Intestinal Barrier Healing Is Superior to Endoscopic and Histologic Remission for Predicting Major Adverse Outcomes in Inflammatory Bowel Disease: The Prospective ERIca Trial.

BACKGROUND & AIMS: Endoscopic and histologic remission have emerged as key therapeutic goals in the management of inflammatory bowel diseases (IBD) that are associated with favorable long-term disease outcomes. Here, we prospectively compared the predictive value of barrier healing with endoscopic and histologic remission for predicting long-term disease behavior in a large cohort of patients with IBD in clinical remission. METHODS: At baseline, patients with IBD in clinical remission underwent ileocolonoscopy with assessment of intestinal barrier function by confocal endomicroscopy. Endoscopic and histologic disease activity, as well as barrier healing, was prospectively assessed along established scores. During subsequent follow-up, patients were closely monitored for clinical disease activity and the occurrence of major adverse outcomes (MAOs): disease flares, IBD-related hospitalization or surgery, and initiation or dose escalation of systemic steroids, immunosuppressants, small molecules, or biological therapy. RESULTS: The final analysis included 181 patients, 100 with Crohn's disease [CD] and 81 with ulcerative colitis (UC). During a mean follow-up of 35 (CD) and 25 (UC) months, 73% of patients with CD and 69% of patients with UC experienced at least 1 MAO. The probability of MAO-free survival was significantly higher in patients with IBD with endoscopic remission compared with endoscopically active disease. In addition, histologic remission predicted MAO-free survival in patients with UC but not CD. Barrier healing on endomicroscopy was superior to endoscopic and histologic remission for predicting MAO-free survival in both UC and CD. CONCLUSIONS: Barrier healing is associated with decreased risk of disease progression in patients with clinically remittent IBD, with superior predictive performance compared with endoscopic and histologic remission. Analysis of barrier function might be considered as a future treatment target in clinical trials. CLINICALTRIALS: gov number, NCT05157750.

Burn Resuscitation Practices in North America: Results of the Acute Burn ResUscitation Multicenter Prospective Trial (ABRUPT).

OBJECTIVES: ABRUPT was a prospective, noninterventional, observational study of resuscitation practices at 21 burn centers. The primary goal was to examine burn resuscitation with albumin or crystalloids alone, to design a future prospective randomized trial. SUMMARY BACKGROUND DATA: No modern prospective study has determined whether to use colloids or crystalloids for acute burn resuscitation. METHODS: Patients ≥18 years with burns ≥ 20% total body surface area (TBSA) had hourly documentation of resuscitation parameters for 48 hours. Patients received either crystalloids alone or had albumin supplemented to crystalloid based on center protocols. RESULTS: Of 379 enrollees, two-thirds (253) were resuscitated with albumin and one-third (126) were resuscitated with crystalloid alone. Albumin patients received more total fluid than Crystalloid patients (5.2 ± 2.3 vs 3.7 ± 1.7 mL/kg/% TBSA burn/24 hours), but patients in the Albumin Group were older, had larger burns, higher admission Sequential Organ Failure Assessment (SOFA) scores, and more inhalation injury. Albumin lowered the in-to-out (I/O) ratio and was started ≤12 hours in patients with the highest initial fluid requirements, given >12 hours with intermediate requirements, and avoided in patients who responded to crystalloid alone. CONCLUSIONS: Albumin use is associated with older age, larger and deeper burns, and more severe organ dysfunction at presentation. Albumin supplementation is started when initial crystalloid rates are above expected targets and improves the I/O ratio. The fluid received in the first 24 hours was at or above the Parkland Formula estimate.

Scoring functions for drug-effect similarity.

MOTIVATION: The difficulty to find new drugs and bring them to the market has led to an increased interest to find new applications for known compounds. Biological samples from many disease contexts have been extensively profiled by transcriptomics, and, intuitively, this motivates to search for compounds with a reversing effect on the expression of characteristic disease genes. However, disease effects may be cell line-specific and also depend on other factors, such as genetics and environment. Transcription profile changes between healthy and diseased cells relate in complex ways to profile changes gathered from cell lines upon stimulation with a drug. Despite these differences, we expect that there will be some similarity in the gene regulatory networks at play in both situations. The challenge is to match transcriptomes for both diseases and drugs alike, even though the exact molecular pathology/pharmacogenomics may not be known. RESULTS: We substitute the challenge to match a drug effect to a disease effect with the challenge to match a drug effect to the effect of the same drug at another concentration or in another cell line. This is welldefined, reproducible in vitro and in silico and extendable with external data. Based on the Connectivity Map (CMap) dataset, we combined 26 different similarity scores with six different heuristics to reduce the number of genes in the model. Such gene filters may also utilize external knowledge e.g. from biological networks. We found that no similarity score always outperforms all others for all drugs, but the Pearson correlation finds the same drug with the highest reliability. Results are improved by filtering for highly expressed genes and to a lesser degree for genes with large fold changes. Also a network-based reduction of contributing transcripts was beneficial, here implemented by the FocusHeuristics. We found no drop in prediction accuracy when reducing the whole transcriptome to the set of 1000 landmark genes of the CMap's successor project Library of Integrated Network-based Cellular Signatures. All source code to re-analyze and extend the CMap data, the source code of heuristics, filters and their evaluation are available to propel the development of new methods for drug repurposing. AVAILABILITY: https://bitbucket.org/ibima/moldrugeffectsdb. CONTACT: steffen.moeller@uni-rostock.de. SUPPLEMENTARY INFORMATION: Supplementary data are available at Briefings in Bioinformatics online.

Data-Driven Radiogenomic Approach for Deciphering Molecular Mechanisms Underlying Imaging Phenotypes in Lung Adenocarcinoma: A Pilot Study.

The heterogeneity of lung tumor nodules is reflected in their phenotypic characteristics in radiological images. The radiogenomics field employs quantitative image features combined with transcriptome expression levels to understand tumor heterogeneity molecularly. Due to the different data acquisition techniques for imaging traits and genomic data, establishing meaningful connections poses a challenge. We analyzed 86 image features describing tumor characteristics (such as shape and texture) with the underlying transcriptome and post-transcriptome profiles of 22 lung cancer patients (median age 67.5 years, from 42 to 80 years) to unravel the molecular mechanisms behind tumor phenotypes. As a result, we were able to construct a radiogenomic association map (RAM) linking tumor morphology, shape, texture, and size with gene and miRNA signatures, as well as biological correlates of GO terms and pathways. These indicated possible dependencies between gene and miRNA expression and the evaluated image phenotypes. In particular, the gene ontology processes "regulation of signaling" and "cellular response to organic substance" were shown to be reflected in CT image phenotypes, exhibiting a distinct radiomic signature. Moreover, the gene regulatory networks involving the TFs TAL1, EZH2, and TGFBR2 could reflect how the texture of lung tumors is potentially formed. The combined visualization of transcriptomic and image features suggests that radiogenomic approaches could identify potential image biomarkers for underlying genetic variation, allowing a broader view of the heterogeneity of the tumors. Finally, the proposed methodology could also be adapted to other cancer types to expand our knowledge of the mechanistic interpretability of tumor phenotypes.

Zirconia-Toughened Alumina Ceramic Wear Particles Do Not Elicit Inflammatory Responses in Human Macrophages.

Ten percent of patients undergoing total hip arthroplasty (THA) require revision surgery. One of the reasons for THA are wear particles released from the implants that can activate the immune defense and cause osteolysis and failure of the joint implant. The discrepancies between reports on toxicity and immunogenicity of the implant materials led us to this study in which we compared toxicity and immunogenicity of well-defined nanoparticles from Al2O3, zirconia-toughened alumina (ZTA), and cobalt chrome (CoCr), a human THP-1 macrophage cell line, human PBMCs, and therefrom-derived primary macrophages. None of the tested materials decreased the viability of THP-1 macrophages nor human primary macrophages at the 24 h time point, indicating that at concentrations from 0.05 to 50 µm3/cell the tested materials are non-toxic. Forty-eight hours of treatment of THP-1 macrophages with 5 µm3/cell of CoCr and Al2O3 caused 8.3-fold and 4.6-fold increases in TNF-α excretion, respectively, which was not observed for ZTA. The comparison between THP-1 macrophages and human primary macrophages revealed that THP-1 macrophages show higher activation of cytokine expression in the presence of CoCr and Al2O3 particles than primary macrophages. Our results indicate that ZTA is a non-toxic implant material with no immunogenic effects in vitro.

Caregiver and adolescent intuitive eating behavior: associations with weight change during family-based treatment for anorexia nervosa.

PURPOSE: Intuitive eating (IE) is an adaptive eating construct for which little research exists in eating disorder (ED) samples. IE is negatively correlated with disordered eating behaviors in healthy adolescents and adults, and similar associations have been found in adults with EDs. This study aims to examine IE in a treatment seeking sample of adolescents and their caregivers to understand the role of IE in weight gain during FBT. METHODS: Descriptive statistics and bivariate correlations were calculated in a sample of 47 pairs of adolescent patients and their caregivers who initiated outpatient FBT at a large academic medical center. Analyses examined associations between caregiver and adolescent IE on the Intuitive Eating Scale (IES), change in percent expected body weight (%EBW) by session 4 and end of treatment (EOT), clinical impairment, and ED pathology. RESULTS: Significant correlations were found between aspects of adolescent IE, ED symptoms, and clinical impairment. Caregiver IES scores (Reliance on Hunger and Satiety Cues, Body-Food Choice Congruence, IES Total) were negatively related to adolescent ED symptoms (EDE-Q Weight Concerns, EDE-Q Shape Concerns, EDE-Q Global) at baseline. Caregiver IE (Eating for Physical Rather than Emotional Reasons) was positively associated with adolescent weight gain at FBT session 4 and EOT, even when statistically adjusting for gender and initial level of care. CONCLUSION: Study results were consistent with past research indicating adolescent IE is negatively associated with ED behaviors, cognitions, and impairment. This study is the first to provide evidence that caregiver IE is positively associated with adolescent weight gain in FBT and is the first to provide evidence that caregiver IE is negatively related to adolescent ED symptoms. Future research should examine adolescent and caregiver IE throughout FBT to understand the role of IE in treatment response. LEVEL OF EVIDENCE: Level III: Evidence obtained from cohort or case-control analytic studies.

Internet-delivered eating disorders prevention program for adolescent girls with type 1 diabetes: Acceptable and feasible.

BACKGROUND: Adolescents with type 1 diabetes are at significantly increased risk for eating disorders and few interventions exist. OBJECTIVE: This study examined the feasibility, acceptability, and preliminary effects of an internet-based eating disorders prevention program adapted specifically for adolescent girls with type 1 diabetes. PARTICIPANTS AND METHODS: Thirty-five girls (16.2 ± 1.1 years) participated Body Project (T1D Style), a 4-week program consisting of four adolescent sessions focused on promoting illness acceptance, challenging sociocultural body image pressures, increasing social support, and teaching assertive communication. Caregivers participated in one session focused on fostering body image positivity and a healthy relationship with food. Pre-intervention, post-intervention, and 3-month follow-up surveys assessed disordered eating, body dissatisfaction, thin-ideal internalization, diabetes acceptance, diabetes distress, and quality of life. Cohen's d effect sizes were calculated at post-intervention and follow-up. Program acceptability was assessed at post-intervention. Manual fidelity and homework completion were monitored. RESULTS: High manual fidelity, retention, and homework completion were achieved. Quantitative and qualitative feedback from teens and caregivers suggested high acceptability. Large effects (d = 1.35-0.83) were observed for dieting, body dissatisfaction, diabetes distress, diabetes acceptance, and diabetes-related quality of life at post-intervention, with large-medium effects (d = 1.16-0.58) at follow-up. Medium-small effects (d = 0.49-0.78) at post-intervention were observed for diabetes-specific disordered eating and thin-ideal internalization, with effects maintained at follow-up. CONCLUSIONS: Results support the acceptability and feasibility of this targeted eating disorders prevention program for adolescent girls with type 1 diabetes. Future clinical trials are warranted to determine its effectiveness compared to a control condition.

Negative affect and binge eating: Assessing the unique trajectories of negative affect before and after binge-eating episodes across eating disorder diagnostic classifications.

OBJECTIVE: Ecological momentary assessment (EMA) studies suggest that among individuals who binge eat, emotional states and binge eating are functionally related. However, it is unclear whether the trajectory of negative affect (NA) is the same across diagnostic groups or if specific changes in affect are unique to each diagnostic category. This study examined the moderating effect of diagnosis on the trajectory of negative affect before and after binge eating. METHOD: Adults with eating disorder diagnoses (anorexia nervosa [AN] = 118, bulimia nervosa [BN] = 133, binge-eating disorder [BED] = 112) completed an EMA where they reported binge eating and negative affect throughout the day. Generalized estimating equation analyses were used to model the trajectories of NA before and after binge eating. RESULTS: For all individuals, the linear trajectory of NA significantly increased before (B = 0.044, p < .001) and decreased following the binge-eating episode (B = -0.054, p < .001). However, diagnosis moderated this trajectory. Specifically, individuals with BN had a greater change in linear trajectories of NA before (B = 2.305, p < .001) and after (B = -4.149, p < .001) binge eating compared to those with BED, but not those with AN. There were no differences in the trajectory of NA between individuals with BED or AN. DISCUSSION: These findings suggest that binge-eating episodes in BN may be more strongly associated with NA than in BED, but similar to binge-eating episodes in AN.

A scoping review of non-specific predictors, moderators, and mediators of family-based treatment for adolescent anorexia and bulimia nervosa: a summary of the current research findings.

PURPOSE: This scoping review presents an up-to-date synthesis of the current evidence base for non-specific predictors, moderators, and mediators of family-based treatment (FBT) for adolescent anorexia and bulimia nervosa. METHODS: We identify ways in which end-of-treatment outcomes have been shown to differ based upon baseline clinical features and person-specific factors and explore psychological mechanisms that may explain differences in treatment response. We draw from this evidence base to outline recommendations for clinical practice, as well as directions for future clinical eating disorder research. RESULTS: Noted findings from review include that early response in weight gain and parental criticism may be particularly influential in treatment for anorexia nervosa. Further, for adolescents with either anorexia or bulimia nervosa, eating-related obsessionality may be a key intervention target to improve outcomes. CONCLUSION: In addition to highlighting a need for attention to specific patient- and caregiver-level factors that impact treatment response, recommendations for research and clinical practice include testing whether certain targeted treatments (e.g., exposure-based approaches) may be suitable within the context of FBT for eating disorders. LEVEL OF EVIDENCE: Level I: Evidence obtained from: at least one properly designed randomized controlled trials; experimental studies.

RNAseq and quantitative proteomic analysis of Dictyostelium knock-out cells lacking the core autophagy proteins ATG9 and/or ATG16.

BACKGROUND: Autophagy is an evolutionary ancient mechanism that sequesters substrates for degradation within autolysosomes. The process is driven by many autophagy-related (ATG) proteins, including the core members ATG9 and ATG16. However, the functions of these two core ATG proteins still need further elucidation. Here, we applied RNAseq and tandem mass tag (TMT) proteomic approaches to identify differentially expressed genes (DEGs) and proteins (DEPs) in Dictyostelium discoideum ATG9‾, ATG16‾ and ATG9‾/16‾ strains in comparison to AX2 wild-type cells. RESULT: In total, we identified 332 (279 up and 53 down), 639 (487 up and 152 down) and 260 (114 up and 146 down) DEGs and 124 (83 up and 41 down), 431 (238 up and 193 down) and 677 (347 up and 330 down) DEPs in ATG9‾, ATG16‾ and ATG9‾/16‾ strains, respectively. Thus, in the single knock-out strains, the number of DEGs was higher than the number of DEPs while in the double knock-out strain the number of DEPs was higher. Comparison of RNAseq and proteomic data further revealed, that only a small proportion of the transcriptional changes were reflected on the protein level. Gene ontology (GO) analysis revealed an enrichment of DEPs involved in lipid metabolism and oxidative phosphorylation. Furthermore, we found increased expression of the anti-oxidant enzymes glutathione reductase (gsr) and catalase A (catA) in ATG16‾ and ATG9‾/16‾ cells, respectively, indicating adaptation to excess reactive oxygen species (ROS). CONCLUSIONS: Our study provides the first combined transcriptome and proteome analysis of ATG9‾, ATG16‾ and ATG9‾/16‾ cells. Our results suggest, that most changes in protein abundance were not caused by transcriptional changes, but were rather due to changes in protein homeostasis. In particular, knock-out of atg9 and/or atg16 appears to cause dysregulation of lipid metabolism and oxidative phosphorylation.

A 24-generation-old founder mutation impairs splicing of RBBP8 in Pakistani families affected with Jawad syndrome.

Jawad syndrome is a multiple congenital anomaly and intellectual disability syndrome with mutation in RBBP8 reported only in two families. Here, we report on two new families from Pakistan and identified a previously reported variant in RBBP8, NM_002894.3:c.1808-1809delTA. We could show that this mutation impairs splicing resulting in two different abnormal transcripts. Finally, we could verify a shared haplotype among all four families and estimate the founder event to have occurred some 24 generations ago.

Impact of the Microbial Origin and Active Microenvironment on the Shape of Biogenic Elemental Selenium Nanomaterials.

The shape of nanomaterials affects their colloidal properties, cellular uptake, and fate in the environment. The microbial origin and microenvironment can play a role in altering the shape of the nanomaterial. However, such studies have never been conducted. Here, we demonstrate that the selenium nanomaterials produced by Escherichia coli K-12 are stable and remain as BioSe-Nanospheres under thermophilic conditions, while those produced by anaerobic granular sludge transform to BioSe-Nanorods, due to a lower quantity of proteins coating these nanoparticles, which has been verified by proteomics analysis as well as using chemically synthesized selenium nanomaterials. Furthermore, the presence of Bacillus safensis JG-B5T transform the purified BioSe-Nanospheres produced by E. coli K-12 to BioSe-Nanorods, though they are not transformed in the absence of B. safensis JG-B5T. This is due to the production of peptidases by B. safensis JG-B5T that cleaves the protein coating the BioSe-Nanospheres produced by E. coli K-12, leading to their transformation to trigonal BioSe-Nanorods, which is the thermodynamically more stable state. These findings suggest that the fate of selenium and probably other redox-active elements released from the biological wastewater treatment units needs to be reevaluated and improved by including microbial criteria for better accuracy.

Would people living with epilepsy benefit from palliative care?

Palliative care (PC) is an approach to the care of persons living with serious illness and their families that focuses on improving quality of life and reducing suffering by addressing complex medical symptoms, psychosocial needs, spiritual well-being, and advance care planning. While PC has traditionally been associated with hospice care for persons with cancer, there is now recognition that PC is relevant to many noncancer diagnoses, including neurologic illness, and at multiple points along the illness journey, not just end of life. Despite the recent growth of the field of neuropalliative care there has been scant attention paid to the relevance of PC principles in epilepsy or the potential for PC approaches to improve outcomes for persons living with epilepsy and their families. We believe this has been a significant oversight and that PC may provide a useful framework for addressing the many sources of suffering facing persons living with epilepsy, for engaging patients and families in challenging conversations, and to focus efforts to improve models of care for this population. In this manuscript we review areas of significant unmet needs where a PC approach may improve patient and family-centered outcomes, including complex symptom management, goals of care, advance care planning, psychosocial support for patient and family and spiritual well-being. When relevant we highlight areas where epilepsy patients may have unique PC needs compared to other patient populations and conclude with suggestions for future research, clinical, and educational efforts.

Parenting and Psychological Health in Youth with Type 1 Diabetes: Systematic Review.

OBJECTIVE: Type 1 diabetes (T1D) is a demanding chronic illness that may result in poorer psychological health in youth. Fortunately, certain parenting practices may be protective against adverse outcomes. However, a systematic review of these relationships in youth with T1D is lacking. Thus, the current systematic review examined the literature on parenting and child psychological health outcomes (both internalizing and externalizing symptoms) in youth with T1D. Particular attention is paid to how demographic factors are associated with these relationships. METHODS: PRISMA guidelines for systematic reviews were followed, and a literature search (PubMed, PsycINFO, and CINAHL) was conducted for studies of youth with T1D that examined the relationship between specific parenting practices or characteristics of the parent-child relationship and youth (<19 years old) internalizing or externalizing symptoms. Forty studies met inclusion criteria. Studies were examined for risk of bias. RESULTS: Results support that family conflict, critical parenting, support, involvement, and relationship quality are associated with psychological health outcomes in youth with T1D, with some associations varying by parent gender, child age, demographic factors, and internalizing versus externalizing outcomes. CONCLUSIONS: Findings highlight the importance of bolstering supportive parenting and decreasing family conflict to improve psychological health in this population. Gaps in the literature related to the dearth of father and secondary caregiver report, lack of sample diversity and attention to the influence of demographic factors, and a limited number of studies examining anxiety were identified. Directions for future research and clinical implications are discussed.

Protocol for the Mason: Health Starts Here prospective cohort study of young adult college students.

BACKGROUND: Young adulthood is a period of increasing independence for the 40% of young adults enrolled in U.S. colleges. Previous research indicates differences in how students' health behaviors develop and vary by gender, race, ethnicity, and socioeconomic status. George Mason University is a state institution that enrolls a highly diverse student population, making it an ideal setting to launch a longitudinal cohort study using multiple research methods to evaluate the effects of health behaviors on physical and psychological functioning, especially during the COVID-19 pandemic. RESULTS: Mason: Health Starts Here was developed as a longitudinal cohort study of successive waves of first year students that aims to improve understanding of the natural history and determinants of young adults' physical health, mental health, and their role in college completion. The study recruits first year students who are 18 to 24 years old and able to read and understand English. All incoming first year students are recruited through various methods to participate in a longitudinal cohort for 4 years. Data collection occurs in fall and spring semesters, with online surveys conducted in both semesters and in-person clinic visits conducted in the fall. Students receive physical examinations during clinic visits and provide biospecimens (blood and saliva). CONCLUSIONS: The study will produce new knowledge to help understand the development of health-related behaviors during young adulthood. A long-term goal of the cohort study is to support the design of effective, low-cost interventions to encourage young adults' consistent performance of healthful behaviors, improve their mental health, and improve academic performance.

Recent Sexual Assault Predicting Changes in Coping Motives for Alcohol Use in First-Year College Women.

Sexual assault and heavy alcohol consumption are common among college students. There is strong evidence that the two are associated, but more remains to be understood about the nature of the relationship. Drinking motives have been found to mediate the relationship between sexual assault and drinking problems and between depression and alcohol risk (Kenney, Anderson, & Stein, 2018; Lindgren, Neighbors, Blayney, Mullins, & Kasen, 2012), however drinking motives have not been studied as an outcome. The current study investigated the impact of a recent sexual assault on the endorsement of coping motives for drinking in first year college women using hierarchical regression analysis with Time 2 coping motives as the outcome variable. Lifetime experience of sexual assault and Time 1 coping motives were entered in the first step of the model and a dichotomous variable indicating a recent sexual assault was entered in the second step of the model. Sexual assault during the first semester of college was found to be a significant predictor of coping motives at the end of the semester after controlling for lifetime history of sexual assault and endorsement of coping motives at Time 1. These findings suggest that coping motives for drinking may change following a sexual assault and are of concern due to the negative outcomes associated with drinking to cope. Drinking motives may be an important target of interventions provided to survivors of sexual assault to reduce risk of future drinking-related problems.

Outpatient treatment for adults with complex eating disorders and co-morbid conditions: a decision making model and case example.

Although Cognitive Behavioral Therapy (CBT-E) for eating disorders has the most empirical support for the outpatient treatment of adult eating disorders (EDs), this model does not include a focus on intense emotion dysregulation, suicidality, and non-suicidal self-injury (NSSI). Furthermore, a subset of patients do not achieve sustained remission with CBT-E. Given that Dialectical Behavior Therapy (DBT) was designed for treatment refractory, complex patients, clinicians must be able to use assessment information to determine which type of treatment to use. The aims of this manuscript are to 1) describe a DBT-based and research-informed conceptual model for treatment decision making for an outpatient non-academic setting, 2) present a case example of a client with significant ED symptoms and complex medical and psychiatric comorbidities, using this decision making model and 3) present descriptive data from a private practice setting in which patients are referred to DBT vs. CBT-E according to this decision making model.

Osmotic induction of cyclooxygenase-2 in RPE cells: Stimulation of inflammasome activation.

Purpose: Systemic hypertension is a risk factor of age-related macular degeneration, a disease associated with chronic retinal inflammation. The main cause of acute hypertension in the elderly is consumption of dietary salt (NaCl) resulting in increased extracellular osmolarity. The aim of the present study was to determine whether extracellular osmolarity regulates the expression of cyclooxygenase (COX) genes in cultured human retinal pigment epithelial (RPE) cells, and whether COX activity is involved in mediating the osmotic expression of key inflammatory (NLRP3 and IL1B) and angiogenic factor (VEGFA) genes. Methods: Extracellular hyperosmolarity was induced by addition of NaCl or sucrose. Gene expression was determined with real-time reverse transcription (RT)-PCR. Cytosolic interleukin-1ß (IL-1ß) and extracellular vascular endothelial growth factor (VEGF) levels were evaluated with enzyme-linked immunosorbent assay (ELISA). Results: Extracellular hyperosmolarity induced a dose-dependent increase in COX2 gene expression when >10 mM NaCl was added to the culture medium, while COX1 gene expression was increased at higher doses (>50 mM of added NaCl). Extracellular hypo-osmolarity decreased COX2 gene expression. High extracellular osmolarity also induced increases in the COX2 protein level. NaCl-induced expression of COX2 was mediated by various intracellular signal transduction molecules (p38 mitogen-activated protein kinase [p38 MAPK], extracellular signal-regulated kinases 1 and 2 [ERK1/2], and phosphatidylinositol-3 kinase [PI3K]), intracellular calcium signaling involving activation of phospholipase Cγ (PLCγ) and protein kinase Cα/ß (PKCα/ß), and the activity of nuclear factor of activated T cell 5 (NFAT5). Inhibition of fibroblast growth factor (FGF), transforming growth factor-ß (TGF-ß), and interleukin-1 (IL-1) receptor activities decreased NaCl-induced COX2 gene expression. Selective inhibition of COX2 activity decreased osmotic expression of the VEGFA, IL1B, and NLRP3 genes, and blocked the NaCl-induced increase in the cytosolic IL-1ß level. Conclusions: The expression of COX2 in RPE cells is osmoresponsive, and depends on NFAT5. COX2 activity stimulates hyperosmotic expression of angiogenic (VEGFA) and inflammatory factor (IL1B and NLRP3) genes, and activation of the NLRP3 inflammasome in RPE cells.

Examination of Psychosocial and Physiological Risk for Bulimic Symptoms in Youth With Type 1 Diabetes Transitioning to an Insulin Pump: A Pilot Study.

Objectives: This study tested hypotheses drawn from a risk model positing that psychosocial risk plus disease-related and treatment factors contribute to bulimic symptoms in youth with type 1 diabetes (T1D) transitioning to an insulin pump. The goal of this study was to examine whether disease-related factors, particularly disease- and treatment-based disruption in hunger and satiety, contribute to report of bulimic symptoms in youth with T1D after accounting for psychosocial risk factors. Methods: 43 youth (ages 10-17, 54% female) with established T1D were recruited before transition from multiple daily injections to insulin-pump therapy from three tertiary pediatric diabetes centers. Participants completed measures of bulimic symptoms, depressive symptoms dietary restraint, and the Diabetes Treatment and Satiety Scale, a diabetes-specific questionnaire assessing hunger and satiety cues and eating behavior in response to blood glucose levels and treatment. Results: Hierarchical multiple regression was used to assess contributions of psychosocial and disease-based risk to report of bulimic symptoms. After assessing the contributions of body mass index, body image dissatisfaction, and dietary restraint, a significant 2-way interaction emerged between depression and diabetes-related uncontrollable hunger related to bulimic symptoms (ß = 1.82, p < .01). Conclusions: In addition to psychosocial risk, disease- and treatment-based hunger and satiety dysregulation appear to be important factors contributing to report of bulimic symptoms in youth with T1D. These preliminary findings have significant treatment implications for bulimic symptoms in youth with T1D.