Bronchial Artery Angiogenesis Drives Lung Tumor Growth

Lung cancer is the leading cause of cancer related deaths and is responsible for over one million deaths worldwide each year. While it is widely acknowledged that angiogenesis plays an integral role in tumor growth, and therapeutic approaches have been taken to inhibit angiogenesis, clinical results have been unexceptional at best. Current research models discount the dual lung circulations that create a unique growth environment for tumors, by utilizing subcutaneous xenograft models that have little relevance to the lung, or orthotopic models in mice, which lack a bronchial circulation. In an effort to bridge the gap between animal models of questionable relevance, and clinical trials, we developed an orthotopic model of lung cancer in nude rats to examine the role of the bronchial artery in tumor growth. Using two methods of quantifying tumor perfusion in vivo we measured an increase in bronchial artery perfusion quantified by fluorescent microsphere injection (206%) and HRCT scan (276%), that paralleled the growth in tumor volume, while pulmonary perfusion remained unchanged. When ablating the bronchial artery after the initiation of tumor growth, we observed a 76% decrease in final tumor volumes at 4 weeks post ablation. In an effort to examine the innate differences in the pulmonary and bronchial circulations’ response to tumor growth, primary endothelial cell lines were isolated from the bronchial artery, pulmonary artery, and pulmonary microvasculature of nude rats for the determination of their angiogenic potential. Bronchial artery endothelial cells uniquely showed increased proliferation, tube formation, and chemotaxis when exposed to angiogenic stimuli (VEGF, CINC-3, Adenocarcinoma Supernatant). We conclude that the pulmonary circulation initially sustains lung tumor establishment. As a tumor increases in size it is the bronchial circulation that proliferates to sustain tumor growth beyond the point at which a tumor can be supported by the pulmonary circulation alone. The increased angiogenic potential of bronchial artery endothelial cells, suggests innate differences between lung circulations is due to its unique vascular niche

Breakfast Dietary Patterns among Mexican Children Are Related to Total-Day Diet Quality

Background: Mexico has experienced shifts in food availability and consumption patterns over the past few decades from traditional diets to those containing more high-energy density foods, resulting in the development of unhealthful dietary patterns among children and adults. However, to our knowledge it is not known whether breakfast consumption patterns contribute to the overall daily diet of Mexican children.Objective: We examined total-day diet among breakfast consumers compared with breakfast skippers, identified and investigated breakfast dietary patterns in relation to energy and nutrient intakes at breakfast and across the day, and examined these patterns in relation to sociodemographic characteristics.Methods: With the use of nationally representative dietary data (one 24-h recall) from the 2012 Mexican National Health and Nutrition Survey, 3760 children aged 4-13 y were categorized into mutually exclusive breakfast patterns with the use of cluster analysis. The association between breakfast patterns and breakfast skippers with dietary intake at breakfast and for the total day was investigated with the use of multivariate linear regression.Results: Most children (83%) consumed breakfast. Six breakfast dietary patterns were identified (milk and sweetened breads, tortillas and beans, sweetened beverages, sandwiches and quesadillas, eggs, and cereal and milk) and reflected both traditional and more Westernized dietary patterns. Sugar-sweetened beverages were consumed across all patterns. Compared with all breakfast dietary patterns, breakfast skippers had the lowest intake of several nutrients of public health concern. Nutrients to limit that were high at breakfast tended to be high for the total day and vice versa for nutrients to encourage.Conclusions: There was not a single pattern that complied perfectly with the Mexican School Breakfast Guidelines, but changes such as increasing dietary fiber by encouraging more whole grains, fruits, vegetables, and beans and reducing sodium and sugar-sweetened beverages could support compliance with these targets and improve overall diet quality

The contribution of at-home and away-from-home food to dietary intake among 2–13-year-old Mexican children

Abstract Objective Away-from-home foods have been shown to have lower nutritional quality and larger portion sizes than many foods prepared at home. We aimed to describe energy and nutrient intakes among 2–13-year-old Mexican children by eating location (at home and away from home), overall, by socio-economic status (SES) and by urbanicity. Design Dietary intake was collected via one 24 h recall in the 2012 Mexican National Health and Nutrition Survey (ENSANUT). Location was reported for each food consumed. Results were adjusted for sex, day of recall, region, weight status, SES and urbanicity. Setting Mexico (nationally representative). Subjects Children aged 2–5 years ( n 1905) and 6–13 years ( n 2868). Results Children consumed the majority of daily energy at home (89% of 2–5-year-olds; 82 % of 6–13-year-olds). The most common away-from-home eating location was school (22 % of 2–5-year-olds; 43 % of 6–13-year-olds), followed by the street (14 % of 2–5-year-olds; 13 % of 6–13-year-olds). The most common foods consumed away from home were wheat/rice and corn mixed dishes, sugar-sweetened beverages, pastries/candy/desserts, milk (2–5-year-olds only) and salty snacks (6–13-year-olds). Multivariate models showed that high-SES 2–5-year-olds consumed 14 % of daily energy away from home v . 8 % among low-SES 2–5-year-olds, and high-SES 6–13-year-olds consumed 21 % of daily energy away from home v . 14 % among low-SES 6–13 year-olds. There were no differences by urban residence. Conclusions Among Mexican children, most foods and beverages were consumed at home. However, the percentage of foods consumed or purchased away from home increased with age and with SES

The transition into adoptive parenthood: adoption as a process of continued unsafe uncertainty when family scripts collide

Our prospective study investigated couples’ expectations of adoptive parenthood and explored how these changed with their actual experience of parenthood. Six heterosexual couples were interviewed just before placement began and six months after the children had arrived. Interpretative Phenomenological Analysis (IPA) was used to analyse both sets of interview data. Expectations of adoptive parenthood mostly transformed smoothly into adoption experience for couples but challenges were experienced when family scripts collided and a continued feeling of unsafe uncertainty then prevailed within these newly formed family systems. Family script collision seemed a particular problem for couples adopting sibling pairs. To further professional practice in working with families over the transition to adoptive parenting we suggest that professionals keep in mind a framework that includes: Internal and external world influences on family members, Intergenerational issues, Family scripts, and the Structural challenges of adoption (IIFS)

Anti-angiogenic nanotherapy inhibits airway remodeling and hyper-responsiveness of dust mite triggered asthma in the Brown Norway rat

Although angiogenesis is a hallmark feature of asthmatic inflammatory responses, therapeutic anti-angiogenesis interventions have received little attention. Objective: Assess the effectiveness of anti-angiogenic Sn2 lipase-labile prodrugs delivered via α(v)β(3)-micellar nanotherapy to suppress microvascular expansion, bronchial remodeling, and airway hyper-responsiveness in Brown Norway rats exposed to serial house dust mite (HDM) inhalation challenges. Results: Anti-neovascular effectiveness of α(v)β(3)-mixed micelles incorporating docetaxel-prodrug (Dxtl-PD) or fumagillin-prodrug (Fum-PD) were shown to robustly suppress neovascular expansion (p<0.01) in the upper airways/bronchi of HDM rats using simultaneous (19)F/(1)H MR neovascular imaging, which was corroborated by adjunctive fluorescent microscopy. Micelles without a drug payload (α(v)β(3)-No-Drug) served as a carrier-only control. Morphometric measurements of HDM rat airway size (perimeter) and vessel number at 21d revealed classic vascular expansion in control rats but less vascularity (p<0.001) after the anti-angiogenic nanotherapies. CD31 RNA expression independently corroborated the decrease in airway microvasculature. Methacholine (MCh) induced respiratory system resistance (Rrs) was high in the HDM rats receiving α(v)β(3)-No-Drug micelles while α(v)β(3)-Dxtl-PD or α(v)β(3)-Fum-PD micelles markedly and equivalently attenuated airway hyper-responsiveness and improved airway compliance. Total inflammatory BAL cells among HDM challenged rats did not differ with treatment, but α(v)β(3)(+ )macrophages/monocytes were significantly reduced by both nanotherapies (p<0.001), most notably by the α(v)β(3)-Dxtl-PD micelles. Additionally, α(v)β(3)-Dxtl-PD decreased BAL eosinophil and α(v)β(3)(+ )CD45(+) leukocytes relative to α(v)β(3)-No-Drug micelles, whereas α(v)β(3)-Fum-PD micelles did not. Conclusion: These results demonstrate the potential of targeted anti-angiogenesis nanotherapy to ameliorate the inflammatory hallmarks of asthma in a clinically relevant rodent model

Reduced blood flow through intrapulmonary arteriovenous anastomoses at rest and during exercise in lowlanders during acclimatization to high altitude

Blood flow through intrapulmonary arteriovenous anastomoses (QIPAVA ) is elevated during exercise at sea level (SL) and at rest in acute normobaric hypoxia. Following high altitude (HA) acclimatization, resting QIPAVA is similar to SL, but it is unknown if this is true during exercise at HA. We reasoned that exercise at HA (5,050 m) would exacerbate QIPAVA due to heightened pulmonary arterial pressure. Using a supine cycle ergometer, seven healthy adults free from intracardiac shunts underwent an incremental exercise test at SL (25, 50, 75% of SL VO2peak ) and at HA (25, 50% of SL VO2peak ). Echocardiography was used to determine cardiac output (Q) and pulmonary artery systolic pressure (PASP) and agitated saline contrast was used to determine QIPAVA (bubble score; 0-5). The principal findings were: (1) Q was similar at SL-rest (3.9 +/- 0.47 l min-1 ) compared with HA-rest (4.5 +/- 0.49 l min-1 ; P = 0.382), but increased from rest during both SL and HA exercise (P < 0.001); (2) PASP increased from SL-rest (19.2 +/- 0.7 mmHg) to HA-rest (33.7 +/- 2.8 mmHg; P = 0.001) and, compared with SL, PASP was further elevated during HA exercise (P = 0.003); (3) QIPAVA was increased from SL-rest (0) to HA-rest (median = 1; P = 0.04) and increased from resting values during SL exercise (P < 0.05), but were unchanged during HA exercise (P = 0.91), despite significant increases in Q and PASP. Theoretical modeling of microbubble dissolution suggests that the lack of QIPAVA in response to exercise at HA is unlikely caused by saline contrast instability

Stepped-wedge randomised trial of laparoscopic ventral mesh rectopexy in adults with chronic constipation: Study protocol for a randomized controlled trial

BACKGROUND: Laparoscopic ventral mesh rectopexy (LVMR) is an established treatment for external full-thickness rectal prolapse. However, its clinical efficacy in patients with internal prolapse is uncertain due to the lack of high-quality evidence. METHODS: An individual level, stepped-wedge randomised trial has been designed to allow observer-blinded data comparisons between patients awaiting LVMR with those who have undergone surgery. Adults with symptomatic internal rectal prolapse, unresponsive to prior conservative management, will be eligible to participate. They will be randomised to three arms with different delays before surgery (0, 12 and 24 weeks). Efficacy outcome data will be collected at equally stepped time points (12, 24, 36 and 48 weeks). The primary objective is to determine clinical efficacy of LVMR compared to controls with reduction in the Patient Assessment of Constipation Quality of Life (PAC-QOL) at 24 weeks serving as the primary outcome. Secondary objectives are to determine: (1) the clinical effectiveness of LVMR to 48 weeks to a maximum of 72 weeks; (2) pre-operative determinants of outcome; (3) relevant health economics for LVMR; (4) qualitative evaluation of patient and health professional experience of LVMR and (5) 30-day morbidity and mortality rates. DISCUSSION: An individual-level, stepped-wedge, randomised trial serves the purpose of providing an untreated comparison for the active treatment group, while at the same time allowing the waiting-listed participants an opportunity to obtain the intervention at a later date. In keeping with the basic ethical tenets of this design, the average waiting time for LVMR (12 weeks) will be shorter than that for routine services (24 weeks)

Safety and Immunogenicity of an HIV-1 Gag DNA Vaccine with or without IL-12 and/or IL-15 Plasmid Cytokine Adjuvant in Healthy, HIV-1 Uninfected Adults

DNA vaccines are a promising approach to vaccination since they circumvent the problem of vector-induced immunity. DNA plasmid cytokine adjuvants have been shown to augment immune responses in small animals and in macaques.We performed two first in human HIV vaccine trials in the US, Brazil and Thailand of an RNA-optimized truncated HIV-1 gag gene (p37) DNA derived from strain HXB2 administered either alone or in combination with dose-escalation of IL-12 or IL-15 plasmid cytokine adjuvants. Vaccinations with both the HIV immunogen and cytokine adjuvant were generally well-tolerated and no significant vaccine-related adverse events were identified. A small number of subjects developed asymptomatic low titer antibodies to IL-12 or IL-15. Cellular immunogenicity following 3 and 4 vaccinations was poor, with response rates to gag of 4.9%/8.7% among vaccinees receiving gag DNA alone, 0%/11.5% among those receiving gag DNA+IL-15, and no responders among those receiving DNA+high dose (1500 ug) IL-12 DNA. However, after three doses, 44.4% (4/9) of vaccinees receiving gag DNA and intermediate dose (500 ug) of IL-12 DNA demonstrated a detectable cellular immune response.This combination of HIV gag DNA with plasmid cytokine adjuvants was well tolerated. There were minimal responses to HIV gag DNA alone, and no apparent augmentation with either IL-12 or IL-15 plasmid cytokine adjuvants. Despite the promise of DNA vaccines, newer formulations or methods of delivery will be required to increase their immunogenicity.Clinicaltrials.gov NCT00115960 NCT00111605

Increased hyaluronan fragmentation during pulmonary ischemia

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