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Measurement of inflammatory mediators of mast cells and eosinophils in native nasal lavage fluid in nasal polyposis.

BACKGROUND: Nasal polyposis (NP) often coexists with asthma, rhinitis and sinusitis. Polyp histology typically shows chronic, eosinophilic inflammation. The inflammatory cell infiltrate generally includes eosinophils, lymphocytes, plasma cells and mast cells. OBJECTIVE: To gain insight into the natural history of NP, we analysed mediator levels and leukocyte values in nasal fluids and eosinophil cationic protein (ECP), total IgE levels and eosinophils in the blood in several groups of both allergic and non-allergic patients with nasal polyps and in patients with allergic rhinitis (AR). METHODS: Thirty-two patients with nasal polyps entered the study. As a control group, we studied 55 patients with AR, i.e. 20 patients with seasonal AR to grass pollen, 24 with AR sensitive to Parietaria and 11 with AR sensitive to house dust mite (HDM). Eighteen patients with nasal polyps were also allergic patients (8 were sensitive to Parietaria and 10 were sensitive to HDM), whereas 14 were non-allergic patients. Tryptase and histamine values were assayed in nasal fluids, whereas total IgE was determined in serum. ECP values were assayed both in nasal fluids and serum. Eosinophils were quantified both in the blood and nasal fluids. RESULTS: Tryptase levels were significantly higher in the nasal lavages from patients with NP than in those from patients without NP (4.7 vs. 3.5 U/l, p < 0.001) and correlated with symptom scores (r(s) = 0.42, p < 0.0001). The median levels of histamine in nasal fluids from patients with NP were also significantly higher than those observed in patients without NP (50.0 vs. 21.3 ng/ml, p < 0.001), but did not correlate with symptom scores. Finally, the median levels of ECP in nasal fluids from patients with NP were significantly higher than those observed in patients without NP (38.1 vs. 16.1 ng/ml, p < 0.001) and correlated with symptom scores (r(s) = 0.38, p < 0.001). Analysis of variance showed that, among the variables studied, the presence of nasal polyps was the factor responsible for the higher levels of tryptase, histamine and ECP in nasal fluids. With regard to leukocyte counts in nasal fluids, no significant differences were observed between rhinitis patients with NP and those without NP. With regard to serum ECP and serum total IgE, no significant differences were detected between the two groups under study. Blood eosinophil levels in patients with NP were significantly higher than those observed in patients without NP (5.8 vs. 5.6, p = 0.002). Analysis of variance showed that both the presence of nasal polyps and the type of sensitisation were important. Considering the total symptom scores, no significant differences were observed between rhinitis patients with NP and those without NP. CONCLUSIONS: The present findings are consistent with the view that chronic eosinophil mucosal inflammatory disease in NP involves a self-sustaining mechanism, i.e. local release of inflammatory mediators, independent of allergen stimulation of nasal mucosa. Increased release of inflammatory mediators contributes to the development of nasal polyps, determining oedema and an increased recruitment of inflammatory cells. Besides eosinophils, mast cells also play a key role in this process.

Adolescent↗

Impulsivity and smoking relapse.

Previous research has shown that elevated trait-impulsivity heightens the risk for initiating tobacco use and indicates that nicotine may be disproportionately rewarding for more impulsive persons. However, the influence of impulsivity on the ability to maintain nicotine abstinence has not been studied. The present study tested the hypothesis that a higher level of trait-impulsivity would predict a more rapid relapse to smoking following 48 hr of nicotine abstinence. Participants were euthymic, regular smokers (N=45), with a history of at least one major depressive episode, who participated in a paid smoking cessation study with biological challenge (tryptophan depletion). Treatment involved a 1-day skills training workshop followed by 48 hr of bioverified abstinence and weekly follow-up for 1 month. Regression analyses indicated that elevated impulsivity predicted shorter time to relapse following the workshop after controlling for treatment condition, baseline nicotine dependence, and age (beta=-.39, R(2) change=.147, p=.011). Greater impulsivity predicted more rapid relapse to smoking, which mediational analyses indicated could not be explained by positive affect, negative affect, or craving. Findings suggest a need to identify alternative mechanisms to explain impulsive smokers' increased difficulty in maintaining abstinence and to develop targeted treatments that address the special needs of smokers high in impulsivity.

Adolescent↗

History of affective disorder and the experience of fatigue in rheumatoid arthritis.

OBJECTIVE: To evaluate how a prior affective disorder (major depression or generalized anxiety disorder) affects current fatigue among individuals with rheumatoid arthritis (RA). To determine whether that relationship is mediated by self-efficacy expectations. METHODS: Forty-eight RA patients with a prior affective disorder and 74 without a history of affective disorder completed a mailed questionnaire that included the Multidimensional Assessment of Fatigue and indicators of neuroticism and self efficacy. RESULTS: RA patients with a history of affective disorder reported higher levels of fatigue than those with no previous affective disturbance. Controlling for neuroticism and self efficacy, affective disorder history continued to predict current fatigue. Mediational analyses revealed both direct and indirect effects (via self efficacy) of history of affective disorder on the experience of fatigue in RA. CONCLUSION: History of affective disorder independently predicts higher levels of fatigue in RA patients, and self efficacy plays a mediating role in this relationship.

Aged↗

Motives for drinking, alcohol consumption, and alcohol-related problems among British secondary-school and university students.

Relationships among reasons for drinking, alcohol consumption, and drinking-related problems were assessed among secondary-school students (N=328) and university students (N=74) in North Wales, United Kingdom, and results were compared with results from North America. The ability of drinking reasons to predict drinking problems was tested in both age groups. Khavari Alcohol Test, Quantity-Frequency-Variability Index, Reasons for Drinking Questionnaire, and Rutgers Alcohol Problems Index were used to measure the variables of interest. Regression and mediational analyses indicated that negative reasons were stronger predictors of drinking problems than were positive reasons among both secondary-school and university students. Results also showed that the effect of both positive and negative drinking reasons on alcohol-related problems was partially mediated by alcohol consumption among both secondary-school students and university students. There were different correlates of problematic drinking among younger and older students, which suggest that different types of intervention should be used with the two age groups.

Adolescent↗

How do outcomes in a specified parent training intervention maintain or wane over time?

In a randomized prevention trial, 238 recently separated mothers and their young sons were assigned to either Parent Management Training (PMT) or a comparison group. Families were intensively assessed at baseline and at each 6-month interval through 30 months. To understand the effects of PMT, we first evaluated effect sizes among family variables over time. Second, because observed parenting was the target of PMT, we hypothesized a sequential pattern of structured changes within and between individuals. Using constructs with mismatched sources of data, we conducted a set of latent growth mediational analyses to test hypothesized mechanisms explaining change. Effect sizes indicated that parenting changed first within 12 months, followed by changes in boy behaviors and finally changes in maternal depression within 30 months. Unique follow-up findings indicated that intervention effects on reductions in maternal depression were mediated by reductions in boy externalizing; intervention effects on externalizing were mediated by reductions in boy depression. As expected, increases in effective parenting predicted reductions in child behavior problems. PMT effects on internalizing were direct and indirect, partially mediated by parenting practices. Results are discussed from a system's perspective on PMT amplifiers.

Adult↗

Pain, sleep disturbance, and fatigue in patients with cancer: using a mediation model to test a symptom cluster.

PURPOSE/OBJECTIVES: To test whether sleep disturbance mediates the effect of pain on fatigue. DESIGN: Cross-sectional. SETTING: Radiation therapy clinic, oncology ambulatory clinic, and inpatient oncology unit in an urban teaching hospital. SAMPLE: 84 patients with cancer with multiple primary diagnoses who were experiencing pain. Fifty-three percent were female and 92% were Caucasian, with a mean age of 54 years. METHODS: All participants completed a symptom questionnaire that included the Brief Pain Inventory-Short Form, the Pittsburgh Sleep Quality Index, and the fatigue subscale of the Profile of Mood States questionnaire. Multistage linear regression was used to test a mediation model. MAIN RESEARCH VARIABLES: Fatigue, pain, and sleep disturbance. FINDINGS: Mediation analyses indicate that pain influences fatigue directly as well as indirectly by its effect on sleep. About 20% (adjusted R2 = 0.20) of the variation in fatigue is explained by pain. Thirty-five percent of the variance in fatigue explained by pain was accounted for by the mediation pathway. CONCLUSIONS: Some of the effect of pain on fatigue is mediated by sleep disturbance, but pain has a direct effect on fatigue as well. IMPLICATIONS FOR NURSING: Although the relationship can be explained only partially by the commonsense point of view that people who are in pain lose sleep and naturally report more fatigue, this finding is important and leads to a potential intervention opportunity. Strategies to improve sleep by better pain management may contribute to decreased fatigue.

Adolescent↗

Complement activation capacity in plasma before and during high-dose prednisolone treatment and tapering in exacerbations of Crohn's disease and ulcerative colitis.

BACKGROUND: Ulcerative colitis (UC) and Crohn's disease (CD) are characterized by intestinal inflammation mainly caused by a disturbance in the balance between cytokines and increased complement (C) activation. Our aim was to evaluate possible associations between C activation capacity and prednisolone treatment. METHODS: Plasma from patients with exacerbations of UC (n = 18) or CD (n = 18) were collected before and during high dose prednisolone treatment (1 mg/kg body weight) and tapering. Friedman's two way analysis of variance, Mann-Whitney U test and Wilcoxon signed-rank sum test were used RESULTS: Before treatment, plasma from CD patients showed significant elevations in all C-mediated analyses compared to the values obtained from 38 healthy controls (p < 0.02), and in mannan binding lectin (MBL)-concentration and MBL-C4-activation capacity (AC) values compared to UC patients (p < 0.02). Before treatment, plasma from UC patients showed significant elevations only in the classical pathway-mediated C3-AC compared to values obtained from healthy controls (p < 0.01). After treatment was initiated, significant reductions, which persisted during follow-up, were observed in the classical pathway-mediated C3-AC and MBL-C4-AC in plasma from CD patients (p < 0.05). CONCLUSION: Our findings indicate that C activation capacity is up-regulated significantly in plasma from CD patients. The decreases observed after prednisolone treatment reflect a general down-regulation in immune activation.

Adult↗

Minority stress and sexual problems among African-American gay and bisexual men.

Minority stress, such as racism and gay bashing, may be associated with sexual problems, but this notion has not been examined in the literature. African-American gay/bisexual men face a unique challenge in managing a double minority status, putting them at high risk for stress and sexual problems. This investigation examined ten predictors of sexual problems among 174 African-American gay/bisexual men. Covarying for age, a forward multiple regression analysis showed that the measures of self-esteem, male gender role stress, HIV prevention self-efficacy, and lifetime experiences with racial discrimination significantly added to the prediction of sexual problems. Gay bashing, psychiatric symptoms, low life satisfaction, and low social support were significantly correlated with sexual problems, but did not add to the prediction of sexual problems in the regression analysis. Mediation analyses showed that stress predicted psychiatric symptoms, which then predicted sexual problems. Sexual problems were not significantly related to HIV status, racial/ethnic identity, or gay identity. The findings from this study showed a relationship between experiences with racial and sexual discrimination and sexual problems while also providing support for mediation to illustrate how stress might cause sexual problems. Addressing minority stress in therapy may help minimize and treat sexual difficulties among minority gay/bisexual men.

Adult↗

Attachment at school age and academic performance.

The association between attachment and school-related cognitive functioning was longitudinally examined for a French Canadian sample of 108 school-age children. The affective quality of mother-child interaction patterns, child cognitive engagement, and quality of child attachment to mother were evaluated during a laboratory visit that included a separation-reunion procedure occurring when the children were approximately 6 years of age. Children's mastery motivation and academic performance were assessed 2 years later (at age 8). Analyses indicated that secure children had higher scores than their insecure peers on communication, cognitive engagement, and mastery motivation. Controlling children were at greatest risk for school underachievement, with the poorest performance on all measures except mastery motivation. Avoidant and ambivalent children were lowest on mastery motivation. Results of mediational analyses support the salience of mother-child interactional processes and child cognitive engagement at school age in explaining relations between attachment and cognitive functioning in school.

Child↗

Pathways linking major depression and immunity in ambulatory female patients.

OBJECTIVES: The goals of this study were to investigate whether depression is associated with cellular immunity in ambulatory patients and to identify neuroendocrine and behavioral pathways that might account for this relationship. METHODS: We studied 32 women who met Diagnostic and Statistical Manual of Mental Disorder, fourth edition, criteria for major depressive disorder and 32 healthy female control subjects. The groups were matched for age and ethnicity. None were taking medication, and all were free of disease involving the immune system. RESULTS: Depressed subjects had reduced proliferative responses to the mitogens concanavalin A and phytohemagglutinin compared with control subjects. Natural killer cell activity was reduced among older depressed subjects but enhanced among younger depressed subjects. Although depression was associated with elevated circulating levels of norepinephrine and estradiol, these hormones could not account for the immunologic differences between depressed and control subjects. Depression was also associated with greater tobacco and caffeine consumption, less physical activity, and poorer sleep quality. Mediational analyses were consistent with physical activity acting as a pathway through which depression was associated with reduced lymphocyte proliferation. CONCLUSIONS: Ambulatory patients with mild to moderately severe depression exhibit reduced mitogen-stimulated lymphocyte proliferative responses and altered natural killer cell cytotoxicity. The relationship between depression and proliferative responses may be mediated by physical activity.

Adult↗

The influence of social support and problematic support on optimism and depression in chronic illness: a prospective study evaluating self-esteem as a mediator.

The present study focused on the mechanism through which social and problematic support affects psychological adjustment in chronic illness. The authors hypothesized that self-esteem would mediate the relations between social and problematic support and adjustment. Eighty-six end-stage renal disease patients were assessed twice for social support problematic support, and self-esteem. Adjustment was assessed twice by depression and optimism. Mediational analyses indicated that social support operated through self-esteem to influence optimism cross-sectionally and prospectively and depression cross-sectionally. Social support was associated with high self-esteem, which in turn increased optimism and was related to decreased depression. Problematic support was unrelated to self-esteem obviating mediational analysis. Disaggregating social support into subscales showed that belonging support predicted decreases in depression, and both tangible and belonging support predicted increases in optimism.

Attitude to Health↗

Differential DNA methylation in blood as potential mediator of the association between ambient PM2.5 and cerebrospinal fluid biomarkers of Alzheimer's disease among a cognitively normal population-based cohort.

Fine particulate matter (PM2.5) is a known risk factor for Alzheimer's disease (AD), with emerging evidence showing its effects detectable in the pre-clinical stage through cerebrospinal fluid (CSF) biomarkers of AD. While studies have linked PM2.5 exposure and AD to DNA methylation (DNAm) alterations, the role of DNAm as potential mediator in the association between PM2.5 and AD biomarkers in cognitively normal individuals remains largely unexplored, and formal mediation analyses addressing this question are scarce. Genome-wide DNAm profiles (Illumina EPIC BeadChips) in whole blood and CSF A&#x3b2;42 concentrations were assessed in 536 cognitively normal individuals from the Emory Healthy Brain Study (EHBS). Residential PM2.5 exposure for the year preceding participants' blood collection was estimated. A multi-stage analytical pipeline, incorporating single-mediator analysis, high-dimensional mediation analysis, and causal mediation analysis, was applied. Nine CpG sites were identified as noteworthy mediators of the relationship between PM2.5 and decreased CSF A&#x3b2;42 concentrations. Causal mediation analysis confirmed significant natural indirect effects (NIE) for eight CpGs, with effect estimates ranging from -0.015--0.029 per 1 ug/m3 increase in PM2.5 exposure. The proportion mediated ranging from 14-43%. Six CpGs are annotated to genes implicated in neuroinflammatory pathways. These findings suggest that differential DNAm, particularly in genes related to neuroinflammation, mediates the association between PM2.5 exposure and CSF A&#x3b2;42 concentrations, highlighting the utility of blood DNAm in detecting and studying biological pathways underlying PM2.5 toxicity in the pre-clinical stages of AD.

Humans↗

Incremental validity of a measure of emotional intelligence.

After the Schutte Self-Report Inventory of Emotional Intelligence (SSRI; Schutte et al., 1998) was found to predict college grade point average, subsequent emotional intelligence (EI)-college adjustment research has used inconsistent measures and widely varying criteria, resulting in confusion about the construct's predictive validity. In this study, we assessed the SSRI's incremental validity for a wide range of adjustment criteria, pitting it against a competing trait measure, the NEO Five-Factor Inventory (NEO-FFI; Costa & McCrae, 1992), and tests of fluid and crystallized intelligence. At a broad bandwidth, the SSRI total score significantly and uniquely predicted variance beyond NEO-FFI domain scores in the UCLA Loneliness Scale, Revised (Russell, Peplau, & Cutrono, 1980) scores. Higher fidelity analyses using previously identified SSRI factors and NEO-FFI item clusters revealed that the SSRI's Optimism/Mood Regulation and Emotion Appraisal factors contributed unique variance to self-reported study habits and social stress, respectively. The potential moderation of incremental validity by gender did not reach significance due to loss of power from splitting the sample, and mediational analyses revealed the SSRI Optimism/Mood Regulation factor was both directly and indirectly related to various criteria. We discuss the small magnitude of incremental validity coefficients and the differential incremental validity of SSRI factor and total scores.

Adolescent↗

National Institute of Mental Health Multimodal Treatment Study of ADHD follow-up: changes in effectiveness and growth after the end of treatment.

OBJECTIVE: Intent-to-treat analyses of the Multimodal Treatment Study of ADHD (MTA) revealed group differences on attention-deficit/hyperactivity disorder symptoms ratings, with better outcome in groups of participants who were assigned the medication algorithm-medication alone (MedMgt) and combined (Comb)--than in those who were not-behavior modification (Beh) alone and community comparison (CC). However, the effect size was reduced by 50% from the end of treatment to the first follow-up. The convergence of outcomes suggests differential changes by treatment group beween 14 and 24 months, which this report explores, both for benefits of treatment and for side effects on growth. METHODS: We documented reported medication use at 14- and 24-month assessments and formed 4 naturalistic subgroups (Med/Med, Med/NoMed, NoMed/Med, and NoMed/NoMed). Then we performed exploratory mediator analyses to evaluate effects of changes in medication use on 14- to 24-month change scores of effectiveness (symptom ratings) and growth (height and weight measures). RESULTS: The randomly assigned groups with the greatest improvement at the end of the treatment phase (Comb and MedMgt) deteriorated during the follow-up phase, but the other 2 groups (Beh and CC) did not. There were no significant differences in the 14- to 24-month growth rates among the randomly assigned groups, in contrast to significant growth suppression in the Comb and MedMgt at the end of the treatment phase. Changes in medication use mediated the 14- to 24-month change in attention-deficit/hyperactivity disorder symptom ratings: the subgroup that reported stopping medication (Med/NoMed) showed the largest deterioration, the subgroup that consistently reported (Med/Med) or never reported (NoMed/NoMed) medication use showed modest deterioration, and the subgroup that reported starting medication (NoMed/Med) showed improvement. Changes in medication use also mediated growth effects: the subgroup that consistently reported medication use (Med/Med) showed reduced height gain compared with the subgroup that never reported medication use (NoMed/NoMed), which actually grew faster than predicted by population norms. CONCLUSION: In the MTA follow-up, exploratory naturalistic analyses suggest that consistent use of stimulant medication was associated with maintenance of effectiveness but continued mild growth suppression.

Adolescent↗

Integration of multiple omics reveals key targets and cellular mechanisms for intervention in sarcopenia.

BACKGROUND: Sarcopenia, an age-related syndrome characterized by progressive loss of muscle mass, strength, and function, presents a significant global health burden with limited therapeutic interventions. This study integrates genomic causality, multi-tissue omics, and cellular mediation analyses to identify and prioritize mechanistically grounded therapeutic targets. METHODS: A multi-tiered analytical framework was applied, beginning with two-sample Mendelian randomization (MR) to infer causal relationships between 4907 plasma proteins (cis-pQTLs from 35,559 individuals) and sarcopenia traits in Pan-UK Biobank participants. Bayesian colocalization and transcriptomic validation in human sarcopenia muscle biopsies were employed to prioritize targets. Cellular mediation analysis quantified contributions of immune and stromal cell subtypes to protein-trait pathways using transcriptomic deconvolution. RESULTS: MR identified 1237 plasma proteins causally associated with sarcopenia traits, with six targets (HGFAC, GATM, HMOX2, F2, LMAN2L, HPGDS) validated through colocalization, transcriptomic expression, and sarcopenia-related dysregulation. Cellular mediation revealed immune mechanisms underlying HGFAC's effects, with CD4+ regulatory T cells mediating 3.49 % of its impact on sarcopenia traits. Prothrombin exhibited muscle-protective effects independent of coagulation. CONCLUSION: This study establishes a causal map linking plasma proteins to sarcopenia through immune-stromal interactions. The integration of MR, multi-omics validation, and cellular mediation prioritizes six proteins as actionable targets, supporting repurposing of thrombin inhibitors and development of immunometabolic therapies. The framework bridges genomic causality with cellular pathophysiology, advancing precision strategies for age-related muscle decline.

Humans↗

The stress process and the social distribution of depression.

Mental health generally and depression in particular have been repeatedly shown to vary in relation to gender, socioeconomic status, marital status, and age. These status differences may be linked to mental health because they tend to define important differences in stress exposure and in the availability of coping resources. This paper examines the capacity of the stress-process model to account for the social distribution of depression. We employ mediation analyses using data from a 1990-1991 survey of Toronto community residents. In general, we found hypothesized risk factors to vary across these statuses with depressive symptoms and disorder and the distribution of protective factors to vary inversely. Results indicate that the model as expressed in our analyses accounts for a substantial minority of observed depression differences across individuals and for a considerable portion of reliably observed variation across social statuses. Our findings with respect to major depressive disorder parallel those for depressive symptomatology. Most compelling is the nearly total explanation of the socioeconomic status association with depressive symptoms and the substantial contribution toward explaining the socioeconomic status-disorder relationship when stress process mediators are accounted for.

Adolescent↗

Heart rate mediation of sex differences in pain tolerance in children.

Despite evidence supporting the existence of important sex-related differences in pain, the mechanisms underpinning such differences are not well understood. The aim of this study is to examine the relationship between sex and pubertal differences in autonomic arousal and pain tolerance to laboratory pain stimuli in healthy children. We tested the following specific hypotheses: (1) females would have greater autonomic arousal and less pain tolerance than males, and (2) this sex difference in pain tolerance would be mediated by autonomic arousal. Participants were 244 healthy children (50.8% female, mean age 12.73+/-2.98 years, range 8-18 years). Separate 4-trial blocks of cutaneous pressure and thermal pain stimuli were presented in counterbalanced order. Heart rate (HR) was recorded during 2-3 min periods preceding each block and a 1-min period between trials. Results indicated lower tolerance in females for cutaneous pressure, but not thermal pain, compared to males. In addition, pre-trial HR was greater for females than males. Mediation analyses suggested that sex differences in pressure pain tolerance were accounted for by sex differences in pre-trial HR. There were also significant effects for puberty, but these did not vary by sex. Overall, early pubertal children had greater pre-trial HR and less pain tolerance than those in late puberty for both cutaneous pressure and thermal pain across sex. These results suggest that autonomic arousal may be a mediator of sex-related differences in pain responses in children.

Adolescent↗

Sexual communication and contraceptive use in adolescent dating couples.

PURPOSE: This study had two aims: first, to examine the relationship between general sexual communication and contraceptive use in sexually active adolescent romantic couples, and second, to explore predictors of open communication from characteristics of adolescent couples and individual adolescents. METHODS: Data were drawn from 209 couples dating a minimum of four weeks who participated in the Study of Tennessee Adolescent Romantic Relationships. Seventy-three adolescent dating couples (ages 14-21 years) that engaged in sexual intercourse and completed a sexual communication questionnaire were included in current analyses. RESULTS: Nearly 30% of couples failed to use contraception at first intercourse and almost half of couples did not use contraception every time they had sex. More open communication about sex from both male and female partners was associated with increased contraceptive use. Additionally, adolescents who were more satisfied in their relationships reported more open communication about sex, and adolescent females who self-silenced reported less open communication about sex. Finally, mediation analyses revealed that boys' and girls' relationship satisfaction and girls' self-silencing indirectly predicted contraceptive use through their effects on general sexual communication. CONCLUSIONS: This is the first known study to address individual and dyadic components of sexual communication using reports from both members of established adolescent dating couples. Findings suggest that open sexual communication between intimate partners is important to sexual decision-making. The clinical implications of these findings are discussed.

Adolescent↗