Search

Rogelio Perez-Padilla,1 Maria Montes de Oca,2 Ireri Thirion-Romero,1 Fernando C Wehrmeister,3 Maria Victorina Lopez,4 Gonzalo Valdivia,5 Jose R Jardim,6 Adriana Muino,4 Ana Maria B Menezes3 On behalf of the PLATINO Group1National Institute of Respiratory Diseases, Mexico City, Mexico; 2Pulmonary Division, Hospital Universitario de Caracas, Universidad Central de Venezuela, and Centro Medico de Caracas, Caracas, Venezuela; 3Post-Graduate Program in Epidemiology, Federal University of Pelotas, Pelotas, Brazil; 4Universidad de la Republica. Hospital Maciel, Montevideo, Uruguay; 5Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile; 6Paulista School of Medicine, Federal University of São Paulo, São Paulo, BrazilCorrespondence: Rogelio Perez-Padilla, Instituto Nacional de Enfermedades Respiratorias, Tlalpan 4502, Col. Sección XVI, 14080, CDMX, Mexico City, Mexico, Email perezpad@gmail.comBackground: Preserved ratio impaired spirometry (PRISm) has been associated with adverse outcomes and increased transition to other spirometric categories over time. We aimed to examine its prevalence, trajectories over time, and outcomes in a population-based sample from Latin America.Methods: Data were obtained from two population-based surveys of adults from three cities in Latin America (PLATINO study), conducted on the same individuals 5– 9 years after their baseline examination. We estimated the frequency of PRISm defined by FEV1/FVC≥ 0.70 with FEV1 < 80%, describing their clinical characteristics, longitudinal transition trajectories over time, factors associated with the transition.Results: At baseline, 2942 participants completed post-bronchodilator spirometry, and 2026 at both evaluations. The prevalence of normal spirometry was 78%, GOLD-stage 1 10.6%, GOLD 2– 4 6.5%, and PRISm was: 5.0% (95% CI 4.2– 5.8). PRISm was associated with less schooling, more reports of physician-diagnosis of COPD, wheezing, dyspnea, missing days at work, having ≥ 2 exacerbations in the previous year but without accelerated lung function decline. Mortality risk was significantly higher in PRISm (HR 1.97, 95% CI 1.2– 3.3) and COPD GOLD 1– 4 categories (HR 1.79, 95% CI 1.3– 2.4) compared with normal spirometry. PRISm at baseline most frequently transitioned to another category at follow-up (46.5%); 26.7% to normal spirometry and 19.8% to COPD. The best predictors of transition to COPD were closeness of FEV1/FVC to 0.70, older age, current smoking, and a longer FET in the second assessment.Conclusion: PRISm, is a heterogeneous and unstable condition prone to adverse outcomes that require adequate follow-up.Keywords: preserved ratio impaired spirometry PRISm, airflow obstruction, COPD, lung function decline

Rogelio Perez-Padilla,1 Fernando C Wehrmeister,2 Maria Montes de Oca,3 Maria Victorina Lopez,4 Jose R Jardim,5 Adriana Muiño,4 Gonzalo Valdivia,6 Ana Maria B Menezes,2 On behalf of the PLATINO group 1National Institute of Respiratory Diseases, Mexico City, Mexico; 2Federal University of Pelotas, Pelotas, Brazil; 3Pulmonary Division, Hospital Universitario de Caracas, Universidad Central de Venezuela, Caracas, Venezuela; 4Faculty of Medicine, University of the Republic, Montevideo, Uruguay; 5Federal University of Sao Paulo, Sao Paulo, Brazil; 6Pontificia Universidad Catolica de Chile, Santiago, Chile Background: We aimed to study the adverse outcomes of symptomatic and asymptomatic non-obstructed individuals and those with mild COPD longitudinally in participants from three Latin-American cities.Methods: Two population-based surveys of adults with spirometry were conducted for these same individuals with a 5- to 9-year interval. We evaluated the impact of respiratory symptoms (cough, phlegm, wheezing or dyspnea) in non-obstructed individuals, and among those classified as Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 1, COPD on exacerbation frequency, mortality and FEV1 decline, compared with asymptomatic individuals without airflow obstruction or restriction.Results: Non-obstructed symptomatic individuals had a marginal increased risk of mortality (HR 1.3; 95% CI 0.9–1.94), increased FEV1 decline (−4.5 mL/year; 95% CI −8.6, −0.4) and increased risk of 2+ exacerbations in the previous year (OR 2.6; 95% CI 1.2–6.5). Individuals with GOLD stage 1 had a marginal increase in mortality (HR 1.5; 95% CI 0.93–2.3) but a non-significant impact on FEV1 decline or exacerbations compared with non-obstructed individuals.Conclusions: The presence of respiratory symptoms in non-obstructed individuals was a predictor of mortality, lung-function decline and exacerbations, whereas the impact of GOLD stage 1 was mild and inconsistent. Respiratory symptoms were associated with asthma, current smoking, and the report of heart disease. Spirometric case-finding and treatment should target individuals with moderate-to-severe airflow obstruction and those with restriction, the groups with consistent increased mortality. Keywords: spirometry, airflow obstruction, COPD, mild COPD, lung function decline, COPD exacerbations, screening for COPD

Background: Recurrent exacerbations are common in COPD patients. Limited information exists regarding exacerbation frequency in COPD patients from epidemiologic studies. We examined the frequency of self-reported exacerbations and the factors influencing exacerbation frequency among COPD patients in a population-based study conducted in Latin America.Methods: We used a post-bronchodilator FEV(1)/FVC ratio of < 0.70 to define COPD. Exacerbation was self-reported and defined by symptoms (deterioration of breathing symptoms that affected usual daily activities or caused missed work).Results: Spirometry was performed in 5,314 subjects. There were 759 subjects with airflow limitation; of these, 18.2% reported ever having had an exacerbation, 7.9% reported having an exacerbation, and 6.2% reported having an exacerbation requiring at least a doctor visit within the past year. The proportion of individuals with an exacerbation significantly increased by Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages, from 4.2% in stage 1 to 28.9% in stages 3 and 4. The self-reported exacerbation rate was 0.58 exacerbations per year. The rate of exacerbations requiring at least a doctor visit and length of stay in hospital due to exacerbations also increased as COPD severity progressed. The factors associated with having an exacerbation in the past year were dyspnea, prior asthma diagnosis, receiving any respiratory therapy, and disease severity of GOLD stages 3 and 4.Conclusions: The proportion of individuals with airflow limitation and self-reported exacerbation increases as the disease severity progresses. Dyspnea, prior asthma diagnosis, receiving any respiratory therapy, and more severe obstruction were significantly associated with having an exacerbation in the past year. [ABSTRACT FROM AUTHOR]

Background: In Mexico, anemia prevalence among women of reproductive age (WRA) decreased from 16.4% in 2006 to 11.6% in 2012, only to increase to 18.3% in 2016. The factors associated with this fluctuation are uncertain., Objective: We conducted a systematic in-depth assessment of the quantitative and qualitative determinants of anemia among WRA in Mexico between 2006 and 2018., Methods: Using multivariate stepwise linear regression, we analyzed Mexico's Encuesta Nacional de Salud y Nutrición (ENSANUT) surveys from 2006, 2012, and 2018 to identify determinants of WRA anemia. We also conducted a review of anemia-relevant programs and policies, including financing documents, and conducted in-depth interviews and focus group discussions with key stakeholders in Mexico., Results: Among non-pregnant women (NPW) 15-49 years, mean hemoglobin (Hb) increased from 13.8 g/dL in 2006 to 14.0 g/dL in 2012, decreasing to 13.2 g/dL in 2018 (p<0.001). Inequities by geographical region and household wealth persisted throughout this period, with household wealth, urban residence and gravidity emerging as significant predictors of Hb among NPW. Qualitative analyses generally supported these findings. The most discussed program was Progresa-Oportunidades-Prospera (POP), where most resources for health were invested and most participants acknowledged that its cancellation in 2019 would lead to worsening in health and nutrition among the poor. Financing analyses showed a drop of funding for nutrition-related programs between 2014 and 2018. Cultural norms around gender roles were still prevalent, along with increasing rates of teenage pregnancy., Conclusions: Anemia prevention efforts need to refocus on poverty alleviation, continuity of adequate coverage and financing of nutrition programs, especially with safety nets, and increase in uptake of family planning, especially among adolescent girls., Competing Interests: Declaration of Competing Interest ☒ The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Zulfiqar Bhutta reports financial support and article publishing charges were provided by Bill and Melinda Gates Foundation. Zulfiqar Bhutta reports financial support was provided by Gates Ventures. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

This article - Recommendations and Guidelines of Integrative Medicine (IM) for COVID-19 Care - was one of the outcomes from an Asia-Pacific Economic Cooperation (APEC) Project (Integrative Medicine (IM) and COVID -19 Care) during the time between May 2022 and March 2023. With the efforts from care providers, researchers, health policy makers and healthcare administrative leaders among APEC economies, the purpose of this file was to provide comprehensive IM systems for COVID-19 care as recommendations and suggestive guidelines including care methods, tools, procedures, symptom conditions and targets selections, and points need to be considered during care applications. All cited COVID-19 care practices have confirmed their efficacy and usefulness either used alone or combined with conventional medicine. This article provides current useful medical information on IM for COVID-19 care which could benefit APEC economies and world health communities on their healthcare system., Competing Interests: There is no conflict of interest from all authors., (© 2024 Korea Institute of Oriental Medicine. Published by Elsevier B.V.)

In this article, three different implementations of an Axon-Hillock circuit are presented, one of the basic building blocks of spiking neural networks. In this work, we explored the design of such circuits using a unipolar thin-film transistor technology based on amorphous InGaZnO, often used for large-area electronics. All the designed circuits are fabricated by direct material deposition and patterning on top of a flexible polyimide substrate. Axon-Hillock circuits presented in this article consistently show great adaptability of the basic properties of a spiking neuron such as output spike frequency adaptation and output spike width adaptation. Additional degrees of adaptability are demonstrated with each of the Axon-Hillock circuit varieties: neuron circuit threshold voltage adaptation, differentiation between input signal importance, and refractory period modulation. The proposed neuron can change its firing frequency up to three orders of magnitude by varying a single voltage brought to a circuit terminal. This allows the neuron to function, and potentially learn, at vastly different timescales that coincide with the biologically meaningful timescales, going from milliseconds to seconds, relevant for circuits meant for interaction with the environment. Thanks to careful design choices, the average measured power consumption is kept in the nW range, realistically allowing upscaling towards the spiking neural networks in the future. The spiking neuron with refractory period modulation presented in this work has an area of 607.3 μm × 492.2 μm, it experimentally demonstrated firing rates as low as 11.926 mHz, and its energy consumption per spike is ≈ 700 pJ at 30 Hz.

COVID-19 vaccines were originally designed based on the ancestral Spike protein, but immune escape of emergent Variants of Concern (VOC) jeopardized their efficacy, warranting variant-proof vaccines. Here, we used preclinical rodent models to establish the cross-protective and cross-neutralizing capacity of adenoviral-vectored vaccines expressing VOC-matched Spike. CoroVaxG.3-D.FR, matched to Delta Plus Spike, displayed the highest levels of nAb to the matched VOC and mismatched variants. Cross-protection against viral infection in aged K18-hACE2 mice showed dramatic differences among the different vaccines. While Delta-targeted vaccines fully protected mice from a challenge with Gamma, a Gamma-based vaccine offered only partial protection to Delta challenge. Administration of CorovaxG.3-D.FR in a prime/boost regimen showed that a booster was able to increase the neutralizing capacity of the sera against all variants and fully protect aged K18-hACE2 mice against Omicron BA.1, as a BA.1-targeted vaccine did. The neutralizing capacity of the sera diminished in all cases against Omicron BA.2 and BA.5. Altogether, the data demonstrate that a booster with a vaccine based on an antigenically distant variant, such as Delta or BA.1, has the potential to protect from a wider range of SARS-CoV-2 lineages, although careful surveillance of breakthrough infections will help to evaluate combination vaccines targeting antigenically divergent variants yet to emerge., (© 2023. Springer Nature Limited.)

A hallmark of eukaryotic aging is a loss of epigenetic information, a process that can be reversed. We have previously shown that the ectopic induction of the Yamanaka factors OCT4, SOX2, and KLF4 (OSK) in mammals can restore youthful DNA methylation patterns, transcript profiles, and tissue function, without erasing cellular identity, a process that requires active DNA demethylation. To screen for molecules that reverse cellular aging and rejuvenate human cells without altering the genome, we developed high-throughput cell-based assays that distinguish young from old and senescent cells, including transcription-based aging clocks and a real-time nucleocytoplasmic compartmentalization (NCC) assay. We identify six chemical cocktails, which, in less than a week and without compromising cellular identity, restore a youthful genome-wide transcript profile and reverse transcriptomic age. Thus, rejuvenation by age reversal can be achieved, not only by genetic, but also chemical means.

In children, arterial ischemic stroke is a much less understood disease compared to in adults due to its lower frequency and different aetiology. However, it is also a serious disease, with a high incidence of severe and permanent sequelae that exceeds 50% of total cases. The acute management of postnatal arterial ischaemic stroke (MNAIS) has changed drastically in recent years, chiefly on account of recanalization treatments (thrombolysis and endovascular therapies). These treatments, which used to not be recommended in childhood, are increasingly implemented in everyday clinical practice. Although the evidence from studies carried out in children is not of high quality due to their retrospective design and the small number of reported cases, they support the hypothesis that these treatments are as safe and effective as they are in adults as long as appropriate eligibility criteria are applied and they are used within a certain time from the onset of symptoms (therapeutic window). This article reviews the MNAIS based on the current scientific evidence. Since the efficacy of these treatments is highly dependent on their early initiation, a paediatric stroke code needs to be in place as an extension of the stroke code applied to adults. It has started to be introduced in Spain since 2019, although there are still large areas of the country where it has yet to be applied., (Copyright © 2023 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.)

More than one million women are diagnosed annually worldwide with a gynecological cancer. Most gynecological cancers are diagnosed at a late stage, either because a lack of symptoms, such as in ovarian cancer or limited accessibility to primary prevention in low-resource countries, such as in cervical cancer. Here, we extend the studies of AR2011, a stroma-targeted and tumor microenvironment responsive oncolytic adenovirus (OAdV), whose replication is driven by a triple hybrid promoter. We show that AR2011 was able to replicate and lyse in vitro fresh explants obtained from human ovarian cancer, uterine cancer, and cervical cancer. AR2011 was also able to strongly inhibit the in vitro growth of ovarian malignant cells obtained from human ascites fluid. The virus could synergize in vitro with cisplatin even on ascites-derived cells obtained from patients heavily pretreated with neoadjuvant chemotherapy. AR2011(h404), a dual transcriptionally targeted derived virus armed with hCD40L and h41BBL under the regulation of the hTERT promoter, showed a strong efficacy in vivo both on subcutaneous and intraperitoneally established human ovarian cancer in nude mice. Preliminary studies in an immunocompetent murine tumor model showed that AR2011(m404) expressing the murine cytokines was able to induce an abscopal effect. The present studies suggest that AR2011(h404) is a likely candidate as a novel medicine for intraperitoneal disseminated ovarian cancer.

Introduction: There is a discrepancy in the literature as to whether authorising or refusing the recovery of organs for transplantation is of direct benefit to families in their subsequent grieving process. This study aims to explore the impact of the family interview to pose the option of posthumous donation and the decision to authorise or refuse organ recovery on the grieving process of potential donors' relatives., Methods and Analysis: A protocol for mixed methods, prospective cohort longitudinal study is proposed. Researchers do not randomly assign participants to groups. Instead, participants are considered to belong to one of three groups based on factors related to their experiences at the hospital. In this regard, families in G1, G2 and G3 would be those who authorised organ donation, declined organ donation or were not asked about organ donation, respectively. Their grieving process is monitored at three points in time: 1 month after the patient's death, when a semistructured interview focused on the lived experience during the donation process is carried out, 3 months and 9 months after the death. At the second and third time points, relatives' grieving process is assessed using six psychometric tests: State-Trait Anxiety Inventory, Beck Depression Inventory-II, Inventory of Complicated Grief, The Impact of Event Scale: Revised, Posttraumatic Growth Inventory and Connor-Davidson Resilience Scale. Descriptive statistics (means, SDs and frequencies) are computed for each group and time point. Through a series of regression models, differences between groups in the evolution of bereavement are estimated. Additionally, qualitative analyses of the semistructured interviews are conducted using the ATLAS.ti software., Ethics and Dissemination: This study involves human participants and was approved by Comité Coordinador de Ética de la Investigación Biomédica de Andalucía (CCEIBA) ID:1052-N-21. The results will be disseminated at congresses and ordinary academic forums. Participants gave informed consent to participate in the study before taking part., Competing Interests: Competing interests: David Rodríguez-Arias was partly supported by the Spanish Ministerio de Ciencia e Innovación during the period of this work., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The COVID-19 pandemic and the confinement that was implemented in Argentina generated a need to implement innovative tools for the strengthening of diabetes care. Diabetes self-management education (DSME) is a core element of diabetes care; however, because of COVID-19 restrictions, in-person diabetes educational activities were suspended. Social networks have played an instrumental role in this context to provide DSME in 2 cities of Argentina and help persons with diabetes in their daily self-management., Objective: The aim of this study is to evaluate 2 diabetes education modalities (synchronous and asynchronous) using the social media platform Facebook through the content of posts on diabetes educational sessions in 2 cities of Argentina during the COVID-19 pandemic., Methods: In this qualitative study, we explored 2 modalities of e-learning (synchronous and asynchronous) for diabetes education that used the Facebook pages of public health institutions in Chaco and La Rioja, Argentina, in the context of confinement. Social media metrics and the content of the messages posted by users were analyzed., Results: A total of 332 messages were analyzed. We found that in the asynchronous modality, there was a higher number of visualizations, while in the synchronous modality, there were more posts and interactions between educators and users. We also observed that the number of views increased when primary care clinics were incorporated as disseminators, sharing educational videos from the sessions via social media. Positive aspects were observed in the posts, consisting of messages of thanks and, to a lesser extent, reaffirmations, reflections or personal experiences, and consultations related to the subject treated. Another relevant finding was that the educator/moderator role had a greater presence in the synchronous modality, where posts were based on motivation for participation, help to resolve connectivity problems, and answers to specific user queries., Conclusions: Our findings show positive contributions of an educational intervention for diabetes care using the social media platform Facebook in the context of the COVID-19 pandemic. Although each modality (synchronous vs asynchronous) could have differential and particular advantages, we believe that these strategies have potential to be replicated and adapted to other contexts. However, more documented experiences are needed to explore their sustainability and long-term impact from the users' perspective., (©Daniela Luz Moyano, María Victoria Lopez, Ana Cavallo, Julia Patricia Candia, Aaron Kaen, Vilma Irazola, Andrea Beratarrechea. Originally published in JMIR Formative Research (https://formative.jmir.org), 16.11.2022.)

Background: Primary prevention strategies for asthma are lacking. Its inception probably starts in utero and/or during the early postnatal period as the developmental origins of health and disease (DOHaD) paradigm suggests., Objectives: The main objective of Nutrition in Early Life and Asthma (NELA) cohort study is to unravel whether the following factors contribute causally to the developmental origins of asthma: (1) maternal obesity/adiposity and foetal growth; (2) maternal and child nutrition; (3) outdoor air pollution; (4) endocrine disruptors; and (5) maternal psychological stress. Maternal and offspring biological samples are used to assess changes in offspring microbiome, immune system, epigenome and volatilome as potential mechanisms influencing disease susceptibility., Population: Randomly selected pregnant women from three health areas of Murcia, a south-eastern Mediterranean region of Spain, who fulfilled the inclusion criteria were invited to participate at the time of the follow-up visit for routine foetal anatomy scan at 19-22 weeks of gestation, at the Maternal-Fetal Medicine Unit of the "Virgen de la Arrixaca" University Clinical Hospital over a 36-month period, from March 2015 to April 2018., Design: Prospective, population-based, maternal-child, birth cohort study., Methods: Questionnaires on exposures and outcome variables were administered to mothers at 20-24 gestation week; 32-36 gestation week; and delivery. Children were surveyed at birth, 3 and 18 months of age and currently at 5 years. Furthermore, physical examinations were performed; and different measurements and biological samples were obtained at these time points., Preliminary Results: Among the 1350 women invited to participate, 738 (54%) were finally enrolled in the study and 720 of their children were eligible at birth. The adherence was high with 612 children (83%) attending the 3 months' visit and 532 children (72%) attending the 18 months' visit., Conclusion: The NELA cohort will add original and unique knowledge to the developmental origins of asthma., (© 2021 The Authors. Paediatric and Perinatal Epidemiology published by John Wiley & Sons Ltd.)

Background: The effective management of cardiovascular (CVD) prevention among the population with exclusive public health coverage in Argentina is low since less than 30% of the individuals with predicted 10-year CVD risk ≥10% attend a clinical visit for CVD risk factors control in the primary care clinics (PCCs)., Methods: We conducted a non-controlled feasibility study using a mixed methods approach to evaluate acceptability, adoption and fidelity of a multi-component intervention implemented in the public healthcare system. The eligibility criteria were having exclusive public health coverage, age ≥ 40 years, residence in the PCC's catchment area and 10-year CVD risk ≥10%. The multi-component intervention addressed (1) system barriers through task shifting among the PCC's staff, protected medical appointments slots and a new CVD form and (2) Provider barriers through training for primary care physicians and CHW and individual barriers through a home-based intervention delivered by community health workers (CHWs)., Results: A total of 185 participants were included in the study. Of the total number of eligible participants, 82.2% attended at least one clinical visit for risk factor control. Physicians intensified drug treatment in 77% of participants with BP ≥140/90 mmHg and 79.5% of participants with diabetes, increased the proportion of participants treated according to GCP from 21 to 32.6% in hypertensive participants, 7.4 to 33.3% in high CVD risk and 1.4 to 8.7% in very high CVD risk groups. Mean systolic and diastolic blood pressure were lower at the end of follow up (156.9 to 145.4 mmHg and 92.9 to 88.9 mmHg, respectively) and control of hypertension (BP < 140/90 mmHg) increased from 20.3 to 35.5%., Conclusion: The proposed CHWs-led intervention was feasible and well accepted to improve the detection and treatment of risk factors in the poor population with exclusive public health coverage and with moderate or high CVD risk at the primary care setting in Argentina. Task sharing activities with CHWs did not only stimulate teamwork among PCC staff, but it also improved quality of care. This study showed that community health workers could have a more active role in the detection and clinical management of CVD risk factors in low-income communities.

Introduction: Patients who are unable to fill prescriptions after discharge are at risk of hospital readmission. Ensuring that patients have prescriptions in hand at the time of discharge is a critical component of a safe and effective discharge process. Using a "Meds to Beds" program, we aimed to increase the percentage of patients discharged from Holtz Children's Hospital with medications in hand from 49% to 80%, reduce turnaround time (TAT) from electronic prescription signature to bedside delivery from 4.9 hours (±2.6 hours) to 2 hours, and increase caregiver satisfaction., Methods: We formed a multidisciplinary team and implemented 4 patient-centered interventions through iterative plan-do-study-act cycles. Statistical process control charts were used to understand the impact of the interventions over 10 months. Hospital length of stay and discharges before 2:00 pm were used as balancing measures. We measured caregiver satisfaction using a telephone survey administered by pediatric residents within 7 days after discharge., Results: The mean percentage of patients discharged with medications in hand increased to 76%. TAT decreased to 3.5 hours (±1.8 hours). Length of stay did not significantly increase, whereas the percentage of patients discharged before 2:00 pm did. Caregivers of patients who had prescriptions delivered to their bedside reported high levels of satisfaction., Conclusions: Using a "Meds to Beds" program, we increased the percentage of patients discharged with medications in hand, decreased TAT with reduced variability, and achieved high levels of caregiver satisfaction. Importantly, there was a shift in the culture of the institution toward improved medication access for patients., (Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background & Aims: Liver disease develops in 15%-72% of patients with cystic fibrosis, and 5%-10% develop cirrhosis or portal hypertension, usually during childhood. Transient elastography (TE) is a noninvasive method to measure liver stiffness. We aimed to validate its accuracy in detection of liver disease and assessment of fibrosis in children with cystic fibrosis., Methods: We performed a cross-sectional study to evaluate the accuracy of TE in analysis of liver disease in 160 consecutive children who presented with cystic fibrosis (9.0 ± 0.4 years old, 53% male) at a tertiary referral pediatric center in Australia, from 2011 through 2016. Patients were classified as having cystic fibrosis-associated liver disease (CFLD) or cystic fibrosis without liver disease (CFnoLD) based on clinical, biochemical, and imaging features. Fibrosis severity was determined from histologic analysis of dual-pass liver biopsies from children with CFLD, as the reference standard. Data from healthy children without cystic fibrosis (n = 64, controls) were obtained from a separate study. Liver stiffness measurements (LSMs) were made by Fibroscan analysis, using the inter-quartile range/median ≤30% of 10 valid measurements. Children with macronodularity or portal hypertension with heterogeneous changes on ultrasound without available biopsy were assigned to the category of stage F3-F4 fibrosis., Results: LSM was made reliably in 86% of children; accuracy increased with age. LSMs were significantly higher in children with CFLD (10.7 ± 2.4 kPa, n = 33) than with CFnoLD (4.6 ± 0.1 kPa, n = 105) (P < .0001) or controls (4.1 ± 0.1kPa) (P < .0001); LSMs were higher in children with CFnoLD than controls (P < .05). At a cut-off value of 5.55kPa, LSM identified children with CFLD with an area under the receiver operating characteristic (AUROC) curve of 0.82, 70% sensitivity, and 82% specificity (P < .0001). Classification and regression tree models that combined LSM and aspartate aminotransferase to platelet ratio index (APRI) identified children with CFLD with an AUROC curve of 0.89, 87% sensitivity, and 74% specificity (odds ratio, 18.6). LSMs correlated with fibrosis stage in patients with CFLD (r = 0.67, P = .0001). A cut-off value of 8.7kPa differentiated patients with stage F3-F4 fibrosis from patients with stage F1-F2 fibrosis (AUROC, 0.87; 75% sensitivity; 100% specificity, P=.0002). The combination of LSMs and APRI improved the differentiation of patients with F3-F4 fibrosis vs F1-F2 fibrosis (AUROC, 0.92; 83% sensitivity; and 100% specificity (P < .01)., Conclusions: LSMs made by TE accurately detect liver disease in children with cystic fibrosis; diagnostic accuracy increases when LSMs are combined with APRI. LSMs also differentiate between children with cystic fibrosis with mild-moderate fibrosis vs advanced fibrosis., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Patients with ovarian cancer present peritoneal ascites at recurrence as a marker of disseminated disease and dismal prognosis. Oncolytic immunotherapy is an emerging approach for the treatment of disseminated cancer. In the present work, we constructed a novel oncolytic adenovirus, AR2011, to target malignant ovarian tumors. AR2011 exhibited a clear lytic effect in vitro in human ovarian cancer cell lines and malignant cells obtained from ascitic fluids (AFs) of patients with ovarian cancer. AR2011 activity was neutralized by antibodies present in 31 samples of patient-derived AFs. However, this blockade was overridden by preloading menstrual blood stem cells (MenSCs) with AR2011 (MenSC-AR), since AFs exerted no in vitro inhibitory effect on viral lytic activity under these conditions. Moreover, soluble factors present in AFs act as MenSC chemoattractants. MenSC-AR treatment of nude mice carrying established peritoneal carcinomatosis following administration of human ovarian cancer cells was able to inhibit tumor growth at levels similar to those observed with AR2011 alone. This study demonstrates that MenSCs can be used to override the blockade that AFs exert on viral oncolytic effects.

Here we describe a collection of methods that have been adapted to isolate and modify tumor-specific promoters (TSPs ) to drive viral replication for cancer therapy and other uses. We will describe as examples the secreted protein acidic and rich in cysteine (SPARC ) and the protease-activated receptor-1 (PAR-1) promoter. We outline strategies to select appropriate TSPs using bioinformatics resources and the methods utilized in their subsequent cloning, assessment of transcriptional activity, and their use in conditionally replicative oncolytic adenoviruses .

Activity of endogenous promoters can be altered by including additional responsive elements (REs). These elements can be responsive to features of the tumor environment or alternatively to signaling pathways specifically activated in cancer cells. These REs incorporated into tumor-specific promoters can improve cancer targeting, the replicative capacity, and lytic activity of conditionally replicative adenovirus. Here we outline an approach to incorporate hypoxia and inflammation REs into a specific fragment of the SPARC promoter and the steps to clone a nucleosome positioning sequence (NPS ) identified in the osteocalcin promoter that contains a Wnt RE upstream of a heterologous synthetic promoter.

Aim: Transient elastography (TE) is a rapid, non-invasive, reproducible assessment of liver fibrosis by liver stiffness measurement (LSM). Uncertainty remains regarding utility in children, unsedated and <6 years of age. The importance of general health at the time of study has not been addressed. We report our experience of TE in unsedated control children, impact of intercurrent illness and using new published reliability criteria., Methods: From April 2011 to March 2013, 173 studies were performed in unsedated, healthy control children and children with intercurrent illness without detectable liver disease presenting to the Royal Children's Hospital, Brisbane, Australia. LSM reliability was assessed using interquartile range/median (IQR/M ≤ 30%) of 10 valid measurements., Results: A total of 123 (F:M, 52:71) of 173 studies (71.1%) gave reliable results. In children 0-2 years reliability was 36%, and >2 years reliable results were obtained in ~80%. LSM increased with age; 0-2 years (3.5 ± 0.5 kPa), 3-5 years (3.8 ± 0.3 kPa) and 6-11 years (4.1 ± 0.2 kPa) with healthy older children 12-18 years similar to adults (4.5 ± 0.2 kPa). LSM did not vary with gender (female, 4.5 ± 0.2 vs. male, 4.8 ± 0.2 kPa). Children with intercurrent, non-hepatological illnesses had higher LSM (5.2 ± 0.2 kPa (range, 2.8-11.1 kPa)) compared to healthy children ((4.1 ± 0.1 kPa, range, 2.1-6.3 kPa); P = 0.0001)., Conclusions: TE in unsedated children is feasible from infancy but most reliable after 2 years. Intercurrent illness increases LSM; hence, study context is important when interpreting results., (© 2016 The Author. Journal of Paediatrics and Child Health © 2016 Paediatrics and Child Health Division (Royal Australasian College of Physicians).)

Background: A low FEV1/FVC from post-bronchodilator spirometry is required to diagnose COPD. Both the FEV1 and the FVC can vary over time; therefore, individuals can be given a diagnosis of mild COPD at one visit, but have normal spirometry during the next appointment, even without an intervention., Methods: We analyzed two population-based surveys of adults with spirometry carried out for the same individuals 5-9 years after their baseline examination. We determined the factors associated with a change in the spirometry interpretation from one exam to the next utilizing different criteria commonly used to diagnose COPD., Results: The rate of an inconsistent diagnosis of mild COPD was 11.7% using FEV1/FVC <0.70, 5.9% using FEV1/FEV6

Brain-derived neurotrophic factor (BDNF) is involved in cocaine craving in humans and drug seeking in rodents. Based on this, the aim of this study was to explore the possible role of serum BDNF in cocaine relapse in abstinent addicts. Forty cocaine dependent subjects (DSM-IV criteria) were included in an inpatient 2 weeks abstinence program. Organic and psychiatric co-morbidities were excluded. Two serum samples were collected for each subject at baseline and at after 14 abstinence days. After discharge, all cocaine addicts underwent a 22 weeks follow-up, after which they were classified into early relapsers (ER) (resumed during the first 14 days after discharge,) or late relapsers (LR) (resumed beyond 14 days after discharge). The only clinical differences between groups were the number of consumption days during the last month before detoxification. Serum BDNF levels increased significantly across the 12 days of abstinence in the LR group (p=0.02), whereas in the ER group BDNF remained unchanged. In the ER group, the change of serum BDNF during abstinence negatively correlated with the improvement in depressive symptoms (p=0.02). These results suggest that BDNF has a role in relapse to cocaine consumption in abstinent addicts, although the underlying neurobiological mechanisms remain to be clarified., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Targeting the tumor stroma in addition to the malignant cell compartment is of paramount importance to achieve complete tumor regression. In this work, we modified a previously designed tumor stroma-targeted conditionally replicative adenovirus (CRAd) based on the SPARC promoter by introducing a mutated E1A unable to bind pRB and pseudotyped with a chimeric Ad5/3 fiber (Ad F512v1), and assessed its replication/lytic capacity in ovary cancer in vitro and in vivo. AdF512v1 was able to replicate in fresh samples obtained from patients: (i) with primary human ovary cancer; (ii) that underwent neoadjuvant treatment; (iii) with metastatic disease. In addition, we show that four intraperitoneal (i.p.) injections of 5 × 10(10) v.p. eliminated 50% of xenografted human ovary tumors disseminated in nude mice. Moreover, AdF512v1 replication in tumor models was enhanced 15-40-fold when the tumor contained a mix of malignant and SPARC-expressing stromal cells (fibroblasts and endothelial cells). Contrary to the wild-type virus, AdF512v1 was unable to replicate in normal human ovary samples while the wild-type virus can replicate. This study provides evidence on the lytic capacity of this CRAd and highlights the importance of targeting the stromal tissue in addition to the malignant cell compartment to achieve tumor regression.

Little information exists regarding the epidemiology of the chronic bronchitis phenotype in unselected chronic obstructive pulmonary disease (COPD) populations. We examined the prevalence of the chronic bronchitis phenotype in COPD and non-COPD subjects from the PLATINO study, and investigated how it is associated with important outcomes. Post-bronchodilator forced expiratory volume in 1 s/forced vital capacity <0.70 was used to define COPD. Chronic bronchitis was defined as phlegm on most days, at least 3 months per year for ≥ 2 yrs. We also analysed another definition: cough and phlegm on most days, at least 3 months per year for ≥ 2 yrs. Spirometry was performed in 5,314 subjects (759 with and 4,554 without COPD). The proportion of subjects with and without COPD with chronic bronchitis defined as phlegm on most days, at least 3 months per year for ≥ 2 yrs was 14.4 and 6.2%, respectively. Using the other definition the prevalence was lower: 7.4% with and 2.5% without COPD. Among subjects with COPD, those with chronic bronchitis had worse lung function and general health status, and had more respiratory symptoms, physical activity limitation and exacerbations. Our study helps to understand the prevalence of the chronic bronchitis phenotype in an unselected COPD population at a particular time-point and suggests that chronic bronchitis in COPD is possibly associated with worse outcomes.

Here we embark in a deep metagenomic survey that revealed the taxonomic and potential metabolic pathways aspects of mangrove sediment microbiology. The extraction of DNA from sediment samples and the direct application of pyrosequencing resulted in approximately 215 Mb of data from four distinct mangrove areas (BrMgv01 to 04) in Brazil. The taxonomic approaches applied revealed the dominance of Deltaproteobacteria and Gammaproteobacteria in the samples. Paired statistical analysis showed higher proportions of specific taxonomic groups in each dataset. The metabolic reconstruction indicated the possible occurrence of processes modulated by the prevailing conditions found in mangrove sediments. In terms of carbon cycling, the sequences indicated the prevalence of genes involved in the metabolism of methane, formaldehyde, and carbon dioxide. With respect to the nitrogen cycle, evidence for sequences associated with dissimilatory reduction of nitrate, nitrogen immobilization, and denitrification was detected. Sequences related to the production of adenylsulfate, sulfite, and H(2)S were relevant to the sulphur cycle. These data indicate that the microbial core involved in methane, nitrogen, and sulphur metabolism consists mainly of Burkholderiaceae, Planctomycetaceae, Rhodobacteraceae, and Desulfobacteraceae. Comparison of our data to datasets from soil and sea samples resulted in the allotment of the mangrove sediments between those samples. The results of this study add valuable data about the composition of microbial communities in mangroves and also shed light on possible transformations promoted by microbial organisms in mangrove sediments.

Background: Chronic obstructive pulmonary disease (COPD) is a costly condition that frequently causes permanent work disabilities. Little information exists regarding the impact of COPD on work force participation and the indirect costs of the disease in developing countries., Objective: To examine the frequency of paid employment and factors influencing it in a Latin-American population-based study., Methods: Post-bronchodilator FEV(1)/FVC < 0.70 (forced expiratory volume in 1 s/forced vital capacity) was used to define COPD. Information regarding paid work was assessed by the question 'At any time in the past year, have you worked for payment?', Results: Interviews were conducted with 5571 subjects; 5314 (759 COPD and 4554 non-COPD) subjects underwent spirometry. Among the COPD subjects, 41.8% reported having paid work vs. 57.1% of non-COPD (P < 0.0001). The number of months with paid work was reduced in COPD patients (10.5 ± 0.17 vs. 10.9 ± 0.06, P < 0.05). The main factors associated with having paid work in COPD patients were male sex (OR 0.33, 95%CI 0.23-0.47), higher education level (OR 1.05, 95%CI 1.01-1.09) and younger age (OR 0.90, 95%CI 0.88-0.92). COPD was not a significant contributor to employment (OR 0.83, 95%CI 0.69-1.00, P = 0.054) in the entire population., Conclusions: Although the proportion of persons with paid work is lower in COPD, having COPD appears not to have a significant impact on obtaining paid employment in the overall population of developing countries.

Rationale: COPD is a debilitating disease with increasing mortality worldwide. The BODE index evaluates disease severity and the St George's Respiratory Questionnaire (SGRQ) measures health status., Objective: To identify the relationship between BODE index and the SGRQ and to test the predictive value of both tools against survival., Methods: Open cohort study of 1398 COPD patients (85% male) followed for up to 10 years., Measurements and Main Results: At the time of the inclusion, clinical data, forced spirometry and 6 min walking distance were determined and BODE index and SGRQ were calculated. Vital status and cause of death were documented at the end of follow-up., Results: The cohort's mean of FEV1% predicted was 46 ± 18%, BODE index was 3.6 ± 2.5, and SGRQ% total score was 49 ± 20. The SGRQ scores increased progressively as severity of COPD increased by BODE quartiles. The correlation between SGRQ and BODE index was good (r = 0.58, p < 0.0001). Both tests correlated with COPD survival (BODE = -0.4 vs. SGRQ = -0.20, p < 0.0001). The area under the curve (AUC) for the BODE index was 0.77 vs. 0.66 for the SGRQ % total score (p < 0.001)., Conclusions: Health status as measured by SGRQ worsens with disease severity evaluated by the BODE index. Both tools predict mortality and provide complimentary information in the evaluation of patients with COPD., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The 6-min walk distance (6MWD) predicted values have been derived from small cohorts mostly from single countries. The aim of the present study was to investigate differences between countries and identify new reference values to improve 6MWD interpretation. We studied 444 subjects (238 males) from seven countries (10 centres) ranging 40-80 yrs of age. We measured 6MWD, height, weight, spirometry, heart rate (HR), maximum HR (HR(max)) during the 6-min walk test/the predicted maximum HR (HR(max) % pred), Borg dyspnoea score and oxygen saturation. The mean ± sd 6MWD was 571 ± 90 m (range 380-782 m). Males walked 30 m more than females (p < 0.001). A multiple regression model for the 6MWD included age, sex, height, weight and HR(max) % pred (adjusted r² = 0.38; p < 0.001), but there was variability across centres (adjusted r² = 0.09-0.73) and its routine use is not recommended. Age had a great impact in 6MWD independent of the centres, declining significantly in the older population (p < 0.001). Age-specific reference standards of 6MWD were constructed for male and female adults. In healthy subjects, there were geographic variations in 6MWD and caution must be taken when using existing predictive equations. The present study provides new 6MWD standard curves that could be useful in the care of adult patients with chronic diseases.

Background: Acute bronchodilator responsiveness is an area of discussion in COPD. No information exists regarding this aspect of the disease from an unselected COPD population. We assessed acute bronchodilator responsiveness and factors influencing it in subjects with and without airway obstruction in an epidemiologic sample., Methods: COPD was defined by GOLD criteria (post-bronchodilator FEV(1)/FVC<0.70). In this analysis, subjects with pre-bronchodilator FEV(1)/FVC <0.70 but > or =0.70 post-bronchodilator were considered to have reversible obstruction. Bronchodilator responsiveness after albuterol 200microg was assessed using three definitions: a) FVC and/or FEV(1) increment > or =12% plus > or =200mL over baseline; b) FEV(1)> or =15% increase over baseline; and c) FEV(1) increase > or =10% of predicted value., Results: There were 756 healthy respiratory subjects, 481 subjects with reversible obstruction and 759 COPD subjects. Depending on the criterion used the proportion of person with acute bronchodilator responsiveness ranged between 15.0-28.2% in COPD, 11.4-21.6% in reversible obstructed and 2.7-7.2% in respiratory healthy. FEV(1) changes were lower (110.6+/-7.40 vs. 164.7+/-11.8mL) and FVC higher (146.5+/-14.2mL vs. -131.0+/-19.6mL) in COPD subjects compared with reversible obstructed. Substantial overlap in FEV(1) and FVC changes was observed among the groups. Acute bronchodilator responsiveness in COPD persons was associated with less obstruction and never smoking., Conclusions: Over two-thirds of persons with COPD did not demonstrate acute bronchodilator responsiveness. The overall response was small and less than that considered as significant by ATS criteria. The overlap in FEV(1) and FVC changes after bronchodilator among the groups makes it difficult to determine a threshold for separating them., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Background: COPD is a highly prevalent disease but underdiagnosed, undertreated and possibly under-recognized by patients. Limited information exists regarding patients' perception of COPD severity. We compared patients' general health status perception, degree of breathlessness and physical activity limitation with the severity of their respiratory condition measured by airway obstruction, in a population-based sample., Methods: We used postbronchodilator FEV(1)/FVC<0.70 to define COPD. Patients' perception of their general health status was derived from the question "in general you would say that your health is: excellent, very good, good, fair or poor?", Results: Spirometry was performed in 5314 subjects: an FEV(1)/FVC ratio below 0.70 was found in 759 subjects. In persons with COPD, general health status decreased with increasing GOLD stages. Over one-half of subjects with stage 2 and one third of those with stages 3 and 4 reported their health status as good to excellent. There was also a disparity between airway obstruction severity and breathlessness intensity. Although the more severe COPD stages were frequently associated with significant compromise of work and everyday activities, patients often tended to provide an optimistic self evaluation of their health status., Conclusions: The discrepancy observed between general health status, dyspnea severity, physical activity limitation and airway obstruction most likely reflect patients' underperception of disease severity, emphasizing the need for improving case-finding measures and multi-component evaluation of COPD subjects.

Background: Recurrent exacerbations are common in COPD patients. Limited information exists regarding exacerbation frequency in COPD patients from epidemiologic studies. We examined the frequency of self-reported exacerbations and the factors influencing exacerbation frequency among COPD patients in a population-based study conducted in Latin America., Methods: We used a post-bronchodilator FEV(1)/FVC ratio of < 0.70 to define COPD. Exacerbation was self-reported and defined by symptoms (deterioration of breathing symptoms that affected usual daily activities or caused missed work)., Results: Spirometry was performed in 5,314 subjects. There were 759 subjects with airflow limitation; of these, 18.2% reported ever having had an exacerbation, 7.9% reported having an exacerbation, and 6.2% reported having an exacerbation requiring at least a doctor visit within the past year. The proportion of individuals with an exacerbation significantly increased by Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages, from 4.2% in stage 1 to 28.9% in stages 3 and 4. The self-reported exacerbation rate was 0.58 exacerbations per year. The rate of exacerbations requiring at least a doctor visit and length of stay in hospital due to exacerbations also increased as COPD severity progressed. The factors associated with having an exacerbation in the past year were dyspnea, prior asthma diagnosis, receiving any respiratory therapy, and disease severity of GOLD stages 3 and 4., Conclusions: The proportion of individuals with airflow limitation and self-reported exacerbation increases as the disease severity progresses. Dyspnea, prior asthma diagnosis, receiving any respiratory therapy, and more severe obstruction were significantly associated with having an exacerbation in the past year.

Background: The PLATINO project was launched in 2002 in order to study the prevalence of chronic obstructive pulmonary disease (COPD) in Latin America. Because smoking is the main risk factor for COPD, detailed data on it were obtained. The aim of this paper was to evaluate the prevalence of smoking and incidence of initiation among middle-aged and older adults (40 years or older). Special emphasis was given to the association between smoking and schooling., Methods: PLATINO is a multicenter study comprising five cross-sectional population-based surveys of approximately 1,000 individuals per site in Sao Paulo (Brazil), Santiago (Chile), Mexico City (Mexico), Montevideo (Uruguay) and Caracas (Venezuela). The outcome variable was smoking status (never, former or current). Current smokers were those who reported to smoke within the previous 30 days. Former smokers were those who reported to quit smoking more than 30 days before the survey. Using information on year of birth and age of smoking onset and quitting, a retrospective cohort analysis was carried out. Smoking prevalence at each period was defined as the number of subjects who started to smoke during the period plus those who were already smokers at the beginning of the period, divided by the total number of subjects. Incidence of smoking initiation was calculated as the number of subjects who started to smoke during the period divided by the number of non-smokers at its beginning. The independent variables included were sex, age and schooling., Results: Non-response rates ranged from 11.1% to 26.8%. The prevalence of smoking ranged from 23.9% (95%CI 21.3; 26.6) in Sao Paulo to 38.5% (95%CI 35.7; 41.2) in Santiago. Males and middle-aged adults were more likely to smoke in all sites. After adjustment for age, schooling was not associated with smoking. Using retrospective cohort analysis, it was possible to detect that the highest prevalence of smoking is found between 20-29 years, while the highest incidence is found between 10-19 years. Age of smoking onset tended to decline over time among females., Conclusion: The prevalence of smoking varied considerably across sites, but was lower among countries with national anti-smoking campaigns.

Purpose: A33 antigen is a membrane-bound protein expressed in intestinal epithelium that is overexpressed in 95% of primary and metastatic colorectal carcinomas but is absent in most epithelial tissues and tumor types. We hypothesized that A33 promoter might be useful in the design of a conditionally replicative adenovirus for the treatment of colorectal cancer (CRC)., Experimental Design: We cloned an A33 promoter fragment (A33Pr) that extends from -105 to +307 bp. Using luciferase activity as a reporter gene, we showed that A33Pr was active in CRC cell lines. We next constructed a conditionally replicative adenovirus named AV22EL where E1A was placed under the control of A33Pr. The tumor-specific oncolytic effect of AV22EL was investigated both in vitro and in vivo., Results: AV22EL induced specific in vitro lysis of human CRC cell lines that expressed A33 and have negligible lytic capacity on cells that lacked or had minimal A33 expression, including normal human colonic cells. In vivo, a marked reduction of tumor growth and increased long-term survival rates were observed in nude mice xenografted with s.c. CRC tumors. Combination with 5-fluorouracil induced an additive effect in vitro with no toxic effects in vivo. Remarkably, AV22EL completely eliminated established hepatic metastases in >90% of mice and restored hepatic function according to biochemical parameters. Its systemic administration induced E1A expression only in the hepatic metastasis but not in normal organs., Conclusions: These data show that AV22EL is a stringently regulated and potent oncolytic agent for the treatment of CRC.

The clinical efficacy of conditionally replicative oncolytic adenoviruses (CRAd) is still limited by the inefficient infection of the tumor mass. Since tumor growth is essentially the result of a continuous cross-talk between malignant and tumor-associated stromal cells, targeting both cell compartments may profoundly influence viral efficacy. Therefore, we developed SPARC promoter-based CRAds since the SPARC gene is expressed both in malignant cells and in tumor-associated stromal cells. These CRAds, expressing or not the Herpes Simplex thymidine kinase gene (Ad-F512 and Ad(I)-F512-TK, respectively) exerted a lytic effect on a panel of human melanoma cells expressing SPARC; but they were completely attenuated in normal cells of different origins, including fresh melanocytes, regardless of whether cells expressed or not SPARC. Interestingly, both CRAds displayed cytotoxic activity on SPARC positive-transformed human microendothelial HMEC-1 cells and WI-38 fetal fibroblasts. Both CRAds were therapeutically effective on SPARC positive-human melanoma tumors growing in nude mice but exhibited restricted efficacy in the presence of co-administered HMEC-1 or WI-38 cells. Conversely, co-administration of HMEC-1 cells enhanced the oncolytic efficacy of Ad(I)-F512-TK on SPARC-negative MIA PaCa-2 pancreatic cancer cells in vivo. Moreover, conditioned media produced by stromal cells pre-infected with the CRAds enhanced the in vitro viral oncolytic activity on pancreatic cancer cells, but not on melanoma cells. The whole data indicate that stromal cells might play an important role on the outcome of the oncolytic efficacy of conditionally replicative adenoviruses.

Background: There is scanty information regarding respiratory medication prescription pattern in Latin America. We examined the use of bronchodilators and corticosteroids in a population-based study conducted in five Latin American cities., Methods: Medication use was derived from questions regarding the use of medication "to help breathing" within the previous 12 months, type of medicine, and frequency of use. To minimize the possibility of overdiagnosis, we used postbronchodilator FEV(1)/FVC<0.70 plus FEV(1)<80% as the definition of obstruction., Results: Interviews were completed in 5571 subjects from 6711 eligible individuals, and spirometry was performed in 5314 subjects. There were 360 (6.5%) treated subjects and 5211 not treated. Treated subjects were more likely to be older, women, unemployed, have higher tobacco consumption, higher body mass index, higher FEV(1) reversibility and airway obstruction. They were also more likely to report prior spirometry, prior diagnosis of COPD, asthma or tuberculosis, and more respiratory symptoms. Over half of treated subjects had neither obstruction nor FEV(1) reversibility, and approximately 30% reported no prior diagnosis of asthma or COPD. Prior respiratory diagnoses and wheezing were more strongly associated with treatment than objective measures of airway obstruction., Conclusions: The use of bronchodilators and/or corticosteroids is common in the general population aged 40 years or older, with over one-half of treated subjects using them without being obstructed.

Setting: Five Latin American cities: São Paulo, Brazil; Mexico City, Mexico; Montevideo, Uruguay; Santiago, Chile; Caracas, Venezuela., Objective: To describe the burden of chronic obstructive pulmonary disease (COPD) in Latin America., Design: This is a multicentre study. Post-bronchodilator spirometry was used and the main outcome measure was FEV(1)/FVC < 0.7 (fixed ratio criterion). Global Obstructive Lung Disease (GOLD) stages were also analysed., Results: The combined population aged > or =40 years in the five countries included in the study was approximately 85.3 million. Of these, it was estimated that 12.2 million have airflow obstruction, which corresponds to our prevalence estimate of 14.3%. The proportion of subjects in Stages II-IV of the GOLD classification was 5.6%. Risk factors presenting the highest aetiological fractions for COPD were age, current smoking, indoor exposure to coal and exposure to dust in the workplace. Smoking, the modifiable factor with the strongest aetiological fraction for COPD, affects 29.2% of adults aged > or =40 years in these cities, corresponding to approximately 25 million smokers in this age group., Conclusion: Prevention of smoking and exposure to pollutants, such as coal and dust, are the interventions most likely to succeed against COPD in Latin America. The information obtained by a collaborative study has been vast and encouraging for other similar studies.

Background: The body mass index (BMI) is a prognostic factor for chronic obstructive pulmonary disease (COPD). Despite its importance, little information is available regarding BMI alteration in COPD from a population-based study. We examined characteristics by BMI categories in the total and COPD populations in five Latin-American cities, and explored the factors influencing BMI in COPD., Methods: COPD was defined as a postbronchodilator forced expiratory volume in the first second/forced vital capacity (FEV(1)/FVC) <0.70. BMI was categorized as underweight (< 20 kg/m(2)), normal weight (20-24.9 kg/m(2)), overweight (25.0-29.9 kg/m(2)), and obese (> or = 30.0 kg/m(2))., Results: Interviews were completed in 5571 subjects from 6711 eligible individuals, and spirometry was performed in 5314 subjects. There were 759 subjects with COPD and 4555 without COPD. Compared with the non-COPD group, there was a higher proportion of COPD subjects in the underweight and normal weight categories, and a lower proportion in the obese category. Over one-half COPD subjects had BMI over 25 kg/m(2). No differences in BMI strata among countries were found in COPD subjects. Factors associated with lower BMI in males with COPD were aging, current smoking, and global initiative for chronic obstructive lung disease (GOLD) stages III-IV, whereas wheeze and residing in Santiago and Montevideo were associated with higher BMI. In females with COPD, current smoking, lower education, and GOLD stages II-IV were associated with lower BMI, while dyspnea and wheeze were associated with higher BMI., Conclusions: BMI alterations are common in COPD with no significant differences among countries. Current smoking, age, GOLD stages, education level, residing in Santiago and Montevideo, dyspnea and wheeze were independently associated with BMI in COPD.

Exercise impairment as measured by the 6-min walk distance (6MWD) test afflicts many patients with chronic obstructive pulmonary disease (COPD) and is known to predict mortality. Reference equations for the 6MWD in adults have been published but not yet validated. The present authors prospectively followed 1,379 COPD patients for 55+/-30 months and tested the predictive value of the baseline 6MWD in metres, the 6MWD work (kg.m(-1)) and as a percentage of predicted values the 6MWD in meters according to two reference equations. All-cause mortality was the validating outcome. The best threshold values were identified for each of the tests using receiver operating characteristic (ROC) curves. The threshold values obtained were: 350 m for the 6MWD, 25,000 kg.m(-1) for the 6MWD work, and 67 and 54% predicted for the two reference equations. All modalities of the testing were similar at predicting COPD mortality and correlated well with the 6MWD test. In conclusion, all modalities of testing predict mortality in chronic obstructive pulmonary disease equally well. In the 6-min walk distance test, a value <350 m is associated with increased mortality and should be regarded as abnormal.

The aim of the present study was to evaluate the association between history of tuberculosis and airflow obstruction. A population-based, multicentre study was carried out and included 5,571 subjects aged > or =40 yrs living in one of five Latin American metropolitan areas: Sao Paulo (Brazil); Montevideo (Uruguay); Mexico City (Mexico); Santiago (Chile); and Caracas (Venezuela). Subjects performed pre- and post-bronchodilator spirometry and were asked whether they had ever been diagnosed with tuberculosis by a physician. The overall prevalence of airflow obstruction (forced expiratory volume in one second/forced vital capacity post-bronchodilator <0.7) was 30.7% among those with a history of tuberculosis, compared with 13.9% among those without a history. Males with a medical history of tuberculosis were 4.1 times more likely to present airflow obstruction than those without such a diagnosis. This remained unchanged after adjustment for confounding by age, sex, schooling, ethnicity, smoking, exposure to dust and smoke, respiratory morbidity in childhood and current morbidity. Among females, the unadjusted and adjusted odds ratios were 2.3 and 1.7, respectively. In conclusion, history of tuberculosis is associated with airflow obstruction in Latin American middle-aged and older adults.

The possibility of inducing a strong immune response to impair tumor growth by ectopically expressing cytokines, followed by the generation of an antitumor memory raised great hopes and enthusiasm as a therapeutic approach. However, the efficacy of this strategy on established tumor models appeared low and the initial results in the clinics were disappointing. Recently, new evidence indicates that cytokine gene combination or the combined use of cytokine genes with additional gene therapy approaches induces a synergistic effect supporting the use of cytokine gene therapy to improve the clinical outcome for cancer patients.

Background: COPD is a major worldwide problem with a rising prevalence. Despite its importance, there is a lack of information regarding underdiagnosis and misdiagnosis of COPD in different countries. As part of the Proyecto Latinoamericano de Investigación en Obstrucción Pulmonar study, we examined the relationship between prior diagnostic label and airway obstruction in the metropolitan areas of five Latin American cities (São Paulo, Santiago, Mexico City, Montevideo, and Caracas)., Methods: A two-stage sampling strategy was used in each of the five areas to obtain probability samples of adults aged >or= 40 years. Participants completed a questionnaire that included questions on prior diagnoses, and prebronchodilator and postbronchodilator spirometry. A study diagnosis of COPD was based on airway obstruction, defined as a postbronchodilator FEV(1)/FVC < 0.70., Results: Valid spirometry and prior diagnosis information was obtained for 5,303 participants; 758 subjects had a study diagnosis of COPD, of which 672 cases (88.7%) had not been previously diagnosed. The prevalence of undiagnosed COPD was 12.7%, ranging from 6.9% in Mexico City to 18.2% in Montevideo. Among 237 subjects with a prior COPD diagnosis, only 86 subjects (36.3%) had postbronchodilator FEV(1)/FVC < 0.7, while 151 subjects (63.7%) had normal spirometric values. In the same group of 237 subjects, only 34% reported ever undergoing spirometry prior to our study., Conclusions: Inaccurate diagnostic labeling of COPD represents an important health problem in Latin America. One possible explanation is the low rate of spirometry for COPD diagnosis.

The successful use of transcriptional targeting for cancer therapy depends on the activity of a given promoter inside the malignant cell. Because solid human tumors evolve as a "cross-talk" between the different cell types within the tumor, we hypothesized that targeting the entire tumor mass might have better therapeutic effect. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein overexpressed in different human cancers malignant melanomas both in the malignant cells compartment as in the stromal one (fibroblasts and endothelial cells). We have shown that expression of the herpes simplex virus-thymidine kinase (TK) gene driven by the SPARC promoter in combination with ganciclovir inhibited human melanoma cell growth in monolayer as well as in multicellular spheroids. This inhibitory effect was observed both in homotypic spheroids composed of melanoma cells alone as well as in spheroids made of melanoma cells and stromal cells. Expression of the TK gene was also efficient to inhibit the in vivo tumor growth of established melanomas when TK was expressed either by the malignant cells themselves or by coadministered endothelial cells. Our data suggest that the use of therapeutic genes driven by SPARC promoter could be a valuable strategy for cancer therapy aiming to target all the cellular components of the tumor mass.

The aim of this study was to determine the prevalence of oxygen desaturation in adults aged>or=40 yrs as altitude above sea level increases. A population-based, cross-sectional study with a multistage cluster sampling of 1,063 subjects from metropolitan Mexico City (Mexico; 2,240 m above sea level), 1,357 from Caracas (Venezuela; 950 m) and 943 from Montevideo (Uruguay; 35 m). The mean of six measurements of arterial oxygen saturation (SP,O2) was estimated using a pulse oximeter. Mean SP,O2 decreased with altitude. No subject from Montevideo had a mean SP,O288%. In conclusion, the prevalence of hypoxaemia was closely related to altitude. Priorities for oxygen prescription must be defined in moderate altitudes because it is unfeasible to provide it to all subjects fulfilling the criteria commonly used.

Preclinical studies demonstrated that certain cytokines are potentially useful for the induction of antitumor immune responses. However, their administration in clinical settings was only marginally useful and evoked serious toxicity. In this study, we demonstrate that the combination of autologous inactivated tumor cells expressing IL-12 and IL-10 induced tumor remission in 50-70% of mice harboring large established colon or mammary tumors and spontaneous lung metastases, with the consequent establishment of an antitumor immune memory. Mice treatment with tumor cells expressing IL-12 was only marginally effective, while expression of IL-10 was not effective at all. Administration of the combined immunotherapy stimulated the recruitment of a strong inflammatory infiltrate that correlated with local, increased expression levels of the chemokines MIP-2, MCP-1, IFN-gamma-inducible protein-10, and TCA-3 and the overexpression of IFN-gamma, but not IL-4. The combined immunotherapy was also therapeutically effective on established lung metastases from both colon and mammary tumors. The antitumor effect of the combined immunotherapy was mainly dependent on CD8+ cells although CD4+ T cells also played a role. The production of IFN-gamma and IL-4 by spleen cells and the development of tumor-specific IgG1 and IgG2a Abs indicate that each cytokine stimulated its own Th pathway and that both arms were actively engaged in the antitumor effect. This study provides the first evidence of a synergistic antitumor effect of IL-12 and IL-10 suggesting that a Th1 and a Th2 cytokine can be effectively combined as a novel rational approach for cancer immunotherapy.

The objective of the study is to compare the efficacy of electro-acupuncture with placebo-acupuncture for the treatment of shoulder pain. This study comprised of a prospective, randomized, placebo controlled trial, with independent evaluator set in a Public primary care clinic in Spain. The participants are patients aged from 25 to 83 years with shoulder pain. Patients were randomly allocated to two treatments over eight weeks, with electro-acupuncture or skin non-penetrating placebo-acupuncture, both able to take diclofenac if needed for intense pain. Primary outcome measure was the difference between groups in pain intensity (visual analogue scale-VAS). Secondary outcomes were differences between groups in pain intensity measured by Lattinen index, in range of motion (goniometer), functional ability (SPADI), quality of life (COOP-WONCA charts), NSAIDS intake, credibility (Borkoveck and Nau scale) and global satisfaction (10 points analogue scale). Assessments were performed before, during and three and six months after treatment. At six month follow-up after treatment the acupuncture group showed a significantly greater improvement in pain intensity compared with the control group [VAS mean difference 2.0 (95% CI 1.2-2.9)]. The acupuncture group had consistently better results in every secondary outcome measure than the control group. Acupuncture is an effective long-term treatment for patients with shoulder pain (from soft tissues lesions) in a primary care setting.