Repetitive schistosoma exposure causes perivascular lung fibrosis and persistent pulmonary hypertension.

BACKGROUND: Pulmonary hypertension (PH) can occur as a complication of schistosomiasis. In humans, schistosomiasis-PH persists despite antihelminthic therapy and parasite eradication. We hypothesized that persistent disease arises as a consequence of exposure repetition. METHODS: Following intraperitoneal sensitization, mice were experimentally exposed to Schistosoma eggs by intravenous injection, either once or three times repeatedly. The phenotype was characterized by right heart catheterization and tissue analysis. RESULTS: Following intraperitoneal sensitization, a single intravenous Schistosoma egg exposure resulted in a PH phenotype that peaked at 7-14 days, followed by spontaneous resolution. Three sequential exposures resulted in a persistent PH phenotype. Inflammatory cytokines were not significantly different between mice exposed to one or three egg doses, but there was an increase in perivascular fibrosis in those who received three egg doses. Significant perivascular fibrosis was also observed in autopsy specimens from patients who died of this condition. CONCLUSIONS: Repeatedly exposing mice to schistosomiasis causes a persistent PH phenotype, accompanied by perivascular fibrosis. Perivascular fibrosis may contribute to the persistent schistosomiasis-PH observed in humans with this disease.

Comparison between free ß subunit of human chorionic gonadotropin (hCG) and total hCG assays in adults with testicular cancer.

OBJECTIVES: We tested the hypothesis that the free-ß subunit (ßhCG) is diagnostically more sensitive with total hCG assays (hCGt) not detecting all tumours secreting ßhCG. The effects of sex, age, and renal failure were investigated as secondary objectives. METHODS: We compared ßhCG with hCGt in 204 testicular cancer patients (99 seminomas, 105 non-seminonatous germ cell tumours). The effects of sex and age were determined in 125 male and 138 female controls and that of renal failure was investigated in 119 haemodialysis patients. Biochemical assessment of gonadal status was performed with LH, FSH, oestradiol and testosterone. RESULTS: Discordant results were common with isolated increases of hCGt observed in 32 (15.7 %) and ßhCG in 14 (6.9 %) patients. Primary hypogonadism was the most common cause of isolated hCGt increases. After therapeutic interventions ßhCG decreased below its upper reference more rapidly than hCGt. We observed unequivocal false negative results in two patients with non-seminomatous germ cell tumours. Both occurred in patients with clinical tumour recurrences; in one instance we observed a false negative hCGt while in the second false negative ßhCG's were documented in serial samples. CONCLUSIONS: The similar false negative rates did not support the hypothesis that ßhCG will detect more patients with testicular cancer than hCGt. In contrast to hCGt, ßhCG was unaffected by primary hypogonadism which is a predictably frequent complication in testicular cancer patients. We therefore recommend ßhCG as the preferred biomarker in testicular cancer.

Pregnancy and Exercise in Mountain Travelers.

ABSTRACT: Pregnant women are traveling to high altitude and evidence-based recommendations are needed. Yet, there are limited data regarding the safety of short-term prenatal high-altitude exposure. There are benefits to prenatal exercise and may be benefits to altitude exposure. Studies evaluating maternofetal responses to exercise at altitude found the only complication was transient fetal bradycardia, a finding of questionable significance. There are no published cases of acute mountain sickness in pregnant women, and data suggesting an increase in preterm labor are of poor quality. Current recommendations across professional societies are overly cautious and inconsistent. Non-evidence-based restrictions to altitude exposure can have negative consequences for a pregnant women's physical, social, mental, and economic health. Available data suggest that risks of prenatal travel to altitude are low. Altitude exposure is likely safe for women with uncomplicated pregnancies. We do not recommend absolute restrictions to high altitude exposure, but rather caution and close self-monitoring.

Contribution of fatty acid oxidation to the pathogenesis of pulmonary hypertension.

Dysregulated metabolism characterizes both animal and human forms of pulmonary hypertension (PH). Enzymes involved in fatty acid metabolism have previously not been assessed in human pulmonary arteries affected by pulmonary arterial hypertension (PAH), and how inhibition of fatty acid oxidation (FAO) may attenuate PH remains unclear. Fatty acid metabolism gene transcription was quantified in laser-dissected pulmonary arteries from 10 explanted lungs with advanced PAH (5 idiopathic, 5 associated with systemic sclerosis), and 5 donors without lung diseases. Effects of oxfenicine, a FAO inhibitor, on female Sugen 5416-chronic hypoxia (SuHx) rats were studied in vivo using right heart catheterization, and ex vivo using perfused lungs and pulmonary artery ring segments. The impact of pharmacologic (oxfenicine) and genetic (carnitine palmitoyltransferase 1a heterozygosity) FAO suppression was additionally probed in mouse models of Schistosoma and hypoxia-induced PH. Potential mechanisms underlying FAO-induced PH pathogenesis were examined by quantifying ATP and mitochondrial mass in oxfenicine-treated SuHx pulmonary arterial cells, and by assessing pulmonary arterial macrophage infiltration with immunohistochemistry. We found upregulated pulmonary arterial transcription of 26 and 13 FAO genes in idiopathic and systemic sclerosis-associated PAH, respectively. In addition to promoting de-remodeling of pulmonary arteries in SuHx rats, oxfenicine attenuated endothelin-1-induced vasoconstriction. FAO inhibition also conferred modest benefit in the two mouse models of PH. Oxfenicine increased mitochondrial mass in cultured rat pulmonary arterial cells, and decreased the density of perivascular macrophage infiltration in pulmonary arteries of treated SuHx rats. In summary, FAO inhibition attenuated experimental PH, and may be beneficial in human PAH.

Endothelial cell PHD2-HIF1α-PFKFB3 contributes to right ventricle vascular adaptation in pulmonary hypertension.

Humans and animals with pulmonary hypertension (PH) show right ventricular (RV) capillary growth, which positively correlates with overall RV hypertrophy. However, molecular drivers of RV vascular augmentation in PH are unknown. Prolyl hydroxylase (PHD2) is a regulator of hypoxia-inducible factors (HIFs), which transcriptionally activates several proangiogenic genes, including the glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3). We hypothesized that a signaling axis of PHD2-HIF1α-PFKFB3 contributes to adaptive coupling between the RV vasculature and tissue volume to maintain appropriate vascular density in PH. We used design-based stereology to analyze endothelial cell (EC) proliferation and the absolute length of the vascular network in the RV free wall, relative to the tissue volume in mice challenged with hypoxic PH. We observed increased RV EC proliferation starting after 6 h of hypoxia challenge. Using parabiotic mice, we found no evidence for a contribution of circulating EC precursors to the RV vascular network. Mice with transgenic deletion or pharmacological inhibition of PHD2, HIF1α, or PFKFB3 all had evidence of impaired RV vascular adaptation following hypoxia PH challenge. PHD2-HIF1α-PFKFB3 contributes to structural coupling between the RV vascular length and tissue volume in hypoxic mice, consistent with homeostatic mechanisms that maintain appropriate vascular density. Activating this pathway could help augment the RV vasculature and preserve RV substrate delivery in PH, as an approach to promote RV function.

Comparing Mortality of Peritoneal and Hemodialysis Patients in an Era of Medicare Payment Reform.

BACKGROUND: Prior studies have shown peritoneal dialysis (PD) patients to have lower or equivalent mortality to patients who receive in-center hemodialysis (HD). Medicare's 2011 bundled dialysis prospective payment system encouraged expansion of home-based PD with unclear impacts on patient outcomes. This paper revisits the comparative risk of mortality between HD and PD among patients with incident end-stage kidney disease initiating dialysis in 2006-2013. RESEARCH DESIGN: We conducted a retrospective cohort study comparing 2-year all-cause mortality among patients with incident end-stage kidney disease initiating dialysis via HD and PD in 2006-2013, using data from the US Renal Data System and Medicare. Analysis was conducted using Cox proportional hazards models fit with inverse probability of treatment weighting that adjusted for measured patient demographic and clinical characteristics and dialysis market characteristics. RESULTS: Of the 449,652 patients starting dialysis between 2006 and 2013, the rate of PD use in the first 90 days increased from 9.3% of incident patients in 2006 to 14.2% in 2013. Crude 2-year mortality was 27.6% for patients dialyzing via HD and 16.7% for patients on PD. In adjusted models, there was no evidence of mortality differences between PD and HD before and after bundled payment (hazard ratio, 0.96; 95% confidence interval, 0.89-1.04; P=0.33). CONCLUSIONS: Overall mortality for HD and PD use was similar and mortality differences between modalities did not change before versus after the 2011 Medicare dialysis bundled payment, suggesting that increased use of home-based PD did not adversely impact patient outcomes.

Wilderness Medical Society Clinical Practice Guidelines for the Prevention and Management of Tick-Borne Illness in the United States.

The Wilderness Medical Society convened an expert panel to develop evidence-based guidelines for the prevention and management of tick-borne illness (TBI). Recommendations are graded based on quality of supporting evidence according to criteria put forth by the American College of Chest Physicians. The guidelines include a brief review of the clinical presentation, epidemiology, prevention, and management of TBI in the United States, with a primary focus on interventions that are appropriate for resource-limited settings. Strong recommendations are provided for the use of DEET, picaridin, and permethrin; tick checks; washing and drying clothing at high temperatures; mechanical tick removal within 36 h of attachment; single-dose doxycycline for high-risk Lyme disease exposures versus "watchful waiting;" evacuation from backcountry settings for symptomatic tick exposures; and TBI education programs. Weak recommendations are provided for the use of light-colored clothing; insect repellents other than DEET, picaridin, and permethrin; and showering after exposure to tick habitat. Weak recommendations are also provided against passive methods of tick removal, including the use of systemic and local treatments. There was insufficient evidence to support the use of long-sleeved clothing and the avoidance of tick habitat such as long grasses and leaf litter. Although there was sound evidence supporting Lyme disease vaccination, a grade was not offered as the vaccine is not currently available for use in the United States.

Greater mindfulness associated with lower pain, fatigue, and psychological distress in women with metastatic breast cancer.

OBJECTIVE: Women with metastatic breast cancer (MBC) report high levels of disease-related symptoms including pain, fatigue, psychological distress, and sleep disturbance. Mindfulness may be particularly relevant to women with MBC given the high symptom burden and psychological toll of this disease; however, the topic is understudied among this patient population. Therefore, we aimed to test the associations between mindfulness and patient-reported symptoms among a sample of women with MBC. METHODS: Sixty-four women with MBC completed baseline questionnaires of mindfulness (Five Facet Mindfulness Questionnaire-Short Form [FFMQ-SF]) and symptoms of pain severity and interference, fatigue, psychological distress, and sleep disturbance as part of a randomized controlled trial of a Mindful Yoga intervention. Correlational analyses of data collected at baseline tested associations between the five mindfulness facets (observing, describing, acting with awareness, nonjudging, and nonreactivity) and patient-reported measures of symptoms. RESULTS: Overall, higher mindfulness was associated with lower symptom levels including lower pain severity, pain interference, fatigue, anxiety, depression, and sleep disturbance. However, degree of association varied by mindfulness facet. Nonreactivity, nonjudging, and describing showed the most frequent associations and largest effect sizes across symptoms, while observing showed the least frequent associations and lowest effect sizes. CONCLUSIONS: Mindfulness-and in particular nonreactivity, nonjudging, and describing-may be a personal resource for women with MBC in coping with complex symptoms of this life-threatening illness. Findings are discussed relative to their implications for interventions aimed at increasing mindfulness in this vulnerable population.

Effects of mindfulness training programmes delivered by a self-directed mobile app and by telephone compared with an education programme for survivors of critical illness: a pilot randomised clinical trial.

BACKGROUND: Patients who are sick enough to be admitted to an intensive care unit (ICU) commonly experience symptoms of psychological distress after discharge, yet few effective therapies have been applied to meet their needs. METHODS: Pilot randomised clinical trial with 3-month follow-up conducted at two academic medical centres. Adult (≥18 years) ICU patients treated for cardiorespiratory failure were randomised after discharge home to 1 of 3 month-long interventions: a self-directed mobile app-based mindfulness programme; a therapist-led telephone-based mindfulness programme; or a web-based critical illness education programme. RESULTS: Among 80 patients allocated to mobile mindfulness (n=31), telephone mindfulness (n=31) or education (n=18), 66 (83%) completed the study. For the primary outcomes, target benchmarks were exceeded by observed rates for all participants for feasibility (consent 74%, randomisation 91%, retention 83%), acceptability (mean Client Satisfaction Questionnaire 27.6 (SD 3.8)) and usability (mean Systems Usability Score 89.1 (SD 11.5)). For secondary outcomes, mean values (and 95% CIs) reflected clinically significant group-based changes on the Patient Health Questionnaire depression scale (mobile (-4.8 (-6.6, -2.9)), telephone (-3.9 (-5.6, -2.2)), education (-3.0 (-5.3, 0.8)); the Generalized Anxiety Disorder scale (mobile -2.1 (-3.7, -0.5), telephone -1.6 (-3.0, -0.1), education -0.6 (-2.5, 1.3)); the Post-Traumatic Stress Scale (mobile -2.6 (-6.3, 1.2), telephone -2.2 (-5.6, 1.2), education -3.5 (-8.0, 1.0)); and the Patient Health Questionnaire physical symptom scale (mobile -5.3 (-7.0, -3.7), telephone -3.7 (-5.2, 2.2), education -4.8 (-6.8, 2.7)). CONCLUSIONS: Among ICU patients, a mobile mindfulness app initiated after hospital discharge demonstrated evidence of feasibility, acceptability and usability and had a similar impact on psychological distress and physical symptoms as a therapist-led programme. A larger trial is warranted to formally test the efficacy of this approach. TRIAL REGISTRATION NUMBER: Results, NCT02701361.

Health Coaching Has Differential Effects on Veterans with Limited Health Literacy and Numeracy: a Secondary Analysis of ACTIVATE.

BACKGROUND: Health coaching is an effective behavior change strategy. Understanding if there is a differential impact of health coaching on patients with low health literacy has not been well investigated. OBJECTIVE: To determine whether a telephone coaching intervention would result in similar improvements in enrollment in prevention programs and patient activation among Veterans with low versus high health literacy (specifically, reading literacy and numeracy). DESIGN: Secondary analysis of a randomized controlled trial. PARTICIPANTS: Four hundred seventeen Veterans with at least one modifiable risk factor: current smoker, BMI ≥ 30, or < 150 min of moderate physical activity weekly. METHODS: A single-item assessment of health literacy and a subjective numeracy scale were assessed at baseline. A logistic regression and general linear longitudinal models were used to examine the differential impact of the intervention compared to control on enrollment in prevention programs and changes in patient activation measures (PAM) scores among patients with low versus high health literacy. RESULTS: The coaching intervention resulted in higher enrollment in prevention programs and improvements in PAM scores compared to usual care regardless of baseline health literacy. The coaching intervention had a greater effect on the probability of enrollment in prevention programs for patients with low numeracy (intervention vs control difference of 0.31, 95% CI 0.18, 0.45) as compared to those with high numeracy (0.13, 95% CI - 0.01, 0.27); the low compared to high differential effect was clinically, but not statistically significant (0.18, 95% CI - 0.01, 0.38; p = 0.07). Among patients with high numeracy, the intervention group had greater increases in PAM as compared to the control group at 6 months (mean difference in improvement 4.8; 95% CI 1.7, 7.9; p = 0.003). This led to a clinically and statistically significant differential intervention effect for low vs high numeracy (- 4.6; 95% CI - 9.1, - 0.15; p = 0.04). CONCLUSIONS: We suggest that health coaching may be particularly beneficial in behavior change strategies in populations with low numeracy when interpretation of health risk information is part of the intervention. CLINICALTRIALS. GOV IDENTIFIER: NCT01828567.

Use of Contrast-Enhanced MRI in Management of Discordant Core Biopsy Results.

OBJECTIVE. Evaluating concordance between core biopsy results and imaging findings is an integral component of breast intervention. Pathologic results deemed benign discordant reflect concern that a malignancy may have been incorrectly sampled. Standard of care currently is surgical excision, although a large percentage of these lesions will be benign at final pathologic analysis. The purpose of this study was to determine whether inclusion of contrast-enhanced MRI would optimize patient care. MATERIALS AND METHODS. Forty-five patients with 46 lesions were identified who underwent contrast-enhanced MRI after receiving discordant ultrasound or stereotactic biopsy results between 2012 and mid 2018. These findings were classified BI-RADS category 4 at diagnostic imaging. Disease-positive was defined as all malignancies and borderline lesions. RESULTS. Fourteen patients had suspicious MRI findings; 31 patients did not. Negative or benign MRI findings were validated by stability at imaging follow-up of at least 1 year in 27 patients (28 lesions) and at least 6 months in four patients. Eight of the total of 46 discordant lesions were ultimately malignant, a rate of 17.3%, an expected result for BI-RADS 4 lesions. Sensitivity, specificity, positive predictive value, and negative predictive value of MRI calculated in the group of 41 patients (42 lesions) with documented stability for at least 1 year were 100%, 93.3%, 85.7%, and 100%. The false-negative rate of MRI was 0%; the false-positive rate was 2 of 30 (6.7%). CONCLUSION. In the management of discordant benign core biopsy results, contrast-enhanced MRI facilitated successful triage of patients to surgery; 31 of the original 45 patients (68.9%) avoided surgery.

Feasibility of a mindful yoga program for women with metastatic breast cancer: results of a randomized pilot study.

PURPOSE: Patients with metastatic breast cancer (MBC) experience high levels of symptoms. Yoga interventions have shown promise for improving cancer symptoms but have rarely been tested in patients with advanced disease. This study examined the acceptability of a comprehensive yoga program for MBC and the feasibility of conducting a randomized trial testing the intervention. METHODS: Sixty-three women with MBC were randomized with a 2:1 allocation to yoga or a support group comparison condition. Both interventions involved eight weekly group sessions. Feasibility was quantified using rates of accrual, attrition, and session attendance. Acceptability was assessed with a standardized self-report measure. Pain, fatigue, sleep quality, psychological distress, mindfulness, and functional capacity were assessed at baseline, post-intervention, and 3 and 6 months post-intervention. RESULTS: We met goals for accrual and retention, with 50% of eligible patients enrolled and 87% of randomized participants completing post-intervention surveys. Sixty-five percent of women in the yoga condition and 90% in the support group attended ≥ 4 sessions. Eighty percent of participants in the yoga condition and 65% in the support group indicated that they were highly satisfied with the intervention. Following treatment, women in the yoga intervention had modest improvements in some outcomes; however, overall symptom levels were low for women in both conditions. CONCLUSIONS: Findings suggest that the yoga intervention content was highly acceptable to patients with MBC, but that there are challenges to implementing an intervention involving eight group-based in-person sessions. Alternative modes of delivery may be necessary to reach patients most in need of intervention.

Vascular Adaptation of the Right Ventricle in Experimental Pulmonary Hypertension.

Optimal right ventricular (RV) function in pulmonary hypertension (PH) requires structural and functional coupling between the RV cardiomyocyte and its adjacent capillary network. Prior investigations have indicated that RV vascular rarefaction occurs in PH, which could contribute to RV failure by reduced delivery of oxygen or other metabolic substrates. However, it has not been determined if rarefaction results from relative underproliferation in the setting of tissue hypertrophy or from actual loss of vessels. It is also unknown if rarefaction results in inadequate substrate delivery to the RV tissue. In the present study, PH was induced in rats by SU5416-hypoxia-normoxia exposure. The vasculature in the RV free wall was assessed using stereology. Steady-state metabolomics of the RV tissue was performed by mass spectrometry. Complementary studies were performed in hypoxia-exposed mice and rats. Rats with severe PH had evidence of RV failure by decreased cardiac output and systemic hypotension. By stereology, there was significant RV hypertrophy and increased total vascular length in the RV free wall in close proportion, with evidence of vessel proliferation but no evidence of endothelial cell apoptosis. There was a modest increase in the radius of tissue served per vessel, with decreased arterial delivery of metabolic substrates. Metabolomics revealed major metabolic alterations and metabolic reprogramming; however, metabolic substrate delivery was functionally preserved, without evidence of either tissue hypoxia or depletion of key metabolic substrates. Hypoxia-treated rats and mice had similar but milder alterations. There is significant homeostatic vascular adaptation in the right ventricle of rodents with PH.

A Coaching by Telephone Intervention on Engaging Patients to Address Modifiable Cardiovascular Risk Factors: a Randomized Controlled Trial.

BACKGROUND: A large proportion of deaths and chronic illnesses can be attributed to three modifiable risk factors: tobacco use, overweight/obesity, and physical inactivity. OBJECTIVE: To test whether telephone-based health coaching after completion of a comprehensive health risk assessment (HRA) increases patient activation and enrollment in a prevention program compared to HRA completion alone. DESIGN: Two-arm randomized trial at three sites. SETTING: Primary care clinics at Veterans Affairs facilities. PARTICIPANTS: Four hundred seventeen veterans with at least one modifiable risk factor (BMI ≥ 30, < 150 min of at least moderate physically activity per week, or current smoker). INTERVENTION: Participants completed an online HRA. Intervention participants received two telephone-delivered health coaching calls at 1 and 4 weeks to collaboratively set goals to enroll in, and attend structured prevention programs designed to reduce modifiable risk factors. MEASUREMENTS: Primary outcome was enrollment in a structured prevention program by 6 months. Secondary outcomes were Patient Activation Measure (PAM) and Framingham Risk Score (FRS). RESULTS: Most participants were male (85%), white (50%), with a mean age of 56. Participants were eligible, because their BMI was ≥ 30 (80%), they were physically inactive (50%), and/or they were current smokers (39%). When compared to HLA only at 6 months, health coaching intervention participants reported higher rates of enrollment in a prevention program, 51 vs 29% (OR = 2.5; 95% CI: 1.7, 3.9; p < 0.0001), higher rates of program participation, 40 vs 23% (OR = 2.3; 95% CI: 1.5, 3.6; p = 0.0004), and greater improvement in PAM scores, mean difference 2.5 (95% CI: 0.2, 4.7; p = 0.03), but no change in FRS scores, mean difference 0.7 (95% CI - 0.7, 2.2; p = 0.33). CONCLUSIONS: Brief telephone health coaching after completing an online HRA increased patient activation and increased enrollment in structured prevention programs to improve health behaviors. CLINICALTRIALS. GOV IDENTIFIER: NCT01828567.

Clinical breast concerns in low-risk pediatric patients: practice review with proposed recommendations.

BACKGROUND: Fibroadenoma is overwhelmingly the most common pediatric breast lesion. Breast malignancy is quite uncommon in children, most frequently metastatic or hematological malignancy. Core biopsy has largely replaced excision for diagnosis of breast masses in adults. OBJECTIVE: The purpose of this study is two-fold: (1) compare utilization at our institution of interventional procedures vs. surgery for breast mass diagnosis in patients ≤18 years and (2) propose guidelines for breast imaging and biopsy in this population. MATERIALS AND METHODS: We extracted data for all patients ≤18 who, between 2004 and 2016, underwent either (a) imaging and/or intervention procedure, or (b) breast surgery, from the Radiology Information System and Pathology Data System, respectively. We recorded age, gender, imaging, procedure, lesion size and histopathology. RESULTS: We found 1,050 pediatric patients ≤18 years who underwent diagnostic breast ultrasound between 2004 and 2016. Of these, 168 patients underwent 199 interventional procedures. One hundred thirty patients underwent 160 core biopsies of solid lesions. Core biopsy pathology diagnosed benign lesions in 99%, of which 84.3% were fibroadenomas (n=135). One malignancy was diagnosed, B cell lymphoma. Two hundred three patients underwent surgical excision for 266 discrete lesions, and 89% were fibroadenomas. Seven benign phyllodes tumors were surgically diagnosed. No malignancies were diagnosed. CONCLUSION: Core biopsy in patients 18 years and younger is well-tolerated, has few risks, and is preferable to surgery in developing breasts, but the goal is to avoid any breast procedure whenever possible. We propose guidelines for pediatric breast imaging, follow-up, core biopsy and excisions.

RTP801 Amplifies Nicotinamide Adenine Dinucleotide Phosphate Oxidase-4-Dependent Oxidative Stress Induced by Cigarette Smoke.

Tobacco smoke (TS) causes chronic obstructive pulmonary disease, including chronic bronchitis, emphysema, and asthma. Rtp801, an inhibitor of mechanistic target of rapamycin, is induced by oxidative stress triggered by TS. Its up-regulation drives lung susceptibility to TS injury by enhancing inflammation and alveolar destruction. We postulated that Rtp801 is not only increased by reactive oxygen species (ROS) in TS but also instrumental in creating a feedforward process leading to amplification of endogenous ROS generation. We used cigarette smoke extract (CSE) to model the effect of TS in wild-type (Wt) and knockout (KO-Rtp801) mouse lung fibroblasts (MLF). The production of superoxide anion in KO-Rtp801 MLF was lower than that in Rtp801 Wt cells after CSE treatment, and it was inhibited in Wt MLF by silencing nicotinamide adenine dinucleotide phosphate oxidase-4 (Nox4) expression with small interfering Nox4 RNA. We observed a cytoplasmic location of ROS formation by real-time redox changes using reduction-oxidation-sensitive green fluorescent protein profluorescent probes. Both the superoxide production and the increase in the cytoplasmic redox were inhibited by apocynin. Reduction in the activity of Sod and decreases in the expression of Sod2 and Gpx1 genes were associated with Rtp801 CSE induction. The ROS produced by Nox4 in conjunction with the decrease in cellular antioxidant enzymatic defenses may account for the observed cytoplasmic redox changes and cellular damage caused by TS.

Mindful Yoga for women with metastatic breast cancer: design of a randomized controlled trial.

BACKGROUND: Women with metastatic breast cancer (MBC) have average life expectancies of about 2 years, and report high levels of disease-related symptoms including pain, fatigue, sleep disturbance, psychological distress, and functional impairment. There is growing recognition of the limitations of medical approaches to managing such symptoms. Yoga is a mind-body discipline that has demonstrated a positive impact on psychological and functional health in early stage breast cancer patients and survivors, but has not been rigorously studied in advanced cancer samples. METHODS: This randomized controlled trial examines the feasibility and initial efficacy of a Mindful Yoga program, compared with a social support condition that controls for attention, on measures of disease-related symptoms such as pain and fatigue. The study will be completed by December 2017. Sixty-five women with MBC age ≥ 18 are being identified and randomized with a 2:1 allocation to Mindful Yoga or a support group control intervention. The 120-min intervention sessions take place weekly for 8 weeks. The study is conducted at an urban tertiary care academic medical center located in Durham, North Carolina. The primary feasibility outcome is attendance at intervention sessions. Efficacy outcomes include pain, fatigue, sleep quality, psychological distress, mindfulness and functional capacity at post-intervention, 3-month follow-up, and 6-month follow-up. DISCUSSION: In this article, we present the challenges of designing a randomized controlled trial with long-term follow-up among women with MBC. These challenges include ensuring adequate recruitment including of minorities, limiting and controlling for selection bias, tailoring of the yoga intervention to address special needs, and maximizing adherence and retention. This project will provide important information regarding yoga as an intervention for women with advanced cancer, including preliminary data on the psychological and functional effects of yoga for MBC patients. This investigation will also establish rigorous methods for future research into yoga as an intervention for this population. TRIAL REGISTRATION: ClinicalTrials.gov identifer: NCT01927081 , registered August 16, 2013.

The Causal Role of IL-4 and IL-13 in Schistosoma mansoni Pulmonary Hypertension.

RATIONALE: The etiology of schistosomiasis-associated pulmonary arterial hypertension (PAH), a major cause of PAH worldwide, is poorly understood. Schistosoma mansoni exposure results in prototypical type-2 inflammation. Furthermore, transforming growth factor (TGF)-ß signaling is required for experimental pulmonary hypertension (PH) caused by Schistosoma exposure. OBJECTIVES: We hypothesized type-2 inflammation driven by IL-4 and IL-13 is necessary for Schistosoma-induced TGF-ß-dependent vascular remodeling. METHODS: Wild-type, IL-4(-/-), IL-13(-/-), and IL-4(-/-)IL-13(-/-) mice (C57BL6/J background) were intraperitoneally sensitized and intravenously challenged with S. mansoni eggs to induce experimental PH. Right ventricular catheterization was then performed, followed by quantitative analysis of the lung tissue. Lung tissue from patients with schistosomiasis-associated and connective tissue disease-associated PAH was also systematically analyzed. MEASUREMENTS AND MAIN RESULTS: Mice with experimental Schistosoma-induced PH had evidence of increased IL-4 and IL-13 signaling. IL-4(-/-)IL-13(-/-) mice, but not single knockout IL-4(-/-) or IL-13(-/-) mice, were protected from Schistosoma-induced PH, with decreased right ventricular pressures, pulmonary vascular remodeling, and right ventricular hypertrophy. IL-4(-/-)IL-13(-/-) mice had less pulmonary vascular phospho-signal transducer and activator of transcription 6 (STAT6) and phospho-Smad2/3 activity, potentially caused by decreased TGF-ß activation by macrophages. In vivo treatment with a STAT6 inhibitor and IL-4(-/-)IL-13(-/-) bone marrow transplantation also protected against Schistosoma-PH. Lung tissue from patients with schistosomiasis-associated and connective tissue disease-associated PAH had evidence of type-2 inflammation. CONCLUSIONS: Combined IL-4 and IL-13 deficiency is required for protection against TGF-ß-induced pulmonary vascular disease after Schistosoma exposure, and targeted inhibition of this pathway is a potential novel therapeutic approach for patients with schistosomiasis-associated PAH.