections or other evident pathological features . Several2, and time spent <90% SO2. In our study, we found a significant positive relationship between OABSS and ESS measurements in the patient group. We identified a significant correlation between OABSS and female gender. We also demonstrated that UI was also higher in female patients. Small number of subjects in the control group is definitely a limitation of the present study. However, in European studies, prevalence of OAB was reported to be 4-15% in men and 14-40% in women (In our study, we found no correlation between OABSS and age, AHI, Min.SOin women .2 measurements were significantly lower in patients that were found to have urgency problems in the patient group, whereas the time spent <90% SO2 was significantly higher. Overactive bladder syndrome induced by nerve destruction has been reported in patients with diabetes (In a study conducted by Ipekci et al.  in 2016,diabetes . Thus, idiabetes . Patientdiabetes  in 2001,diabetes  in 2016,diabetes .We did not observe any difference in BWT measurements between the patient and control groups. In patients with OAB, BWT measurements are usually performed with transvaginal US in women, and consistent results have been reported . In a stIn our study, we did not demonstrate any significant difference in the IPSS-QoL scores between male subjects in the patient and the control groups. In a study by Kemmer et al. in 2009  that incThe authors consider that the present study is worthy as it is the first study to evaluate the relationship between OSAS and BWT. Small number of subjects in the patient group and the control group is a limitation of the study. We did not find any difference in BWT measurements between the patient and the control groups. However, OAB symptom scores were higher in patients with OSAS compared with the control group and there was a positive correlation between OABSS and BWT measurements in patients with OSAS. The authors therefore suggest that weak correlation between OSAS and BWT measurements can be detected by increasing the number of control subjects.In conclusion, OSAS is associated with OAB syndrome. Urgency, which is considered to be a key symptom of OAB, is also known to be associated with hypoxia in patients with OSAS. These findings have clinical implications, as untreated OAB and urgency may cause a relevant attenuation in quality of life of affected patients. Therefore, OAB should be investigated in all patients with OSAS.The present study observed no difference in BWT measurements between the patients and the control group. However, the present study found a correlation between BWT measurements and OAB scores in patients with OSAS. Further studies are required to gain a better understanding of possible use of BWT measurements for OAB in patients with OSAS.


The Klotho protein is a recently discovered protein and its overexpression is associated with life extension. Klotho deficiency or silencing of the Klotho gene in mice leads to an accelerated aging and short life, whereas overexpression of Klotho in mice extends lifespan. Klotho participates in many metabolic pathways and is highly expressed in the kidneys, the choroid plexus and neurons. It plays a key role in the calcium-phosphate metabolism, remyelination, and cognitive processes. The present paper is a short review of the literature on the role of Klotho in neurodegenerative disorders, with special attention paid to multiple sclerosis. The neuroprotective function of Klotho is also reported. It is also important to consider potential clinical applications of Klotho that might be useful in the treatment of many diseases. The Klotho protein was discovered in 1997 . The KloBoth in mice and humans, the Klotho gene is located on chromosome 13q12; it encompasses 50 kb and consists of 5 exons. As in the mouse gene, in the human Klotho, two transcripts encoding membrane or secretory protein are formed from one gene by alternative RNA splicing . The Klo2+ absorption by stabilizing the Ca2+ transient receptor potential vanilloid 5 (TRPV5) channel in the plasma membrane. It inhibits renal 1-alpha 25 hydroxylase activity, thus decreasing the levels of circulating calcitriol. Therefore, hyperphosphatemia, hypercalcemia, elevated plasma calcitriol, vascular calcification, and premature aging can be observed in Klotho-deficient mice [Three types of the Klotho protein are distinguished, i.e., cell membrane-related, intracellular, and secretory forms. Klotho associated with the cell membrane (transmembrane Klotho) can be detected in the kidneys, pituitary gland, inner ear, brain, parathyroid glands, pancreas, large intestine, skeletal muscles, bladder, ovaries, testes, and epithelial breast cells . The larent mice . FGF23 lent mice .Klotho has been shown to inhibit 1-α hydroxylase, an enzyme responsible for the production of 1,25-dihydroxyvitamin D3, which is an active form of vitamin D . Lower lOn the molecular level, permanent chronic inflammation, cell proliferation disorders, or cellular aging leads to the formation of a number of age-related chronic diseases, such as obesity, diabetes, atherosclerosis, Alzheimer’s disease (AD), cancer, renal diseases, or degenerative diseases . The secKlotho is produced in large amounts in the brain by ependymal cells of the choroid plexus, Purkinje EC cells, and hippocampal neurons. It is also detected in the cerebral white matter . It was Aging of the brain is related to structural atrophy of the cortex and functional deterioration, especially in the frontal and temporal regions. The process depends on genetics. Inhibition of aging was detected in mice which were carriers of one copy of the KL-VS haplotype , which is associated with longevity . YokoyamM146V, APPswe, tauP301L) and healthy animals [The neural Klotho can protect against the development of age-related neurodegenerative diseases. Masso et al. compared the levels of secreted Klotho (s-KL) in different brain regions between young and older mice and between triple transgenic 3xTg-AD models of AD  . BindingMultiple sclerosis (MS) is a chronic inflammatory disease that is identified as one of the major neurological disorders in young adults. The disease is characterized by the infiltration of autoreactive immune cells into the central nervous system, resulting in degeneration of the myelin and axons . Costa eZeldich et al.  conducte3) for 6 months and 22 patients without MS (control group). In each group, the amount of the secreted form of Klotho and the “redox status” of CSF samples were investigated (using the ELISA kit and a ferric reducing antioxidant power assay—FRAP). The amount of Klotho in the CSF in RRMS was significantly lower (233.62 pg/ml) compared to that in the control group (541.62 pg/ml)—a nearly 2.3-fold decrease in comparison to the controls. The level of the FRAP in MS patients was 1.5-fold lower than in the controls—the mean for the control group was 314.93 μM, and 211.98 μM for MS patients. Additionally, a significant negative correlation was found between Klotho concentration and the Expanded Disability Status Scale (EDSS). However, a significantly positive correlation was observed between Klotho concentration and the FRAP in the CSF. Those results indicated that a decreased level of Klotho in the CSF was related to increased disability in patients with MS. Furthermore, Klotho regulates antioxidant properties of the CSF. The antioxidant power of the CSF was significantly lower in MS patients. Those results were consistent with the hypothesis according to which Klotho exerts neuroprotective effects by modulating oxidative stress.Emami Aleagha et al. conducted another interesting study on the role of Klotho in MS . CerebroAhmadi et al.  tried toCurrently, scientists try to find a potential strategy to increase the level of Klotho in the brain. The administration of exogenous Klotho is limited by the protein weight (130 kDa)—such a large protein cannot cross the blood-brain barrier. Another way is to find molecules that act as Klotho mimetics which could enhance DNA transcription and translation and reduce Klotho degradation. Abraham et al. initiated a program to identify small molecules that could increase Klotho at the transcriptional level . Two comLatanoprost (LA) is an ocular hypotensive agent used in the treatment of glaucoma targeting prostaglandin F2α (FP) receptor. The study of Yamamoto et al. demonstrated that a neuroprotective effect of LA is due to the Klotho-mediated suppression of calpain activation . It was Klotho is highly expressed in the brain. Many studies have demonstrated a neuroprotective role of Klotho. In the human brain, the secreted isoform of the Klotho protein plays a crucial role in neuronal activity, which is the key to aging and neurodegenerative processes. Due to activation of OPCs, soluble Klotho could be used as a therapeutic strategy for brain tissue regeneration. As a cofactor that modulates affinity for various receptors, Klotho regulates calcium homeostasis and oxidative stress. In the CSF, Klotho can participate in the suppression of cytokine/chemokine expression in the central nervous system, supporting the activation of neuronal cells. From a clinical point of view, the Klotho level in the CSF can be used as a biomarker of MS severity. Although it is still not known why Klotho suppresses aging, maintaining Klotho levels by stimulating endogenous Klotho production or administering exogenous Klotho protein may be a potential therapeutic target to slow down the aging process and reduce the incidence of age-related diseases. Finally, as a regulator of remyelination in the white matter, Klotho can become a new therapeutic substance for MS and other demyelinating and neurodegenerative diseases.


N = 80; SUD with comorbid schizophrenia or major depressive disorder), SUD only (N = 80), and SMI only . MANCOVA analyses reflected differences in self-criticism and problem avoidance, with a higher use of these in the DD and SUD groups. The coping strategies used differed depending on the presence/absence of a SUD, but not depending on psychiatric diagnosis. At one-year follow-up, social support was the only strategy that predicted the presence of relapses in DD patients with schizophrenia (positively), and in SMI patients with major depressive disorder (negatively). Thus, social support was associated with relapses, but the relationship was different depending on psychiatric diagnosis. Further studies should analyze the implications of social support as a coping strategy in different mental disorders, as well as its usefulness in individualized interventions.Coping strategies have an impact on substance use disorders (SUD), relapses, and clinical variables, but knowledge on this area is scarce. We explored the coping strategies used during treatment in patients with dual diagnosis (DD), SUD, and severe mental illness (SMI), and the relation with clinical course and relapses at one-year follow-up. A sample of 223 patients was divided into three groups depending on diagnosis: DD ( During recent years, scientific interest in how people cope with stress and adversity has increased significantly, since coping strategies are known to have an influence on the differences observed among people under stress, and have proven their importance as a stabilizing factor, facilitating individual adjustment and leading to better health ,2,3. Coping strategies are understood as specific actions that individuals use in order to manage, change, and/or reduce the consequences of exposition to stressors ,5. It isOne of the main areas of study regarding coping strategies is their relationship with substance use disorders (SUD), since the use of adaptive strategies during stressful situations or events is a key factor in how individuals respond and their possible substance use . When coFurthermore, numerous studies have confirmed the high comorbidity between SUD and severe mental illness (SMI). This condition, commonly known as dual diagnosis (DD), is especially observed among patients with major depressive disorder and schizophrenia spectrum disorders. In this context, up to 50% of patients with such psychopathologies are also diagnosed with a comorbid SUD ,17. DD iDespite the strong relationship between SUD and coping, and the clinical implications on the strategies used by patients to cope with stressful events, very few studies have explored coping strategies in DD patients, and even fewer have considered the type of SMI diagnosed. Available studies show how DD patients with schizophrenia or major depression disorder tend to use more maladaptive coping when compared to patients with only a SUD diagnosis ,29,30. WMoreover, in both DD and SMI patients with major depressive disorder or schizophrenia, training and encouraging the use of coping strategies oriented to problem solving and emotional regulation is associated with a decrease in drug abuse and suicidal attempts ,35, imprConsidering the insufficient knowledge on the use of coping strategies in patients with DD, we decided to examine whether there were any differences in the use of such strategies among our SUD, DD, and SMI groups, given that DD and SMI are the two most prevalent psychiatric diagnoses in SUD patients. We then compared the results with the Spanish normative data, to check whether our groups were within the norm. Additionally, we explored if any of the strategies considered had a predictive value on patients’ relapses within a one-year follow-up, since relapses are one of the main problems in the recovery of DD patients ,28,40,41N = 80), SUD (N = 80), and SMI (N = 63). The DD group had 37 patients with schizophrenia (46.3%) and 43 with major depressive disorder (53.7%), and the SMI group had 32 patients with schizophrenia (50.8%) and 31 with major depressive disorder (49.2%). Our study is a multicenter research, with participants from different public and private clinical centers specialized in SMI and SUD treatments. All patients were in therapeutic programs for their corresponding diagnoses and had obtained negative results in all their abstinence urine analyses. The total sample consisted of 223 voluntary male patients, assigned to three groups according to their clinical diagnoses: DD group (Our inclusion criteria were: (1) Male gender ; (2) aged 19 to 55 years; (3) currently under treatment for their mental disorders, but in a clinically stable condition; (4) the diagnoses of major depressive disorder or schizophrenia in the DD and SMI groups had been established according to DSM-5 criteria ; (5) a cPatients were referred to our study from their respective treatment centers by their treating psychiatrists or psychologists, who followed our inclusion/exclusion criteria for referral. Once the participants agreed to be subjects in our study, they were provided and signed an informed consent. Then, a postgraduate psychologist from our research group conducted the assessment protocol of our study in two sessions. The participants were not compensated for their participation and the only benefit they obtained was a report of their results. The assessment protocol was approved by the Research Committee of the University of Barcelona (IRB00003099) and is part of a wider research project. The present study complied with the tenets of the Declaration of Helsinki.For the follow-up, the same postgraduate psychologist visited each treatment center at 3, 6, and 12 months to collect the questionnaires completed by each patient in the sample. The follow-up data were collected using a structured 21-item questionnaire, specifically designed for our study. The main variables registered were relapses (presence/absence), patients’ treatment status, suicide attempts (yes/no), and number of medical consultations (outside the patients’ main treatment facilities) during the follow-up period. A structured interview specifically designed for the present study was conducted with each patient to assess variables such as age, civil status, years of schooling, social situation, and living arrangements, among others. This interview was also employed to collect data on diagnosis according to DSM-5 criteria, personal/family psychiatric and medical records, history of suicide attempts, and SMI/SUD age of onset. In addition, the structured clinical interview for DSM-IV-TR Axis I Disorders (SCID-I)  was admiThe drug abuse screening test (DAST-20)  was usedRegarding psychiatric symptoms, the schizophrenia patients in the DD and SMI groups were administered the positive and negative syndrome scale  . The PANCoping strategies were assessed through the coping strategies inventory (CSI)  in its SThe four secondary scales are: Problem engagement, emotion engagement, problem disengagement, and emotion disengagement. The two tertiary scales are engagement and disengagement Whereas in the Spanish version of the CSI, the scores from the primary scales can be transformed into percentiles, the secondary and tertiary scales did not show strong psychometric properties, and there are no normative data for them , so the Descriptive statistics  were obtained for the sociodemographic and clinical variables, and differences in such variables among groups were explored by univariate analyses of variance (ANOVA) for continuous data. Nonparametric tests were conducted, including Chi-Square, Kruskal–Wallis, and Mann–Whitney tests, depending on the type of variable analyzed. Multivariate analyses of covariance (MANCOVA) were performed introducing the primary scales of the CSI as dependent variables, and the group  as the independent variable, in order to detect differences in the strategies used by the three groups. Post-hoc comparisons were adjusted by Bonferroni’s correction. Other MANCOVA analyses were carried out to compare the results in each group according to their psychiatric diagnoses (DD and SMI), and to elucidate the role of schizophrenia and major depressive disorder in them. In all the variance analyses, age was considered as a covariate to control its possible effect, given that our groups differed significantly in this variable, the SMI patients being older on average. The coping strategies used in each group were also compared, using the Spanish normative data available for the primary scales of the CSI . pη2 was obtained as a measure of the effect size, the cut-off points being 0.01 , 0.04 (medium), and 0.1 (large) [We also explored the differences in coping regarding addiction relapses during the 12-month follow-up period with MANCOVA analyses. The independent variables were diagnosis group and presence/absence of relapses at one-year follow-up, the dependent variables were the primary coping scales, and age was a covariate. The possible inter-group differences for coping strategies in the DD and SMI groups were also explored, according to psychiatric diagnosis and relapses at one-year follow-up. In all the MANCOVA analyses, the partial eta square  (large) . Finally, logistic regression models were applied to determine possible predictors of the results in each group for the one-year follow-up. Logistic regression coefficients and their standard errors were back-transformed to generate odds-ratios (ORs) and their 95% confidence intervals. All statistical analyses were carried out using the SPSS/PC+ statistics package , and tests were two-tailed with the type I error set at 5%. p = 0.004), civil status (p = 0.008), living arrangements (p = 0.006), and employment situation (p = 0.015). The SMI group had an older mean age, and more SMI patients were living with friends or in protected flats. Having a disability pension was associated with DD and SMI diagnoses (>60%), while being employed was associated with a single diagnosis of SUD. Sociodemographic data for the three groups are shown in p = 0.023), and also in the onset age of SMI, with the DD patients being younger at first diagnosis of SMI, on average (p = 0.030). However, the duration of the SUD and the SMI did not show significant differences between the two groups. In addition, the SUD patients were less likely to be using psychiatric medication (p = 0.007) and had a lower medical disease comorbidity rate (p = 0.022) than the DD and SMI patients. Regarding clinical data see , there wp = 0.040). Finally, no differences in the HDRS results were observed for those patients with major depressive disorder. The DD and SUD groups showed no differences in severity of addiction regarding the scores in the DAST-20 or the months of abstinence. The most prevalent substances of abuse were cocaine and alcohol, with a high rate of polydrug use (up to 56%) in both groups. However, there were differences in the composite scale of PANSS for those patients with schizophrenia, depending on whether they were in the DD or the SMI group. In this sense, the SMI patients showed a higher predominance of negative symptoms than the DD patients (p < 0.001), and lower scores in problem avoidance (p < 0.001), when compared to the SMI group. In contrast, no differences in the coping scales were found between the DD and SMI groups regarding psychiatric diagnosis (schizophrenia or major depressive disorder), or regarding the presence or absence of SUD .CSI scale scores in the DD, SUD, and SMI groups, and the comparisons among them, are shown in When considering the Spanish normative data, an analysis of percentiles see  showed tComparisons among the three groups detected differences regarding addiction relapses at 3, 6, and 12 months see , their pp = 0.035) and 12 months (p = 0.008), with the SMI patients also being more likely to be discharged from treatment. In addition, suicide attempts did not differ among the groups at three months, but they showed differences at 6 (p = 0.040) and 12 months (p = 0.007). At six months follow-up, a higher rate of suicide attempts was observed in the DD and SUD groups. SUD and SMI patients showed similar rates, although the highest was observed in the DD group at 2 months, especially for those patients with major depressive disorder. Overall, 21.8% of the DD patients had one suicide attempt at one-year follow-up. Regarding the patients’ treatment status, we did not observe any differences at three months follow-up. However, the DD and SMI patients were more likely to be still in treatment than those with SUD at 6 (p < 0.001), the SUD group showed the lowest quantity , with the SMI group being in the middle position.Finally, in all the follow-up periods, the DD group presented the highest number of medical consultations outside their main treatment facilities  = 3.258; 2ηp = 0.033; p = 0.041), with a lower score in those DD patients who had suffered relapses. With respect to relapses, no other differences in coping were observed among the DD, SUD, and SMI groups at one-year follow-up. MANCOVA analyses were performed to explore the possible differences in coping strategies in the DD, SUD, and SMI groups at one-year follow-up in relation to the presence/absence of relapses. The results revealed differences in social support  = 4.356; 2ηp = 0.059; p = 0.041) and social withdrawal  = 10.206; 2ηp = 0.127; p = 0.002). The DD patients with schizophrenia who had suffered relapses (14.82 ± 1.91) obtained a higher score in self-criticism. In contrast, in the DD patients with major depressive disorder, a higher score in self-criticism was obtained by those who had not relapsed (14.75 ± 1.12). Furthermore, for social withdrawal, patients with schizophrenia who had relapsed (14.48 ± 1.38) obtained a higher score, whereas in the major depressive disorder patients, a higher score was obtained by those who did not relapse at one-year follow-up (12.10 ± 1.07).When the coping strategies in the DD group were further analyzed, considering relapses at one-year follow-up and psychiatric diagnosis, differences were found in self-criticism  = 12.079; 2ηp = 0.175; p = 0.001), with a lower score for schizophrenia patients with relapses (8.85 ± 1.84), while in the major depressive disorder patients, the lower score in social support was obtained by those who had not relapsed (9.24 ± 0.99).The analysis of strategies in the SMI group, considering relapses at one-year follow-up and psychiatric diagnosis, yielded differences in social support . In contrast, the relationship between this strategy and relapses was not significant (p = 0.750) for the DD patients with major depressive disorder at one-year follow-up. Furthermore, in the SMI group, social support was positively associated with relapses in those patients with major depressive disorder , whereas this strategy was not a significant predictor of relapses for those patients with schizophrenia in the SMI group (p = 0.613).When exploring the predictive value of social support in relapses for the DD group, a negative association was found in the schizophrenia patients .Regarding the other clinical variables, the coping strategies analyzed in our study did not function as significant predictors of the patients’ treatment situation , suicide attempts, or number of medical consultations at any follow-up period  when facing problems, in contrast with patients with SMI only. This observation is in line with previous findings  and coulThe comparison with the Spanish normative data for the coping strategies pointed out that, independently from the diagnostic group, when coping with stress all patients tend to use self-criticism (self-blame and guilt), wishful thinking , and social withdrawal . Thus, patients with DD, SUD, and SMI may be using disengagement strategies that are associated with unsuccessful ways of coping ,15,29, wFurthermore, the analyses of our data at 3, 6, and 12-month follow-up provided interesting results in relation to possible differences among the DD, SUD, and SMI groups when taking into account the presence of SUD and/or SMI. Consistent with previous research ,22,23, wWe also explored the possible influence of coping among the DD, SUD, and SMI groups at one-year follow-up, taking into account the presence of relapses. The results showed that the use of the social support strategy was lower in those DD patients who had suffered relapses; that is, these patients presented a less frequent use of seeking people’s support as a coping strategy. Thus, having two comorbid conditions like SUD and schizophrenia, or like SUD and major depressive disorder, seems to pose notable difficulties in asking for support, or in preserving a strong social network that would give such support when needed ,33,34,36When we further analyzed the strategies used by DD patients, together with relapses and psychiatric diagnosis, we observed differences in their tendency to experience self-blame and guilt (self-criticism), and to isolate from others . These two strategies seemed to play a different role depending on the psychiatric diagnosis of the DD patients, since those with schizophrenia who had suffered relapses showed a higher use of self-criticism and social withdrawal, whereas a higher use of these strategies was observed in those with major depression disorder but no relapses. Our results for DD patients with schizophrenia are in line with previous data ,33,35, wFor SMI patients, social support was the only strategy that presented differences when taking into account psychiatric diagnosis and relapses at one-year follow-up. SMI patients with schizophrenia who had suffered relapses showed a lesser use of asking for help as a coping strategy, while those with major depressive disorder who had not suffered any relapses also presented a lesser use of this strategy. Thus, this is the first work presenting data about social support as a coping strategy that might have a different impact on how patients deal with problems depending on whether they have schizophrenia or major depressive disorder. Our findings support the idea of working towards a precision model in psychiatry , which cWhen we explored the strategies and their predictive value for relapses at one-year follow-up, we found that social support was linked to relapses in patients with DD and SMI, but not in patients with SUD only. Social support seemed to have a protective value for those DD patients with schizophrenia, but not for those DD patients with major depression disorder. This result is not consistent with previous data pointing out that social support is related to a better mental health ,3, and sOur study has a few strengths and some potential limitations. One strong point is the fact that we present follow-up data up to one year for a large sample of patients with DD, SUD, and SMI, and we associate these data with the strategies used by these patients. Our results also point out that, although social support has been considered traditionally as a strategy to prevent relapses, its effect may not be positive in all DD or in SMI patients. As potential limitations, we measured coping using a self-reported questionnaire, only once and not during follow-up periods, so we cannot compare whether gaining months of abstinence or being under treatment changes the coping strategies used by each diagnostic group. In addition, only male patients were included in our sample, and the age range was considerable. Moreover, the fact that all the patients were included in our study under the condition of being clinically stable, in order to prevent their participation from interfering in their therapeutic process, limits the clinical applicability of our findings. Future studies should consider these limitations in order to advance our knowledge in this area, and to provide clinicians with relevant data to improve treatment in relapse prevention programs. To our knowledge, this is the first study that compares coping strategies in patients with DD, SUD, and SMI, including the two most prevalent comorbid disorders (schizophrenia and major depressive disorder). It also considers how coping may differ among these groups and how some strategies might influence the presence of relapses at one-year follow-up. More specifically, the strategies of self-criticism and problem avoidance were used differently among the three groups depending on the presence of an addictive disorder, but not depending on the psychiatric condition. Thus, the SUD and DD groups showed a higher use of these strategies than the SMI patients did. Regarding the treatment of addictions, some clinical implications of these findings are the need to tailor treatment programs to reduce such disengagement strategies, and to train patients in coping that leads to an active problem-solving approach. Thus, treatment for SUD could include sessions following the solution-focused therapy model or the problem-solving therapy model, which are compatible with the approaches most currently used in addiction treatment.Overall, when referring to the follow-up data, the DD group presented the type of clinical complications  previously associated with poorer prognosis and treatment outcomes. Moreover, taking into account the follow-up data for relapses at one year, we observed that only the strategy of social support had a predictive value. The protective effect of this strategy seems to be mediated by the presence/absence of SUD, as well as by the type of SMI (schizophrenia or major depressive disorder), with benefits only for those patients with SUD and comorbid schizophrenia. Regarding the other diagnoses studied here, treatment and follow-up programs in clinical practice may consider that promoting social support will not always be a therapeutic approach for patients to cope with stressors in the early remission phase, especially for those with major depressive disorder. Future studies should consider our findings to improve available knowledge in this area, in order to design more precise and effective therapeutic interventions and relapse prevention programs.


The relationship of religious affiliation and mental health is complex, and being part of a minority religious group could have negative effects on mental health. In this study, we assessed the association between religious affiliation and major depressive episode (MDE) in older adults (> = 60 years) from China, Ghana, India, Mexico, Russia and South Africa.n = 21,410). Religious affiliation was self-reported by participants, and we defined MDE based on ICD-10 classification. We estimated the association of MDE with religious affiliation versus no religious affiliation, and minority versus majority affiliation.We conducted a secondary analysis of data from the Study on global Ageing and adult health (SAGE), with six nationally-representative community-based samples (We observed no association between having a religious affiliation (vs. no affiliation) and the odds of MDE in older adults. In most cases minorities had higher odds of MDE as compared with the majority religion, but the associations were only significant for Muslims in Ghana and for Muslims, Hindus and Other in South Africa.While the results were significant only for two countries, we observed higher odds of MDE among minorities in most of them. Older adults who are members of religious minorities might be at risk for mental health problems, and there is a need for public health interventions aimed at them.The online version of this article (10.1186/s12889-019-6806-1) contains supplementary material, which is available to authorized users. A major depressive episode (MDE) is characterized by a combination of depressive symptoms and significant distress or impairment in social life . MDE is The etiology of major depressive disorder includes the interactions of diverse biological, psychological and social factors , of whicHowever, the relationship between religion and depression is complex, with differing associations depending on which indicator of religious involvement is measured. As an example, in one study feeling that one received guidance from religion was associated with lower odds of developing depression, but religious attendance was not . Other sThe potential protective effect of religion on mental health might be due to an increase in social networks and social contact through participation in church activities , and to One religion-related aspect that might be associated with mental health is the experience of being a member of a religious minority (defined as a religion with less members than others in a given country)  The healIn this article, we investigate the association between religious affiliation (RA) and MDE in older adults in six lower- and middle-income countries: China, Ghana, India, Mexico, Russia and South Africa. The countries were part of the Study on global AGEing and adult health (SAGE), and together they represent a variety of politic and economic contexts, and are also diverse in terms of the current state and historical evolution of religious faiths. In China, the majority of the population declare having no religious affiliation. There are no major inter-faith conflicts, but Tibetan Buddhists and Muslim groups have clashed with the government. In Ghana, Christians are the religious majority, and there are some tensions between them and the Muslim minority. In India, the relationship between the Hindu majority and Muslims has been difficult and even violent at some points, and Muslims have been victims of discrimination by the government. In Mexico, the relationship between members of the Catholic majority and religious minorities  is mostly peaceful, with some violent conflicts over land ownership between Catholics and Evangelical Christian groups in rural areas. In Russia, since the end of the Soviet Union, Orthodox Christianism returned to a prominent position as the main religion in the country. Finally, in South Africa Christianism is the majority religion, with few interfaith conflicts in the recent past.The objectives of this analysis were: 1) To explore the association between RA and MDE, with the hypothesis that having a RA, versus having no RA, would be protective for mental health; 2) To explore the association between minority RA and MDE, with the hypothesis that having a minority RA, versus having a majority RA, would be a risk factor for mental health problems.n = 21,410). The SAGE sampling design included various sampling stages, and was stratified, designed to be representative at the national level for each country included. The ultimate sampling unit were households. All household members aged 50 years or older, and one randomly selected member 18–49 years of age, responded the study questionnaire. The cognitive status of older adults was evaluated by interviewers before applying the questionnaire. When a cognitive impairment was identified, a proxy respondent was utilized and depressive symptoms were not fully evaluated (the proxy respondent only answered if the older adult had been sad). Cognitive limitations were identified in 1.8% of the sample. For this analysis, only questionnaires responded by the older adult him/herself were employed. All data collection procedures were standardized, and staff was previously trained to conduct procedures. Wave 0 of SAGE corresponded to the World Health Survey of 2002–2004 [Data came from the first wave of SAGE, conducted in 2007–2010, with a sample of 34,124 participants 50 years old or older, and 8340 participants between 18 and 49 years old. The study included six low- and middle-income countries: China, Ghana, India, Mexico, the Russian Federation and South Africa. In this article, we analyze data from older adult participants (aged 60 or older )  a household questionnaire for information about household chores distribution, house conditions and household socioeconomic position; 2) an individual questionnaire inquiring about health and health determinants, disability, work history, chronic conditions, risk factors, health services response, caregivers and subjective wellbeing; 3) a proxy-respondent questionnaire for health, functional status, chronic conditions and health services utilization; and 4) a module of verbal autopsy to determine probable cause of death of members of the household during the previous 24 months. The questionnaires were developed for SAGE, and are available in the World Health Organization’s web page at The questionnaire of SAGE included an abbreviated version of the World Mental Health Survey version of the Composite International Diagnostic Interview (WMH-CIDI), which asks about history of depressive episodes in the last year, as well as depressive symptoms in the last two weeks. We followed an algorithm developed and previously used by the SAGE team  that comThe main independent variable was religious affiliation, assessed in the SAGE questionnaire by the question “Do you belong to a religious denomination?” The response categories were: unaffiliated, Buddhist, Traditional Chinese Religion, Christian, Hindu, Muslim, Jewish, Indigenous, Sikh, Other. For this analysis, we kept the categories unaffiliated, Buddhist, Christian, Hindu and Muslim, and grouped the rest as “Other” (a category that comprised less than 0.5% in each country). While there is no general agreed-upon definition of what a minority is, a rough definition might be that minorities are social groups that are numerically inferior to others in a given country . For thiThe models were adjusted by variables related to both religious affiliation and MDE, including sociodemographic, household, health conditions and social networks variables.The sociodemographic variables were gender, age , living with a partner (either by marriage or de facto), educational attainment , and having health insurance coverage.We also considered socioeconomic position, defined as the relative position in household wealth. We used the methodology previously described by Fernández-Niño et al. , computiHealth-related variables included multimorbidity and physical disability. As in a previous work , we compFinally, we included three variables, each one representing a different domain of social networks: 1) not living alone; 2) participation in non-religious social activities ; and 3) having someone to trust. All of the above variables were dichotomic (yes = 1 and no =0).We conducted exploratory analyses with central tendency (mean or median) and dispersion measures (standard deviation and interquartile range) for quantitative variables, and proportions and confidence intervals at the 95% level (CI 95%) for categorical variables. We estimated the standardized prevalence rate of MDE with the direct method, using as population of reference the world population provided by the World Health Organization . We condp-values. We estimated two models: one comparing the unaffiliated vs each religious affiliation, and another comparing the majority religion for each country vs the other religious affiliations and the unaffiliated.To estimate the association of religious affiliation and MDE we employed logistic regression models, and report the results as odds ratios (OR) and their respective CI 95% and All analyses considered the complex sampling design, and were done with Stata 14 .All participants in SAGE signed and informed consent. Approval for the SAGE study was obtained from institutional review boards in each participant country, and endorsed by the World Health Organization’s committee. This article presents the results of a secondary analysis of data from that study. The information collected by wave 1 of the SAGE study is public. Authorization from SAGE was obtained for the present analysis via the internet.Women comprised 53.8% of the study sample. The mean age of the study sample was 69.9 (SD = 7.6) years, with most participants in the 60–69 years range. As for educational attainment, 33.9% of participants reported no formal education, 33.7% had primary education or less, 25.7% had secondary education, and 6.7% had some college education or more. In Table In the sample as a whole, the majority of participants (37.7%) reported having no religious affiliation. The next more frequent affiliation was Christian 27.1%) followed by Hindu (16.5%). However, these unadjusted percentages have no straightforward interpretation, as the sample from China (where most participants were unaffiliated) was larger than the others and therefore descriptive statistics for the whole sample are mainly reflective of that sample. Table 7.1% follThe 12-month prevalence of MDE was 6.5% (CI 95% 6.2–6.9) for the whole sample, 7. 5% (CI 95% 7.0–8.0) among women and 5.4% (CI 95% 4.9–5.9) among men. The prevalence of MDE by country and religious affiliation appears in Table The crude logistic regression model for the whole sample . Likewise, the “Other” category in South Africa might have been a very different mixture than the same category in other countries. A more precise investigation of the subject should consider all of these aspects.A limitation of our study was the cross-sectional design, as the association of religious affiliation and mental health could theoretically go in both directions. Another limitation was that religious affiliation is only one aspect of religion, and doesn’t necessarily indicate spirituality, the importance attributed to religious beliefs, and other elements that the literature has reported as related to depression. Using a variety of measures of religion-related aspects might have changed our results, especially if those aspects are associated with being part of a religious minority. However, with the current data it is difficult to hypothesize in which direction the results would have changed. Also, the percentage of the population affiliated with some denominations is very low for some countries, resulting in zero or a small number of respondents for some combinations of category-country, so that the analysis of the association of specific denominations and MDE might be non-significant due to lack of power. Finally, MDE is an extreme of the continuum between emotional well-being and disorder, so that our results apply to what could be considered the graver cases of depression.To conclude, our results suggest an association between minority religion membership and MDE. This finding is important for public health, as it points to a social source of health inequity that could be addressed through public policies protecting minorities. To our knowledge, this is the first study to explore this issue in a sample of older adults from diverse sociocultural contexts. Older adults who are members of religious minorities might be at risk for mental health problems, and there is a need for public health interventions aimed at them.Additional file 1:Table S1. Characteristics of participants by religious affiliation, SAGE round one. Table S2. Characteristics of participants by religious affiliation, SAGE round one. (DOCX 20 kb)


In the stroma nearby the tumor mass we were able to demonstrate the presence of virus DNA in the stromal compartment, supporting its potential to be transferred from epithelial cells to the stromal ones. Thus, this case report favors the notion that human papillomavirus DNA can be vehiculated by exosomes in the blood of neoplastic patients and that it can be transferred, at least in vitro, to normal and neoplastic cells. Furthermore, we showed the presence of viral DNA and RNA in pluripotent stem cells of non-tumor tissue, suggesting that after viral integration (as demonstrated by p16 and RNA in situ hybridization positivity), stem cells might have been activated into cancer stem cells inducing neoplastic transformation of normal tissue through the inactivation of p53, p21, and Rb. It is conceivable that the virus has elicited its oncogenic effect in this specific site and not elsewhere, despite its wide anatomical distribution in the patient, for a local condition of immune suppression, as demonstrated by the increase of T-regulatory (CD4/CD25/FOXP3 positive) and T-exhausted (CD8/PD-1positive) lymphocytes and the M2 polarization (high CD163/CD68 ratio) of macrophages in the neoplastic microenvironment. It is noteworthy that our findings depicted a static picture of a long-lasting dynamic process that might evolve in the development of tumors in other anatomical sites.Here we present the case of a patient affected by rectal squamous cell carcinoma in which we demonstrated the presence of Human Papillomavirus (HPV) by a variety of techniques. Collectively, the virus was detected not only in the tumor but also in some regional lymph nodes and in non-neoplastic mucosa of the upper tract of large bowel. By contrast, it was not identifiable in its common sites of entry, namely oral and ano-genital region. We also found HPV DNA in the plasma-derived exosome. Next, by  Human papillomavirus (HPV) DNA has been detected in a variety of cancer, including colorectal cancer (CRC) –4. ThrouWhile there is a strong association between HPV and squamous cell carcinoma of some sites , the putative role of the virus in colorectal carcinogenesis still remains controversial . Detectiper 1,000 CRC; its diagnosis is based on the restrictive criteria given by Williams et al. , and RNA in situ hybridization (ISH) for E6/E7 viral oncogenes mRNA in neoplastic and non-neoplastic tissues, including lymph nodes and sites far from the rectum. We also found HPV DNA in the plasma-derived from the patient, and by in vitro studies, we confirmed the capability of HPV DNA positive exosomes to transfer its DNA to recipient cells.Here we present the case of a patient affected by rectal SCC in which we demonstrated HPV by immunohistochemistry, polymerase chain reaction (PCR), chromogenic A 53 years-old caucasian man presented to our hospital complaining of sub-occlusive syndrome that lasted for 1 week. Family and medical history was unremarkable. Physical examination including digital rectal examination was negative. Colonoscopy showed a 5.0 × 4.5 × 4 cm lesion, 10 cm from the anal verge. The lesion was ulcerated and bleeding, it narrows the lumen and renders difficult to be overcome. Computed tomography (CT)-scan identified a heteroplastic and locally advanced lesion with enlarged lymph nodes (the greatest measuring 13 mm in maximum diameter) along the sigmoid chain. Neither pulmonary, hepatic, splenic localizations nor pleural or peritoneal effusions were identified. An anterior resection of the rectum and regional lymph nodes was performed without colostomy. Postoperatively, the patient underwent adjuvant radiotherapy of 45 Gy delivered to the pelvis in 25 fractions over 5 weeks. To date, after 60 months follow-up, the patient is alive and in good conditions, with no evidence of recurrence. Ethics approval for this study was obtained from the Institutional Review Board at the University of Siena  and written informed consent was obtained from the patient for the publication of this case report and any potentially-identifying information/images.Grossly, an exophytic ulcerative mass with predominantly intraluminal growth and narrowing of the lumen was identified. The lesion measured 5.0 × 4.0 × 3.5 cm and extended throughout the muscular layer but without mesorectal involvement in the extraperitoneal tract of the specimen. On cut section, the mass had a relatively homogeneous appearance with focal areas of necrosis and hemorrhages. Microscopic examination demonstrated a moderately differentiated squamous cell carcinoma with basaloid features and koilocyte-like cells , inset. E6/E7 mRNA transcripts   and RNA ISH for , Italy) .By IHC for p16, a useful surrogate biomarker of HPV integration and E7 over-expression  and in spunctated” pattern with distinct multiple dot-like intranuclear signals by CISH  as well as at distant sites (ascending/descending colon). It is reasonable that HPV penetrated in the host by one of the known site of entry. Following, the virus disappeared from the original site thanks to clearing mechanisms (that are highly active during the early phase of HPV infection) and it was no more detectable there (Previous studies on cervical, oropharingeal, and breast diseases demonstrated the presence of circulating HPV DNA in the blood of affected patients , 32–35. le there –16. It ile there  charactele there –19, 37 ale there . Notablyle there , 40. It le there , non-canle there –44. Due Although important studies have been made for the understanding of HPV tumorigenicity in non-genital cancers, significant questions still remain. Our case-study seems to highlight the direct relationship of HPV with the pathogenesis of a squamous cell CRC; however, further studies including case control and cohort studies are necessary to evidence the causal link between HPV infection and colon cancer. The presence of HPV DNA positive plasma-derived exosomes in our patient shed important light on poorly understood mechanisms of HPV DNA horizontal transfer and on unconventional route of HPV spreading and carcinogenesis. It is noteworthy that HPV-induced cancerogenesis has a long-lasting history and our findings depicted only a static picture of a dynamic process for which we cannot exclude the development of cancers in other anatomic sites of the patient after viral spreading and DNA integration.MRA, MC, and SL conceived and developed the study. LM, SDC, AC, AG, and BJR performed experiments. MC, MRA, SL, and SDC analyzed data. RV, ALF, TC, and VN collected and provided patient samples. MC, SL, MRA, and PT wrote the paper. PT provided his experience in fruitful discussion. All the authors discussed the results and commented on the manuscript.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.