Acculturation, Sun Tanning Behavior, and Tanning Attitudes Among Asian College Students in the Northeastern USA.

BACKGROUND: College students participate in high levels of tanning, a skin cancer risk behavior due to ultraviolet radiation exposure, yet little is known about Asian college students' behavior. This study examined the relationship between tanning attitudes, acculturation to the USA (cultural assimilation), and tanning behavior. METHOD: An online survey was used to recruit 211 Asian college students in the northeastern USA (47.4% born outside of the USA) to respond to questions about recent tanning behavior, sun protection strategies, attitudes about tanning, and acculturation to the USA. RESULTS: Attitudes about tanning, particularly desire for a darker skin tone and social norms, along with acculturation to the USA, were predictive of intentional tanning. The sample reported high levels of sun protection, which was associated with low acculturation. CONCLUSION: The significant role of acculturation in this study indicates that it may be a useful factor to include in future tanning intervention studies of relevant populations.

Sun Exposure, Tanning Behaviors, and Sunburn: Examining Activities Associated With Harmful Ultraviolet Radiation Exposures in College Students.

Understanding the behaviors that lead to sunburn is an important objective toward developing intervention strategies to reduce risk for skin cancers. Our cross-sectional study surveyed 400 college students aged 18 and older at a public state university in the northeastern US in 2018 to assess tanning behaviors, outdoor activities, sun protection, and sunburn over the past year. Sunburn was exceedingly common; over half reported one or more sunburns in the past 12 months. Outdoor intentional and unintentional tanning were also common. Male sex, White race, sun sensitive skin type, and outdoor intentional and unintentional tanning were independently associated with increased odds of sunburn. Water and non-water sports, sunbathing, and vacations were also associated with sunburn. These results indicate that tanning and outdoor activities such as sports are important behaviors on which to focus for sunburn prevention among college students. Understanding the behaviors that are associated with sunburn provides useful opportunities to prevent skin cancer among young people.

Indoor Tanning Trends Among US Adults, 2007-2018.

Objectives. To examine indoor tanning trends among US adults, and the relation to indoor tanning youth access legislation.Methods. This study analyzed the Health Information National Trends Survey (HINTS), a mailed survey, from the years 2007, 2011, 2013, 2014, 2017, and 2018 (combined n = 20 2019).Results. Indoor tanning prevalence decreased significantly over time among all US adults from 2007 (10%) to 2018 (4%; P < .001), among young adults aged 18 to 34 years (14% to 4%; P < .001), and among both women (14% to 4%; P < .001) and men (5% to 4%; P < .05). Indoor tanning significantly decreased in states that enacted youth access legislation by 2018, but did not significantly decrease for other states. Frequent indoor tanning was common in 2018; about one quarter of respondents who reported any indoor tanning did so 25 times or more in the past year.Conclusions. This study identifies several challenges in continuing to reduce indoor tanning in the United States. Youth access legislation may be effective for reducing tanning among the broader population of tanners; however, there remains a need for focus on highly frequent tanners, as well as men.

Evaluation of a culturally sensitive social and emotional well-being program for Aboriginal and Torres Strait Islanders.

OBJECTIVE: To evaluate Deadly Thinking, a social and emotional well-being promotion program targeted to remote and rural Aboriginal and Torres Strait Islander communities. Deadly Thinking aims to improve emotional health literacy, psychological well-being and attitudes towards associated help-seeking. DESIGN: Participants completed pre/post-test evaluations via a brief self-report survey immediately before and after the Deadly Thinking workshop. SETTING: Aboriginal and Torres Strait Islander communities in rural and regional Australia. PARTICIPANTS: Data were obtained from 413 participants (69.8% female, mean age 41.6 years), of whom 70.4% identified as Aboriginal or Torres Strait Islanders. INTERVENTION: Deadly Thinking workshops involve participant's engaging with a series of videos and facilitated group discussions with other participants related to social and emotional well-being topics relevant to individuals and communities. MAIN OUTCOME MEASURES: Participants completed measures of psychological distress, suicidal ideation, substance use, changes in attitudes towards help-seeking and help-seeking intentions and satisfaction with the workshop. Additionally, participants in a train-the-trainer workshop rated their perceived confidence to deliver the program post-workshop. RESULT: Participants reported positive perceptions of community safety and well-being and low rates of marked distress, with no significant difference between train-the-trainer and community workshop participants. Results indicated significant improvement in help-seeking intentions post-workshop and high rates of satisfaction with workshop components. CONCLUSION: Initial evaluation indicates good acceptability and feasibility of delivering the Deadly Thinking program in rural and remote Indigenous communities; however, more robust evaluation of the program is warranted using controlled conditions to measure effectiveness, particularly for changing in help-seeking behaviour.

'I am happier with my fairer complexion': factors associated with former indoor tanning and reasons for quitting in college women.

This study of 312 female undergraduates investigated the association of recently, formerly, or never indoor tanning with self-perceptions and social influence, and examined reasons to tan and not to tan. Previous research on indoor tanning has focused on recent or current tanners, and few studies have examined former indoor tanners. By examining self-perceptions and social influence, this study aimed to understand how these common tanning correlates, measured in former indoor tanners, compared to those who have never tanned indoors (i.e., never tanners) and those who have recently tanned indoors. Appearance and global self-perceptions were more positive in former indoor tanners compared to never tanners and recent tanners. Recent indoor tanning was positively associated with both higher outdoor tanning frequency and having a higher number of friends performing skin cancer risk behaviors, and formerly indoor tanning was also associated with both, but to a lesser extent. Appearance and social influence were commonly described as reasons for indoor tanning, and perceived health risk, appearance, and social influence were described as prominent reasons for tanning cessation. This study improves what is known about former indoor tanners, which may be useful for behavior change maintenance efforts and developing approaches for skin cancer screening interventions.

Psychological distress in remote mining and construction workers in Australia.

OBJECTIVES: To assess the prevalence and correlates of psychological distress in a sample of remote mining and construction workers in Australia. Design, setting: A cross-sectional, anonymous Wellbeing and Lifestyle Survey at ten mining sites in South Australia and Western Australia, administered at meetings held during 2013-2015. PARTICIPANTS: 1124 employees at remote construction, and open cut and underground mining sites completed the survey. MAIN OUTCOME MEASURES: General psychological distress (Kessler Psychological Distress Scale, K10) and self-reported overall mental health status; work, lifestyle and family factors correlated with level of psychological distress. RESULTS: The final sample comprised 1124 workers; 93.5% were men, 63% were aged 25-44 years. 311 respondents (28%) had K10 scores indicating high/very high psychological distress, compared with 10.8% for Australia overall. The most frequently reported stressors were missing special events (86%), relationship problems with partners (68%), financial stress (62%), shift rosters (62%), and social isolation (60%). High psychological distress was significantly more likely in workers aged 25-34 years (v ≥ 55 years: odds ratio [OR], 3.2; P = 0.001) and workers on a 2 weeks on/1 week off roster (v 4 weeks on/1 week off: OR, 2.4; P < 0.001). Workers who were very or extremely stressed by their assigned tasks or job (OR, 6.2; P = 0.004), their current relationship (OR, 8.2; P < 0.001), or their financial situation (OR, 6.0; P < 0.001) were significantly more likely to have high/very high K10 scores than those not stressed by these factors. Workers who reported stress related to stigmatisation of mental health problems were at the greatest risk of high/very high psychological distress (v not stressed: OR, 23.5; P < 0.001). CONCLUSIONS: Psychological distress is significantly more prevalent in the remote mining and construction workforce than in the overall Australian population. The factors that contribute to mental ill health in these workers need to be addressed, and the stigma associated with mental health problems reduced.

GLP-1 receptors exist in the parietal cortex, hypothalamus and medulla of human brains and the GLP-1 analogue liraglutide alters brain activity related to highly desirable food cues in individuals with diabetes: a crossover, randomised, placebo-controlled trial.

AIMS/HYPOTHESIS: Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue that has been demonstrated to successfully treat diabetes and promote weight loss. The mechanisms by which liraglutide confers weight loss remain to be fully clarified. Thus, we investigated whether GLP-1 receptors are expressed in human brains and whether liraglutide administration affects neural responses to food cues in diabetic individuals (primary outcome). METHODS: In 22 consecutively studied human brains, expression of GLP-1 receptors in the hypothalamus, medulla oblongata and parietal cortex was examined using immunohistochemistry. In a randomised (assigned by the pharmacy using a randomisation enrolment table), placebo-controlled, double-blind, crossover trial, 21 individuals with type 2 diabetes (18 included in analysis due to lack or poor quality of data) were treated with placebo and liraglutide for a total of 17 days each (0.6 mg for 7 days, 1.2 mg for 7 days, and 1.8 mg for 3 days). Participants were eligible if they had type 2 diabetes and were currently being treated with lifestyle changes or metformin. Participants, caregivers, people doing measurements and/or examinations, and people assessing the outcomes were blinded to the medication assignment. We studied metabolic changes as well as neurocognitive and neuroimaging (functional MRI) of responses to food cues at the clinical research centre of Beth Israel Deaconess Medical Center. RESULTS: Immunohistochemical analysis revealed the presence of GLP-1 receptors on neurons in the human hypothalamus, medulla and parietal cortex. Liraglutide decreased activation of the parietal cortex in response to highly desirable (vs less desirable) food images (p < 0.001; effect size: placebo 0.53 ± 0.24, liraglutide -0.47 ± 0.18). No significant adverse effects were noted. In a secondary analysis, we observed decreased activation in the insula and putamen, areas involved in the reward system. Furthermore, we showed that increased ratings of hunger and appetite correlated with increased brain activation in response to highly desirable food cues while on liraglutide, while ratings of nausea correlated with decreased brain activation. CONCLUSIONS/INTERPRETATION: For the first time, we demonstrate the presence of GLP-1 receptors in human brains. We also observe that liraglutide alters brain activity related to highly desirable food cues. Our data point to a central mechanism contributing to, or underlying, the effects of liraglutide on metabolism and weight loss. Future studies will be needed to confirm and extend these findings in larger samples of diabetic individuals and/or with the higher doses of liraglutide (3 mg) recently approved for obesity. TRIAL REGISTRATION: ClinicalTrials.gov NCT01562678 FUNDING : The study was funded by Novo Nordisk, NIH UL1 RR025758 and 5T32HD052961.

Skin Cancer Diagnosis Among People With Disabilities.

INTRODUCTION: People with disabilities face unique challenges that may affect skin cancer prevention, diagnosis, and access to treatment. These challenges could be exacerbated by the COVID-19 pandemic. In 2022, the prevalence of self-reported skin cancer diagnoses, delayed medical care because of the coronavirus disease 2019 (COVID-19) pandemic, and skin cancer risk factors among people with disabilities were estimated. METHODS: Data from the 2020 National Health Interview Survey (N=31,568 U.S. adults) were analyzed. Skin cancer diagnosis, age at the time of skin cancer diagnosis, skin cancer risk factors (e.g., sun protection), and delayed medical care because of the COVID-19 pandemic were included. Disability status was measured using the Washington Group Short Set on Functioning, which includes vision, hearing, mobility, communication, self-care, and cognitive disabilities. RESULTS: Although 8.8% of U.S. adults reported having a disability, people with disabilities accounted for 14.7% of all self-reported skin cancer diagnoses, including 17.5% of melanoma diagnoses. Notably, people with disabilities were on average, older (mean age=59.8 years) than people without disabilities (mean age=46.8 years). Models that adjusted for age and other demographics revealed that people with disabilities had higher odds of delaying medical care because of the COVID-19 pandemic (OR=1.65, 95% CI=1.41, 1.94); people with disabilities reported being diagnosed with skin cancer later in life (age 61.5 vs 54.0 years; p<0.001) but had odds of reporting any skin cancer (OR=1.11, 95% CI=0.93, 1.32) or melanoma diagnosis (OR=1.33, 95% CI=0.95, 1.87) similar to those of people without disabilities. CONCLUSIONS: Because of disability-related challenges, older age, and delaying medical care during the pandemic, people with disabilities may be at increased risk for inequitable skin cancer outcomes.

Evolution of allometry in antirrhinum.

Correlated variation in shape and size (allometry) is a major component of natural diversity. We examined the evolutionary and genetic basis for allometry using leaves and flower petals of snapdragon species (Antirrhinum). A computational method was developed to capture shape and size variation in both types of organ within the Antirrhinum species group. The results show that the major component of variation between species involves positively correlated changes in leaf and petal size. The correlation was maintained in an F2 population derived from crossing two species with organs of different sizes, suggesting that developmental constraints were involved. Identification of the underlying genes as quantitative trait loci revealed that the larger species carried alleles that increased organ size at all loci. Although this was initially taken as evidence that directional selection has driven diversity in both leaf and petal size, simulations revealed that evolution without consistent directional selection, an undirected walk, could also account for the parental distribution of organ size alleles.

Young adults' stigmatizing perceptions about individuals with skin cancer: the influence of potential cancer cause, cancer metaphors, and gender.

Objective: This study examined the influence of three potential predictors of stigmatising cancer perceptions: the controllability of the cancer cause, metaphors used to describe the cancer experience, and the target's gender.Method: 306 undergraduates (Mage = 20) were recruited via subject pool, balancing males and females. Participants read a fictitious post by a patient/blogger with skin cancer that described different potential causes for their cancer varying with respect to its controllability, used varying types of commonly invoked cancer metaphors, and indicated their gender with names.Main outcome measures: Potential stigmatisation of the blogger in the form of negative affective responses, perceptions of flawed character, desired social distance and expectations for post-traumatic growth were assessed using mixed methods. The perceived age of the blogger and expectations for their survival were also explored.Results: More blame, less sympathy, and less favourable perceptions of character were ascribed to the hypothetical blogger when their cancer was described as due to their lifestyle rather than genetics and thus potentially construed as more controllable. Females using a war metaphor resulted in more positive responses compared to a female using no metaphorical language.Conclusion: Stigmatisation of individuals with skin cancer may depend on the potential cause of cancer, and to some extent, metaphors and gender.

Interventions to Improve Prognostic Understanding in Advanced Stages of Life-Limiting Illness: A Systematic Review.

CONTEXT: Among patients with advanced life-limiting illness, an inaccurate understanding of prognosis is common and associated with negative outcomes. Recent years have seen an emergence of new interventions tested for their potential to improve prognostic understanding. However, this literature has yet to be synthesized. OBJECTIVES: To identify and characterize tested interventions, summarize intervention findings, and outline directions for future research. METHODS: Systematic searches were conducted in five databases - PubMed/MEDLINE (NLM), EMBASE (Elsevier), CINAHL (EBSCO), PsycINFO (OVID), and Cochrane Central Register of Controlled Trials (Wiley) - to identify interventions evaluated within a randomized controlled design for their impact on prognostic understanding. RESULTS: Of the 2354 initial articles, 12 were selected for final inclusion, representing nine unique interventions. Intervention types included decision aids accompanying medical consults, palliative care consultations, communication training for patients and physicians, and targeted discussions regarding prognosis and treatment decision making. Common components of interventions included provision of prognostic information, assistance with end-of-life care planning, and provision of decisional and emotional support during discussions. Most interventions were associated with some indication of improvement in prognostic understanding. However, even after intervention, inaccurate prognostic understanding was common, with 31-95 percent of patients in intervention groups exhibiting inaccurate perceptions of their prognosis. CONCLUSION: Prognostic understanding interventions hold the potential to improve patient understanding and thus informed decision making, but limitations exist. Future research should examine why many patients receiving intervention may continue to maintain inaccurate perceptions, and identify which intervention components can best enhance informed, value-consistent decision making.

Detection of clinically relevant exonic copy-number changes by array CGH.

Array comparative genomic hybridization (aCGH) is a powerful tool for the molecular elucidation and diagnosis of disorders resulting from genomic copy-number variation (CNV). However, intragenic deletions or duplications--those including genomic intervals of a size smaller than a gene--have remained beyond the detection limit of most clinical aCGH analyses. Increasing array probe number improves genomic resolution, although higher cost may limit implementation, and enhanced detection of benign CNV can confound clinical interpretation. We designed an array with exonic coverage of selected disease and candidate genes and used it clinically to identify losses or gains throughout the genome involving at least one exon and as small as several hundred base pairs in size. In some patients, the detected copy-number change occurs within a gene known to be causative of the observed clinical phenotype, demonstrating the ability of this array to detect clinically relevant CNVs with subkilobase resolution. In summary, we demonstrate the utility of a custom-designed, exon-targeted oligonucleotide array to detect intragenic copy-number changes in patients with various clinical phenotypes.

Adolescent sleep and technology-use rules: results from the California Health Interview Survey.

OBJECTIVES: This study reports on adolescent sleep, technology-use rules at home, and their potential association using the 2017 California Health Interview Survey (CHIS). METHODS: CHIS cross-sectional, representative survey data was collected between June-December 2017 via telephone. Weekday bedtimes, rise times, and night time in bed in the past week, as well as whether technology-use rules were implemented at home, were examined among 448 adolescent residents of California (mean age = 14.5, range = 12-17; 48% women). RESULTS: The average weekday nightly time in bed was 9.04 hours among 12- to 13-year-olds and 7.89 hours among 14- to 17-year-olds. The majority reported having technology-use rules and those who did, spent 35 more minutes in bed. Although a significant relationship was found between having technology-use rules and earlier bedtime, one was not found for time in bed, when controlling for demographics. CONCLUSIONS: Many California adolescents do not meet recommended sleep guidelines. Yet, technology-use rules appear to be associated with earlier bedtime. Results have implications for policy-making and adolescent sleep interventions.

Barriers to mammography screening among racial and ethnic minority women.

RATIONALE: Breast cancer is the second leading cause of cancer death among women. Disparities in breast cancer mortality rates adversely affect racial/ethnic minority women. Mammography screening is the most effective early detection method and means of reducing mortality rates. Yet, barriers prevent racial/ethnic minority women from participating in regular screening. OBJECTIVE: This review aimed to summarize self-reported barriers to mammography screening in racial/ethnic minority women in studies using open-ended assessments and closed-ended assessments. METHOD: Literature searches were conducted in two databases, PsycINFO and PubMed. Barriers were detailed in full by barrier type (psychological/knowledge-related, logistical, cultural/immigration-related, and social/interpersonal) and summarized briefly by race/ethnicity (African American/Black, Asian/Pacific Islander, Hispanic, American Indian/Native American, and Middle Eastern). RESULTS: Twenty-two open-ended and six closed-ended studies were identified as eligible for this review. Overall, racial/ethnic minority women identified common logistical and psychological/knowledge-related barriers. Additionally, women reported cultural/immigration-related and social/interpersonal barriers that were closely tied to their racial/ethnic identities. CONCLUSIONS: It was concluded that cultural/immigration-related barriers may be the only barrier type that is unique to racial/ethnic minority women. Thus, designing studies of barriers around race and ethnicity is not always appropriate, and other demographic factors are sometimes a more important focus. The variability in 'barrier' definitions, how data were collected and reported, and the appropriateness of closed-ended measures were also examined. This literature may benefit from detailed and strategically designed studies that allow more clear-cut conclusions and better comparison across studies as well as improving closed-ended measures by incorporating insights from investigations using open-ended inquiry.

Effects of school start time on students' sleep duration, daytime sleepiness, and attendance: a meta-analysis.

Research conducted over the past three decades finds that many children and adolescents do not meet recommended sleep guidelines. Lack of sleep is a predictor of a number of consequences, including issues at school such as sleepiness and tardiness. Considering the severity of this public health issue, it is essential to understand more about the factors that may compromise children's and adolescents' sleep. This meta-analysis examined the effects of school start time (SST) on sleep duration of students by aggregating the results of five longitudinal studies and 15 cross-sectional comparison group studies. Results indicated that later starting school times are associated with longer sleep durations. Additionally, later start times were associated with less daytime sleepiness (7 studies) and tardiness to school (3 studies). However, methodological considerations, such as a need for more longitudinal primary research, lead to a cautious interpretation. Overall, this systematic analysis of SST studies suggests that delaying SST is associated with benefits for students' sleep and, thus, their general well-being.

How a mild influenza B infection can kill: A case of pulmonary hemorrhage.

Viral influenza is a seasonal infection associated with significant morbidity and mortality. Rapidly fatal hemorrhagic pneumonia has been described in previously healthy individuals with ß-hemolytic Streptococcus pneumoniae in a small series of patients, but it is not common in patients coinfected with influenza B and ß-hemolytic Streptococcus, particularly since influenza B is considered less pathogenic than influenza A. However, despite being uncommon, this coinfection seems to be associated with high morbidity and mortality, particularly in healthy individuals. We present a case of a 46-year-old previously healthy white woman presenting with 4 days of shortness of breath, sore throat, subjective fevers, and nonproductive cough with rapidly fatal hemorrhagic pneumonia confirmed to have Group A ß-hemolytic Streptococcus and influenza B coinfection. On admission, she had a temperature of 103° F, room air oxygen saturation of 95%, a positive nasal swab for influenza B, and negative rapid strep test. Initial chest radiograph showed increased bibasilar interstitial markings. She was admitted to a regular floor and started on oseltamivir. Preliminary throat culture was positive for Group A ß-hemolytic Streptococcus and penicillin V was started. Respiratory status deteriorated requiring intubation and transfer to Intensive Care Unit. Subsequently, copious bleeding was noted in her endotracheal tube. A bedside bronchoscopy with bronchoalveolar lavage revealed a hemorrhagic pneumonitis. Despite aggressive efforts, she developed shock, arrested, and died Western District Office of the Chief Medical Examiner, Roanoke, VA, USA postadmission. Blood cultures, bronchoalveolar lavage, and postmortem pulmonary tissue grew Group A ß-hemolytic Streptococcus, only resistant to erythromycin.

Treatment of HAART-induced lactic acidosis with B vitamin supplements.

Lactic acidosis, a rare but life-threatening condition is fairly common in HIV-infected individuals. The cause of lactic acidosis appears to stem from the use of HAART, causing mitochondrial dysfunction and the depletion of flavoprotein cofactors necessary for electron transport. Deficiencies of riboflavin or thiamin can contribute to the development of hyperlactic acidemia. Further, the high incidence of liver disease (hepatitis B or C and alcoholic liver disease) in this population predisposes HIV patients to metabolic abnormalities. Supplementation with thiamin or riboflavin, depending on the individual patient's condition, can reduce elevated lactic acid levels.

The utility of C4d, C9, and troponin T immunohistochemistry in acute myocardial infarction.

CONTEXT: Full activation and involvement of the complement pathway follows acute myocardial infarction. Complement fragment C4d is a stable, covalently bound marker of complement activation. Troponin T is specific for cardiomyocytes. OBJECTIVES: To determine the specificity of C4d, C9, and troponin T immunoreactivity in necrotic myocytes and to establish whether they can be used to delineate acute myocardial infarction. DESIGN: Twenty-six autopsy cases with a total of 54 myocardium areas of infarction were reviewed retrospectively. Immunohistochemistry for C4d, C9, and troponin T was used on paraffin sections of formalin-fixed tissue. Controls consisted of 5 cases without evidence of infarction, and histologically normal myocardium functioned as an internal control. RESULTS: C4d and C9 antibodies reacted strongly and diffusely with necrotic myocytes in all samples of infarctions for up to 2 days (19 of 19; 100%). Adjacent histologically normal myocytes were nonreactive, resulting in a clear delineation between damaged and viable myocardium. Reactivity declined with increased duration and was absent in scars. Troponin T showed loss of staining in preinflammatory lesions (8 of 13; 62%); however, nonspecific patchy loss of staining was present in negative controls and in viable myocardium. Immunostains provided new diagnoses in 2 cases, including evidence of reinfarction and a newly diagnosed acute myocardial infarction. CONCLUSIONS: C4d and C9 have comparable reactivity and specificity for necrotic myocytes. C4d and C9 staining of necrotic myocytes is apparent before the influx of inflammatory cells, demonstrating utility in early myocardial infarction. Patchy loss of Troponin T in some cases of histologically normal myocardium limited its usefulness as a sole marker of infarction.

Fatigue in coccidioidomycosis. Quantification and correlation with clinical, immunological, and nutritional factors.

While described in the past, the frequency and degree of fatigue associated with symptomatic coccidioidomycosis has never been quantified. Using the Fatigue Severity Scale (FSS), severe fatigue (FSS score = 41) was found in 65% of cases of active coccidioidomycosis compared to 42% in cohort of control subjects with chronic medical diseases (P=0.024). Fatigue in patients with symptomatic coccidioidomycosis declined significantly over four months (P=0.023). Severe fatigue in patients with symptomatic coccidioidomycosis was significantly associated with low body mass index (BMI; P=0.024) but was not significantly associated with either serum leptin (r2=0.078, P=0.261) or serum TNF-alpha (r2=0.028, P=0.504) concentrations. Severe fatigue is a common condition among patients with active coccidioidomycosis and is associated with a declining BMI.

IGFBP-3 activates TGF-beta receptors and directly inhibits growth in human intestinal smooth muscle cells.

We have shown that human intestinal smooth muscle cells produce IGF-I and IGF binding protein-3 (IGFBP-3). Endogenous IGF-I acts in autocrine fashion to stimulate growth of these cells. IGFBP-3 inhibits the binding of IGF-I to its receptor and thereby inhibits IGF-I-stimulated growth. In several carcinoma cell lines and some normal cells, IGFBP-3 regulates growth independently of IGF-I. Two mechanisms for this effect have been identified: IGFBP-3 can directly activate transforming growth factor-beta (TGF-beta) receptors or it can undergo direct nuclear translocation. The aim of the present study was to determine whether IGFBP-3 acts independently of IGF-I and to characterize the mechanisms mediating this effect in human intestinal smooth muscle cells. The direct effects of IGFBP-3 were determined in the presence of an IGF-I receptor antagonist to eliminate its IGF-I-dependent effects. Affinity labeling of TGF-beta receptors (TGF-betaRI, TGF-betaRII, and TGF-betaRV) with 125I-labeled TGF-beta1 showed that IGFBP-3 displaced binding to TGF-betaRII and TGF-betaRV in a concentration-dependent fashion. IGFBP-3 stimulated TGF-betaRII-dependent serine phosphorylation (activation) of both TGF-betaRI and of its primary substrate, Smad2(Ser465/467). IGFBP-3 also caused IGF-I-independent inhibition of basal [3H]thymidine incorporation. The effects of IGFBP-3 on Smad2 phosphorylation and on smooth muscle cell proliferation were independent of TGF-beta1 and were abolished by transfection of Smad2 siRNA. Immunoneutralization of IGFBP-3 increased basal [3H]thymidine incorporation, implying that endogenous IGFBP-3 inhibits proliferation. We conclude that endogenous IGFBP-3 directly inhibits proliferation of human intestinal smooth muscle cells by activation of TGF-betaRI and Smad2, an effect that is independent of its effect on IGF-I-stimulated growth.