Glaucomatous aqueous humor vesicles are smaller and differ in composition compared to controls.

Cells communicate with each other using vesicles of varying sizes, including a specific repertoire known as exosomes. We isolated aqueous humor (AH)-derived vesicles using two different methods: ultracentrifugation and an exosome isolation kit. We confirmed a unique vesicle size distribution in the AH derived from control and primary open-angle glaucoma (POAG) patients using various techniques, including Nanotracker, dynamic light scattering, atomic force imaging, and electron microscopy. Bonafide vesicle and/or exosome markers were present by dot blot in both control and POAG AH-derived vesicles. Marker levels differed between POAG and control samples, while non-vesicle negative markers were absent in both. Quantitative labeled (iTRAQ) proteomics showed a reduced presence of a specific protein, STT3B, in POAG compared to controls, which was further confirmed using dot blot, Western blot, and ELISA assays. Along the lines of previous findings with AH profiles, we found vast differences in the total phospholipid composition of AH vesicles in POAG compared to controls. Electron microscopy further showed that the addition of mixed phospholipids alters the average size of vesicles in POAG. We found that the cumulative particle size of type I collagen decreased in the presence of Cathepsin D, which normal AH vesicles were able to protect against, but POAG AH vesicles did not. AH alone had no effect on collagen particles. We observed a protective effect on collagen particles with an increase in artificial vesicle sizes, consistent with the protective effects observed with larger control AH vesicles but not with the smaller-sized POAG AH vesicles. Our experiments suggest that AH vesicles in the control group provide greater protection for collagen beams compared to POAG, and their increased vesicle sizes are likely contributing factors to this protection.

Stem Cells and Natural Agents in the Management of Neurodegenerative Diseases: A New Approach.

Neurodegenerative diseases refer to a group of neurological disorders as a consequence of various destructive illnesses, that predominantly impact neurons in the central nervous system, resulting in impairments in certain brain functions. Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, and other neurodegenerative disorders represent a major risk to human health. In order to optimize structural and functional recovery, reconstructive methods integrate many approaches now, to address the complex and multivariate pathophysiology of neurodegenerative disorders. Stem cells, with their unique property of regeneration, offer new possibilities in regenerative and reconstructive medicine. Concurrently, there is an important role for natural products in controlling many health sufferings and they can delay or even prevent the onset of various diseases. In addition, due to their therapeutic properties, they have been used as neuroprotective agents to treat neurodegenerative disorders. After decades of intensive research, scientists made advances in treating these disorders so far, but current therapies are still not capable of preventing the illnesses from progressing. Therefore, in this review, we focused on a new perspective combining stem cells and natural products as an innovative therapy option in the management of neurodegenerative diseases.

Quantifying the robustness of causal inferences: Sensitivity analysis for pragmatic social science.

Social scientists seeking to inform policy or public action must carefully consider how to identify effects and express inferences because actions based on invalid inferences may not yield the intended results. Recognizing the complexities and uncertainties of social science, we seek to inform inevitable debates about causal inferences by quantifying the conditions necessary to change an inference. Specifically, we review existing sensitivity analyses within the omitted variables and potential outcomes frameworks. We then present the Impact Threshold for a Confounding Variable (ITCV) based on omitted variables in the linear model and the Robustness of Inference to Replacement (RIR) based on the potential outcomes framework. We extend each approach to include benchmarks and to fully account for sampling variability represented by standard errors as well as bias. We exhort social scientists wishing to inform policy and practice to quantify the robustness of their inferences after utilizing the best available data and methods to draw an initial causal inference.

Calebin A, a Compound of Turmeric, Down-Regulates Inflammation in Tenocytes by NF-κB/Scleraxis Signaling.

Calebin A (CA) is one of the active constituents of turmeric and has anti-inflammatory and antioxidant effects. Excessive inflammation and cell apoptosis are the main causes of tendinitis and tendinopathies. However, the role of CA in tendinitis is still unclear and needs to be studied in detail. Tenocytes in monolayer or 3D-alginate cultures in the multicellular tendinitis microenvironment (fibroblast cells) with T-lymphocytes (TN-ME) or with TNF-α or TNF-ß, were kept without treatment or treated with CA to study their range of actions in inflammation. We determined that CA blocked TNF-ß-, similar to TNF-α-induced adhesiveness of T-lymphocytes to tenocytes. Moreover, immunofluorescence and immunoblotting showed that CA, similar to BMS-345541 (specific IKK-inhibitor), suppressed T-lymphocytes, or the TNF-α- or TNF-ß-induced down-regulation of Collagen I, Tenomodulin, tenocyte-specific transcription factor (Scleraxis) and the up-regulation of NF-κB phosphorylation; thus, its translocation to the nucleus as well as various NF-κB-regulated proteins was implicated in inflammatory and degradative processes. Furthermore, CA significantly suppressed T-lymphocyte-induced signaling, similar to TNF-ß-induced signaling, and NF-κB activation by inhibiting the phosphorylation and degradation of IκBα (an NF-κB inhibitor) and IκB-kinase activity. Finally, inflammatory TN-ME induced the functional linkage between NF-κB and Scleraxis, proposing that a synergistic interaction between the two transcription factors is required for the initiation of tendinitis, whereas CA strongly attenuated this linkage and subsequent inflammation. For the first time, we suggest that CA modulates TN-ME-promoted inflammation in tenocytes, at least in part, via NF-κB/Scleraxis signaling. Thus, CA seems to be a potential bioactive compound for the prevention and treatment of tendinitis.

A new antibiotic kills pathogens without detectable resistance.

Antibiotic resistance is spreading faster than the introduction of new compounds into clinical practice, causing a public health crisis. Most antibiotics were produced by screening soil microorganisms, but this limited resource of cultivable bacteria was overmined by the 1960s. Synthetic approaches to produce antibiotics have been unable to replace this platform. Uncultured bacteria make up approximately 99% of all species in external environments, and are an untapped source of new antibiotics. We developed several methods to grow uncultured organisms by cultivation in situ or by using specific growth factors. Here we report a new antibiotic that we term teixobactin, discovered in a screen of uncultured bacteria. Teixobactin inhibits cell wall synthesis by binding to a highly conserved motif of lipid II (precursor of peptidoglycan) and lipid III (precursor of cell wall teichoic acid). We did not obtain any mutants of Staphylococcus aureus or Mycobacterium tuberculosis resistant to teixobactin. The properties of this compound suggest a path towards developing antibiotics that are likely to avoid development of resistance.

General Practice Patients' Readiness to be Treated With Brief Intervention to Reduce Alcohol Consumption: A Cross-Sectional Study With Between-Subject Design.

AIMS: To treat excessive alcohol consumption, general practices (GPs) are recommended to use non-directive implementation strategies. Directive implementation, however, may be perceived by general practice patients as something positive because of possibly indicating higher GP engagement and a more consistent treatment. In our study, we aimed to assess the readiness of patients to be treated with BI in the hypothetical event of excessive alcohol consumption either by a GP using non-directive recommendations according to WHO or by a GP using directive instructions. Additionally, we assessed the patients' dispositional readiness to disclose alcohol-associated personal information, termed alcohol consumption self-disclosure, in order to analyze its influence on their readiness to be treated with brief intervention (BI). METHODS: When consulting their GP, a convenience sample of general practice patients was asked by questionnaire. By means of a between-subject design, they were asked for the readiness to be treated either with non-directive BI or with directive BI. Repeated-measure ANCOVA was used to analyze the main- and interaction effects. RESULTS: A sample of 442 general practice patients preferred the non-directive BI, F(1, 423) = 5.56, P < 0.05. We found moreover a two-way interaction between implementation and alcohol consumption self-disclosure, F(1, 423) = 18.89, P < 0.001, showing that only patients with low self-disclosure preferred the non-directive BI, t(428) = 3.99, P < 0.001. CONCLUSIONS: Future research should investigate the reasons for the patients' preference for the non-directive BI and may develop strategies to overcome the possibly low readiness of general practice patients to be treated with BI.

Toward a robust science of suicide: Epistemological, theoretical, and methodological considerations in advancing suicidology.

Suicidology is at a crossroads, the crux of which came into plain view recently when Hjelmeland/Knizek's critique of mainstream suicidology was followed by two ardent essays defending suicidology as it currently exists. We stake out a middle-way approach leveraging sociology's unique disciplinary perspective to bridge the two sides to construct a robust transdisciplinary toolbox that helps suicidology advance as science and improve how we study suicide and, therefore, what we know. The essay first examines the underlying structural and cultural reasons for the talking past each other, before turning towards our own understanding of science, methods, and the study of suicide.

Curcumin Attenuates Environment-Derived Osteoarthritis by Sox9/NF-kB Signaling Axis.

Inflammation has a fundamental impact on the pathophysiology of osteoarthritis (OA), a common form of degenerative arthritis. It has previously been established that curcumin, a component of turmeric (Curcuma longa), has anti-inflammatory properties. This research evaluates the potentials of curcumin on the pathophysiology of OA in vitro. To explore the anti-inflammatory efficacy of curcumin in an inflamed joint, an osteoarthritic environment (OA-EN) model consisting of fibroblasts, T-lymphocytes, 3D-chondrocytes is constructed and co-incubated with TNF-α, antisense oligonucleotides targeting NF-kB (ASO-NF-kB), or an IkB-kinase (IKK) inhibitor (BMS-345541). Our results show that OA-EN, similar to TNF-α, suppresses chondrocyte viability, which is accompanied by a significant decrease in cartilage-specific proteins (collagen II, CSPG, Sox9) and an increase in NF-kB-driven gene proteins participating in inflammation, apoptosis, and breakdown (NF-kB, MMP-9, Cox-2, Caspase-3). Conversely, similar to knockdown of NF-kB at the mRNA level or at the IKK level, curcumin suppresses NF-kB activation, NF-kB-promotes gene proteins derived from the OA-EN, and stimulates collagen II, CSPG, and Sox9 expression. Furthermore, co-immunoprecipitation assay shows that curcumin reduces OA-EN-mediated inflammation and chondrocyte apoptosis, with concomitant chondroprotective effects, due to modulation of Sox-9/NF-kB signaling axis. Finally, curcumin selectively hinders the interaction of p-NF-kB-p65 directly with DNA-this association is disrupted through DTT. These results suggest that curcumin suppresses inflammation in OA-EN via modulating NF-kB-Sox9 coupling and is essential for maintaining homeostasis in OA by balancing chondrocyte survival and inflammatory responses. This may contribute to the alternative treatment of OA with respect to the efficacy of curcumin.

Heart failure in adult congenital heart disease: tetralogy of Fallot.

The number of rTOF patients who survive into adulthood is steadily rising, with currently more than 90% reaching the third decade of life. However, rTOF patients are not cured, but rather have a lifelong increased risk for cardiac and non-cardiac complications. Heart failure is recognized as a significant complication. Its occurrence is strongly associated with adverse outcome. Unfortunately, conventional concepts of heart failure may not be directly applicable in this patient group. This article presents a review of the current knowledge on HF in rTOF patients, including incidence and prevalence, the most common mechanisms of heart failure, i.e., valvular pathologies, shunt lesions, left atrial hypertension, primary left heart and right heart failure, arrhythmias, and coronary artery disease. In addition, we will review information regarding extracardiac complications, risk factors for the development of heart failure, clinical impact and prognosis, and assessment possibilities, particularly of the right ventricle, as well as management strategies. We explore potential future concepts that may stimulate further research into this field.

Who Gets the Benefit of the Doubt? Performance Evaluations, Medical Errors, and the Production of Gender Inequality in Emergency Medical Education.

Why do women continue to face barriers to success in professions, especially male-dominated ones, despite often outperforming men in similar subjects during schooling? With this study, we draw on role expectations theory to understand how inequality in assessment emerges as individuals transition from student to professional roles. To do this, we leverage the case of medical residency so that we can examine how changes in role expectations shape assessment while holding occupation and organization constant. By analyzing a dataset of 2,765 performance evaluations from a three-year emergency medicine training program, we empirically demonstrate that women and men are reviewed as equally capable at the beginning of residency, when the student role dominates; however, in year three, when the colleague role dominates, men are perceived as outperforming women. Furthermore, when we hold resident performance somewhat constant by comparing feedback to medical errors of similar severity, we find that in the third year of residency, but not the first, women receive more harsh criticism and less supportive feedback than men. Ultimately, this study suggests that role expectations, and the implicit biases they can trigger, matter significantly to the production of gender inequality, even when holding organization, occupation, and resident performance constant.

Chronic Inflammation in PCOS: The Potential Benefits of Specialized Pro-Resolving Lipid Mediators (SPMs) in the Improvement of the Resolutive Response.

PCOS as the most common endocrine disorder of women in their reproductive age affects between 5-15 % of the female population. Apart from its cardinal symptoms, like irregular and anovulatory cycles, hyperandrogenemia and a typical ultrasound feature of the ovary, obesity, and insulin resistance are often associated with the disease. Furthermore, PCOS represents a status of chronic inflammation with permanently elevated levels of inflammatory markers including IL-6 and IL-18, TNF-α, and CRP. Inflammation, as discovered only recently, consists of two processes occurring concomitantly: active initiation, involving "classical" mediators including prostaglandins and leukotrienes, and active resolution processes based on the action of so-called specialized pro-resolving mediators (SPMs). These novel lipid mediator molecules derive from the essential ω3-poly-unsaturated fatty acids (PUFAs) DHA and EPA and are synthesized via specific intermediates. The role and benefits of SPMs in chronic inflammatory diseases like obesity, atherosclerosis, and Diabetes mellitus has become a subject of intense research during the last years and since PCOS features several of these pathologies, this review aims at summarizing potential roles of SPMs in this disease and their putative use as novel therapeutics.

Examining longer-term effects of parental death in adolescents and young adults: Evidence from the national longitudinal survey of adolescent to adult health.

Using longitudinal data spanning a 7-year period, we investigated the behavioral and psycho-social effects resulting from a parent's death during early childhood or teenage years on adolescent and early adulthood functioning. Findings confirmed previous work demonstrating various behavioral problems and social-psychological adjustment deficits during adolescence. Results suggested that most detrimental adjustment behaviors among parentally bereaved youth fade as they entered into young adulthood. Yet, premature school withdrawals and diminished interests in college attendance at Wave 1 left many of these young adults with diminished academic accomplishments, lingering economic disadvantages and for females a hesitancy to marry as their lives progressed into adulthood.

Intraguild predation leads to cascading effects on habitat choice, behaviour and reproductive performance.

Intraguild predation (IGP) is a commonly recognized mechanism influencing the community structure of predators, but the complex interactions are notoriously difficult to disentangle. The mesopredator suppression hypothesis predicts that a superpredator may either simultaneously repress two mesopredators, restrain the dominant one and thereby release the subdominant mesopredator, or elicit different responses by both mesopredators. We show the outcome arising from such conditions in a three-level predator assemblage (Eurasian eagle owl Bubo bubo L., northern goshawk Accipiter gentilis L. and common buzzard Buteo buteo L.) studied over 25 years. In the second half of the study period, the eagle owl re-colonized the study area, thereby providing a natural experiment of superpredator introduction. We combined this set-up with detailed GIS analysis of habitat use and a field experiment simulating intrusion by the superpredator into territories of the subdominant mesopredator, the buzzard. Although population trends were positive for all three species in the assemblage, the proportion of failed breeding attempts increased significantly in both mesopredators after the superpredator re-colonized the area. We predicted that superpredator-induced niche shifts in the dominant mesopredator may facilitate mesopredator coexistence in superpredator-free refugia. We found significant changes in nesting habitat choice in goshawk, but not in buzzard. Since competition for enemy-free refugia and the rapid increase in population density may have constrained niche shifts of the subdominant mesopredator, we further predicted behavioural changes in response to the superpredator. The field experiment indeed showed a significant increase in aggressive response of buzzards towards eagle owl territory intrusion over the course of 10 years, probably due to phenotypic plasticity in the response towards superpredation risk. Overall, our results show that intraguild predation can be a powerful force of behavioural change, simultaneously influencing habitat use and aggressiveness in predator communities. These changes might help to buffer mesopredator populations against the negative effects of intraguild predation.

Cardiac Fibrosis in Aortic Stenosis and Hypertensive Heart Disease Assessed by Magnetic Resonance T1 Mapping.

BACKGROUND: Continuous pressure overload may lead to subclinical myocardial tissue changes in patients with hypertensive heart disease (HHD) and aortic stenosis (AS). The study aim was to detect interstitial fibrosis using quantitative cardiovascular magnetic resonance. METHODS: Fifteen patients with HHD (arterial hypertension + septal wall thickness ≥13 mm), 33 with AS (eight mild, 15 moderate, 10 severe), and 60 healthy controls were enrolled. Native T1 maps (modified Look-Locker inversion recovery) were obtained in a basal, mid-ventricular, and apical shortaxis slice of the left ventricle to assess cardiac fibrosis. Focal fibrosis was assessed with late gadolinium enhancement (LGE). RESULTS: Patients with HHD and controls did not differ regarding the native myocardial T1 values, both per slice and per segment. In AS patients, apical native T1 values were lower than in controls, and there was a trend towards higher T1 values in the septum in severe AS (1172.6 ± 62.0 ms versus 1152.9 ± 43.9 ms). Five HHD patients and 11 AS patients had non-ischemic fibrosis in LGE images. Native T1 times did not differ between LGE-positive and LGEnegative groups (both with inclusion and exclusion of segments with LGE). CONCLUSIONS: T1 mapping did not reveal any evidence of abnormal interstitial fibrosis in HHD subjects with mild hypertrophy. In severe AS, a trend towards more interstitial fibrosis was present, but absolute differences were small for decision making.

Nurses' perspectives: hospitalized older patients and end-of-life decision-making.

AIMS: To explore pressing issues identified by nurses caring for older patients in US NICHE (Nurses Improving Care for the Healthsystem Elders) hospitals, regarding palliative care and end-of-life (EOL) decision-making. Objectives are to (1) identify the most pressing palliative care and EOL decision-making issues and strategies to address them and (2) identify the association of nursing demographics (age, gender, race, education and experience), institutional/unit characteristics and these issues. BACKGROUND: Critical care nurses have an integral role in supporting older patients and families faced with palliative care and EOL decision-making issues. Despite national imperatives to improve the quality of palliative care, patients continue to experience uncontrolled pain, inadequate communication, disregard of their wishes and life prolonging interventions. These contribute to increased hospitalizations and costs. Understanding the prevalent issues is needed to address patient needs at the end-of-life. DESIGN: It is a mixed method study. METHODS: A secondary analysis of the NICHE Geriatric Institutional Assessment Profile (GIAP) database (collected 1/08-9/13) was conducted using the sample of Critical Care RNs who provided comments regarding palliative care and EOL decision-making. Qualitative data were analyzed using Dedoose software. Data clusters and patterns of co-occurring codes were explored through an iterative analysis process. Themes were examined across nurse demographics, institutional and unit characteristics. RESULTS: Comments specifically addressing issues regarding EOL decision-making were provided by 393 critical care nurses from 156 hospitals (x‾ age = 42·3 years, 51% BSN degree). Overarching theme was discordance in goals of care (prolonging life versus quality of life), ineffective physician-patient-family communication, lack of time and unrealistic expectations. CONCLUSIONS: Nurses' descriptions highlight the need for increased communication, staff education and availability of palliative care services. RELEVANCE TO PRACTICE: Palliative care and EOL decision-making will remain a nursing priority as people age and require increased care.

Suicide ideation and bullying among US adolescents: examining the intersections of sexual orientation, gender, and race/ethnicity.

OBJECTIVES: We examined how race/ethnicity, gender, and sexual orientation shape adolescents' likelihood of being bullied and vulnerability to suicide ideation. METHODS: We analyzed pooled data from the 2009 and 2011 Youth Risk Behavior Surveys (n = 75 344) to assess race/ethnicity, gender, and sexual orientation variation in being bullied and suicide ideation. RESULTS: White and Hispanic gay and bisexual males, White lesbian and bisexual females, and Hispanic bisexual females were more likely to be bullied than were White heterosexual adolescents. Black lesbian, gay, and bisexual youths' vulnerability to being bullied was not significantly different from that of White heterosexual youths. Black and Hispanic heterosexual youths were less likely to be bullied than were White heterosexual youths. Despite differences in the likelihood of being bullied, sexual minority youths were more likely to report suicide ideation, regardless of their race/ethnicity, their gender, or whether they have been bullied. CONCLUSIONS: Future research should examine how adolescents' intersecting identities shape their experience of victimization and suicidality. School personnel should develop antibullying and antihomophobia policies in response to the disproportionate risk of being bullied and reporting suicidality among sexual minority youths.

Can Social Ties be Harmful? Examining the Spread of Suicide in Early Adulthood.

Durkheim posited that social relationships protect individuals against suicide; however, substantial research demonstrates that suicide can spread through the very ties Durkheim theorized as protective. With this study, we use Waves I, III, and IV of the National Longitudinal Study of Adolescent Health, to investigate whether young adults' suicide attempts and thoughts are in part products of exposure to suicidal behaviors via their social relationships. We find that young adults who have had family members or friends attempt suicide are more likely to report suicide ideation or even suicide attempts, over both the short and long run. This finding is robust to many important controls for risk and protective factors for suicide. Our findings have implications for the sociology of suicide, not the least of which, is that social ties have the power to harm in addition to the power to protect.

Are Suicidal Behaviors Contagious in Adolescence?: Using Longitudinal Data to Examine Suicide Suggestion.

Though Durkheim argued that strong social relationships protect individuals from suicide, we posit that these relationships have the potential to increase individuals' vulnerability when they expose them to suicidality. Using three waves of data from the National Longitudinal Study of Adolescent Health, we evaluate whether new suicidal thoughts and attempts are in part responses to exposure to the suicide attempts of role models, specifically friends and family. We find that the suicide attempts of role models do in fact trigger new suicidal thoughts and in some cases attempts, even after significant controls are introduced. Moreover, we find that these effects fade with time, that girls are more vulnerable to them than boys, and that the relationship to the role model-for teenagers at least-matters. Friends appear to be more salient role models for both boys and girls. Our findings suggest that exposure to suicidal behaviors in significant others may teach individuals new ways to deal with emotional distress, namely by becoming suicidal. This reinforces the idea that the structure - and content - of social networks conditions their role in preventing suicidality. Specifically, social ties can be conduits of not just social support, but also anti-social behaviors, like suicidality.