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Background: The use of extracorporeal membrane oxygenation (ECMO) in the trauma population has been reported to have a mortality benefit in patients with severe refractory hypoxic respiratory failure. This study compares the early initiation of ECMO for the management of severe adult respiratory distress syndrome (ARDS) versus a historical control immediately preceding the use of ECMO for trauma patients., Methods: A retrospective study was conducted at a single verified Level I trauma center. The study population was limited to trauma patients diagnosed with severe ARDS using the Berlin definition (PaO2/FIO2 ratio < 100). Patients managed with ECMO versus conventional ventilation (CONV) were compared. The primary outcome of interest was mortality; secondary outcomes included hospital length of stay, intensive care unit-free days, and ventilator-free days., Results: Fifteen ECMO patients managed from March 2013 to November 2014 were identified, as were 14 CONV patients managed from March 2012 to February 2013 who met the Berlin definition of severe ARDS. Data related to age, Injury Severity Scores (ISSs), admission lactic acid levels, base deficit, the number of transfused red blood cell units within the first 24 hours, and presence of severe traumatic brain injury were collected and were not statistically different between the groups. Likewise, Murray Lung Injury (MLI), Sequential Organ Failure Assessment (SOFA), and Acute Physiology and Chronic Health Evaluation II (APACHE II) scores determined at the onset of severe ARDS were not statistically different between the groups. Median hospital stay (CONV, 28.0 days [14.0-47.0]; ECMO, 43.5 days [30.0-93.0]; p = 0.15), intensive care unit-free days (CONV, 0.0 days [0.0-5.0]; ECMO, 5.0 days [0.0-7.0]; p = 0.26), and ventilator-free days (CONV, 0.0 days [0.0-10.0]; ECMO, 8.0 days [0.0-19.0]; p = 0.13) were not statistically different between the groups. Mortality in the ECMO group was significantly reduced compared with the CONV group (ECMO, 13.3%; CONV, 64%; p = 0.01). Timing from the onset of severe ARDS to ECMO intervention occurred at a mean 1.9 ± 1.4 days., Conclusion: Patients who were treated with ECMO for severe ARDS had an improved mortality compared with historical controls. ECMO should be considered at the early onset of severe ARDS to improve survival., Level of Evidence: Therapeutic study, level IV.

Whole-exome sequencing of 13 individuals with developmental delay commonly accompanied by abnormal muscle tone and seizures identified de novo missense mutations enriched within a sub-region of GNB1, a gene encoding the guanine nucleotide-binding protein subunit beta-1, Gβ. These 13 individuals were identified among a base of 5,855 individuals recruited for various undiagnosed genetic disorders. The probability of observing 13 or more de novo mutations by chance among 5,855 individuals is very low (p = 7.1 × 10(-21)), implicating GNB1 as a genome-wide-significant disease-associated gene. The majority of these 13 mutations affect known Gβ binding sites, which suggests that a likely disease mechanism is through the disruption of the protein interface required for Gα-Gβγ interaction (resulting in a constitutively active Gβγ) or through the disruption of residues relevant for interaction between Gβγ and certain downstream effectors (resulting in reduced interaction with the effectors). Strikingly, 8 of the 13 individuals recruited here for a neurodevelopmental disorder have a germline de novo GNB1 mutation that overlaps a set of five recurrent somatic tumor mutations for which recent functional studies demonstrated a gain-of-function effect due to constitutive activation of G protein downstream signaling cascades for some of the affected residues., (Copyright © 2016 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Extracorporeal membrane oxygenation (ECMO) has been used to provide "lung rest" through the use of low tidal volume (6 ml/kg) and ultralow tidal volume (<6 ml/kg) ventilation in acute respiratory distress syndrome (ARDS). Low and ultralow tidal volume ventilation can result in low dynamic respiratory compliance and potentially increased retention of airway secretions. We present our experience using automated rotational percussion beds (ARPBs) and bronchoscopy in four ARDS patients to manage increased pulmonary secretions. These beds performed automated side-to-side tilt maneuver and intermittent chest wall percussion. Their use resulted in substantial reduction in peak and plateau pressures in two patients on volume control ventilation, while the driving pressures (inspiratory pressure) to attain the desired tidal volumes in patients on pressure control ventilation also decreased. In addition, mean partial pressure of oxygen in arterial blood (PaO2)/fraction of inspired oxygen (FiO2) ratio (109 pre-ARPB vs. 157 post-ARPB), positive end-expiratory pressure (10 cm H2O vs. 8 cm H2O), and FiO2 (0.88 vs. 0.52) improved after initiation of ARPB. The improvements in the respiratory mechanics and oxygenation helped us to initiate early ECMO weaning. Based on our experience, the use of chest physiotherapy, frequent body repositioning, and bronchoscopy may be helpful in the management of pulmonary secretions in patients supported with ECMO.

The use of extracorporeal membrane oxygenation (ECMO) in adults has rapidly increased as the technology has evolved, although there is little definitive evidence that it is beneficial in this group. ECMO is now being used in acute respiratory distress syndrome (and was used extensively for this indication during the influenza H1N1 pandemic), as a bridge to lung or heart transplant, and in postcardiac arrest patients. We review the current evidence and indications for ECMO, focusing on its principles and practical aspects in adult patients with respiratory or cardiac failure., (Copyright © 2016 Cleveland Clinic.)

Under defined differentiation conditions, human embryonic stem cells (hESCs) can be directed toward a mesendoderm (ME) or neuroectoderm (NE) fate, the first decision during hESC differentiation. Coupled with lineage-specific G1 lengthening, a divergent ciliation pattern emerged within the first 24 hr of induced lineage specification, and these changes heralded a neuroectoderm decision before any neural precursor markers were expressed. By day 2, increased ciliation in NE precursors induced autophagy that resulted in the inactivation of Nrf2 and thereby relieved transcriptional activation of OCT4 and NANOG. Nrf2 binds directly to upstream regions of these pluripotency genes to promote their expression and repress NE derivation. Nrf2 suppression was sufficient to rescue poorly neurogenic iPSC lines. Only after these events had been initiated did neural precursor markers get expressed at day 4. Thus, we have identified a primary cilium-autophagy-Nrf2 (PAN) control axis coupled to cell-cycle progression that directs hESCs toward NE., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Common FTO variants are associated with obesity. However, it has recently been shown that homozygous FTO c.947G>A variant, which predicts p.R316Q, and c.956C>T, which predicts p.S319F, are associated with a malformation syndrome inherited in an autosomal recessive pattern. We present a similar homozygous FTO c.965G>A variant that predicts p.R322Q, associated with a lethal malformation syndrome in a consanguineous Yemeni family. Functional studies showed that the p.R316Q, p.S219F, and p.R322Q variants render the FTO protein inactive. We further expand on the phenotype of homozygous FTO loss-of-function mutations to include eye abnormalities, gingival overgrowth, craniosynostosis, and cutaneous photosensitivity., (© 2015 Wiley Periodicals, Inc.)

Williams syndrome (WS) is a neurodevelopmental disorder caused by a genomic deletion of ∼28 genes that results in a cognitive and behavioral profile marked by overall intellectual impairment with relative strength in expressive language and hypersocial behavior. Advancements in protocols for neuron differentiation from induced pluripotent stem cells allowed us to elucidate the molecular circuitry underpinning the ontogeny of WS. In patient-derived stem cells and neurons, we determined the expression profile of the Williams-Beuren syndrome critical region-deleted genes and the genome-wide transcriptional consequences of the hemizygous genomic microdeletion at chromosome 7q11.23. Derived neurons displayed disease-relevant hallmarks and indicated novel aberrant pathways in WS neurons including over-activated Wnt signaling accompanying an incomplete neurogenic commitment. We show that haploinsufficiency of the ATP-dependent chromatin remodeler, BAZ1B, which is deleted in WS, significantly contributes to this differentiation defect. Chromatin-immunoprecipitation (ChIP-seq) revealed BAZ1B target gene functions are enriched for neurogenesis, neuron differentiation and disease-relevant phenotypes. BAZ1B haploinsufficiency caused widespread gene expression changes in neural progenitor cells, and together with BAZ1B ChIP-seq target genes, explained 42% of the transcriptional dysregulation in WS neurons. BAZ1B contributes to regulating the balance between neural precursor self-renewal and differentiation and the differentiation defect caused by BAZ1B haploinsufficiency can be rescued by mitigating over-active Wnt signaling in neural stem cells. Altogether, these results reveal a pivotal role for BAZ1B in neurodevelopment and implicate its haploinsufficiency as a likely contributor to the neurological phenotypes in WS., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Latino children experience more prevalent and severe tooth decay than non-Hispanic white and non-Hispanic black children. Few theory-based, evaluated and culturally appropriate interventions target parents of this vulnerable population. To fill this gap, the Contra Caries Oral Health Education Program, a theory-based, promotora-led education program for low-income, Spanish-speaking parents of children aged 1-5 years, was developed. This article describes qualitative findings of the acceptability of curriculum content and activities, presents the process of refinement of the curriculum through engaging the target population and promotoras, and presents results from the evaluation assessing the acceptability of the curriculum once implemented., Methods: Focus groups were conducted with low-income Spanish-speaking parents of children 1-5 years living in a city in an agricultural area of California. Interviews were digitally recorded, translated and transcribed, checked for accuracy and the resulting data was thematically coded and analyzed using a social constructionist approach. The Contra Caries Oral Health Education Program was then implemented with a separate but similar sample, and after completing the program, participants were administered surveys asking about acceptability and favorite activities of the education program. Data were entered into a database, checked for accuracy, open-ended questions were categorized, and responses to close-ended questions counted., Results: Twelve focus groups were conducted (N = 51), 105 parents attended the Contra Caries Oral Health Education Program, and 83 parents filled out surveys. Complete attendance and retention was high (89% and 90%, respectively). This study found that their children's oral health is a high priority. Parents were not only interested in, but actually attended classes focused on increasing their knowledge and skills with respect to early childhood oral health. The Contra Caries content and format was perceived as acceptable by parents. Strong opinions about curriculum content were expressed for including information on how caries starts and progresses, weaning from the bottle, oral health care for children and adults, motivational strategies for children's tooth brushing, dental visits and cavity restorations., Conclusions: The Contra Caries Oral Health Education Program was acceptable to low-income, Spanish-speaking parents of children 1-5 years. Participating in the curriculum development and revision process likely played an important role in the parents' high acceptability of the program.

Cognitive behavioral therapy (CBT), particularly when it includes an exposure component, is an empirically supported psychosocial treatment for anxiety disorders that has been shown to be highly efficacious, desirable to patients, and cost-effective. However, access to and receipt of exposure-based treatment CBT anxiety remains lacking despite these benefits. The current study reviewed electronic medical records at a large public outpatient psychiatry clinic in order to clarify what usual care for anxiety disorders entails, and to determine the extent to which effective psychosocial treatment is accessible to, and implemented with anxiety disorder patients. Database queries generated from the billing and medical record system at the Los Angeles County Adult Outpatient Psychiatry Clinic identified 582 patients presenting with an anxiety disorder diagnosis in a 6-month time frame. These patients' electronic medical records were reviewed using a standardized data collection form. Findings indicated that the majority of patients received pharmacological treatment for their anxiety. The majority of the psychosocial treatment delivered was supportive therapy. Among the minority of patients who did initiate CBT, an even smaller minority received treatment that included an exposure component, and those who did receive exposure likely received a sub-optimal dose. Understanding usual care delivery patterns is an important preliminary step to identifying and addressing barriers to optimal anxiety disorder treatment in adult community mental health settings., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Mortality of severe acute respiratory distress syndrome (ARDS) remains high. Once conventional mechanical ventilation fails, alternative modes of therapy are used; most of which have limited evidence to support their use. No definitive guidelines exist for the management of these patients with alternate modalities of treatment. We conducted a cross-sectional national survey of 302 adult critical care training programs in the United States to understand the current preferences of intensivists regarding the use of different therapies for severe ARDS, including the use of extracorporeal membrane oxygenation (ECMO). A total of 381 responses were received: 203 critical care faculty and 174 critical care trainees. Airway pressure release ventilation was the initial choice of treatment reported by most when conventional mechanical ventilation strategy failed followed by inhaled nitric oxide and prone positioning. Extracorporeal membrane oxygenation availability was reported by 80% of the respondents at their institutions. Most respondents (83%) would consider ECMO in patients who fail optimal mechanical ventilation strategies, and the majority (60%) believed that ECMO use can facilitate lung protective ventilation, but few favored its use as a first-line modality. The majority of respondents reported limited knowledge of ECMO and desired specific ECMO education during training.

Human respiratory syncytial virus (HRSV) is a major cause of lower respiratory tract disease in children and the elderly for which there is still no effective vaccine. We have previously shown that PanAd3-RSV, which is a chimpanzee adenovirus-vectored vaccine candidate that expresses a secreted form of the HRSV F protein together with the N and M2-1 proteins of HRSV, is immunogenic in rodents and nonhuman primates, and protects mice and cotton rats from HRSV challenge. Because the extent to which protection demonstrated in rodent models will translate to humans is unclear, we have exploited the calf model of bovine RSV (BRSV) infection, which mimics HRSV disease in children more closely than do experimental models of unnatural laboratory hosts, to evaluate the safety and efficacy of the PanAd3-RSV vaccine. We show that PanAd3-RSV alone and in combination with a modified vaccinia Ankara expressing the same HRSV antigens (MVA-RSV) induced neutralizing antibodies and cellular immunity in young seronegative calves and protected against upper and lower respiratory tract infection and pulmonary disease induced by heterologous BRSV challenge. There was no evidence either of enhanced pulmonary pathology or of enhanced respiratory disease in vaccinated calves after BRSV challenge. These findings support the continued evaluation of the vectored RSV vaccines in man., (Copyright © 2015, American Association for the Advancement of Science.)

Bovine respiratory syncytial virus (BRSV) is an important cause of respiratory disease in young calves. The virus is genetically and antigenically closely related to human (H)RSV, which is a major cause of respiratory disease in young infants. As a natural pathogen of calves, BRSV infection recapitulates the pathogenesis of respiratory disease in man more faithfully than semi-permissive, animal models of HRSV infection. With the increasing availability of immunological reagents, the calf can be used to dissect the pathogenesis of and mechanisms of immunity to RSV infection, to analyse the ways in which the virus proteins interact with components of the innate response, and to evaluate RSV vaccine strategies. Passively transferred, neutralising bovine monoclonal antibodies, which recognise the same epitopes in the HRSV and BRSV fusion (F) protein, can protect calves against BRSV infection, and depletion of different T cells subsets in calves has highlighted the importance of CD8(+) T cells in viral clearance. Calves can be used to model maternal-antibody mediated suppression of RSV vaccine efficacy, and to increase understanding of the mechanisms responsible for RSV vaccine-enhanced respiratory disease., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Hepatopulmonary syndrome (HPS) is a rare complication of liver cirrhosis that may result in refractory hypoxemia even after liver transplantation. ECMO has been rarely used after liver transplantation or in patients with HPS., Methods: We present a patient with HPS who underwent liver transplantation and developed refractory hypoxemia requiring postoperative ECMO support at our institution. During our review of literature we found nine reports of ECMO use for cardiorespiratory failure after liver transplant in the past., Results: Our patient had persistent intrapulmonary shunting and developed severe respiratory failure after liver transplant. Additionally, the patient was found to have an atrial septal defect (ASD) and required percutaneous closure while receiving ECMO support. Literature review suggests that survival among these patients who were supported with ECMO after liver transplant was 50% and catastrophic bleeding complications were described in only one report., Conclusions: With careful selection of post-liver transplant patients and judicious management of anticoagulation, ECMO can be safely instituted in this cohort.

Adenovirus vaccine vectors generated from new viral serotypes are routinely screened in pre-clinical laboratory animal models to identify the most immunogenic and efficacious candidates for further evaluation in clinical human and veterinary settings. Here, we show that studies in a laboratory species do not necessarily predict the hierarchy of vector performance in other mammals. In mice, after intramuscular immunization, HAdV-5 (Human adenovirus C) based vectors elicited cellular and humoral adaptive responses of higher magnitudes compared to the chimpanzee adenovirus vectors ChAdOx1 and AdC68 from species Human adenovirus E. After HAdV-5 vaccination, transgene specific IFN-γ(+) CD8(+) T cell responses reached peak magnitude later than after ChAdOx1 and AdC68 vaccination, and exhibited a slower contraction to a memory phenotype. In cattle, cellular and humoral immune responses were at least equivalent, if not higher, in magnitude after ChAdOx1 vaccination compared to HAdV-5. Though we have not tested protective efficacy in a disease model, these findings have important implications for the selection of candidate vectors for further evaluation. We propose that vaccines based on ChAdOx1 or other Human adenovirus E serotypes could be at least as immunogenic as current licensed bovine vaccines based on HAdV-5., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Extracorporeal membrane oxygenation (ECMO) use during pregnancy and the postpartum period are thought to be associated with an increased risk for maternal or fetal bleeding complications. We present our recent institutional experience in managing pregnant and postpartum patients with ECMO. We also performed a literature review of modern use of ECMO in pregnant and postpartum patients utilizing Pubmed and Embase databases. ECMO was used for severe cardiopulmonary failure due to multiple conditions. Based on published reports, overall maternal and fetal survival on ECMO were 80% and 70%, respectively. Mild-to-moderate vaginal bleeding was reported in a few cases, with rare occurrences of catastrophic postpartum hemorrhage. There was no consensus on an optimal anticoagulation strategy in these patients, though most preferred to keep anticoagulation at lower therapeutic levels. We conclude that ECMO, in well-selected pregnant and postpartum patients, appears to be safe and associated with low risk of maternal and fetal complications.

We have identified a range of food phytochemicals that inhibit Janus Kinase 2 (JAK2) and Adenosine Monophosphate Kinase (AMPK). A mutated and dysregulated form of JAK2, a tyrosine kinase, is associated with several diseases including Crohn's disease. Using an in vitro, time-resolved fluorescence (TR-FRET) assay, we tested 49 different types of food extracts, plus 10 concentrated fractions of increasing hydrophobicity from each extract, to find foods containing JAK2 inhibitors. The food extracts tested included grains, meat, fish, shellfish, dairy products, herbs, mushrooms, hops, fruits and vegetables. Several fruits were potent inhibitors of JAK2: blackberry, boysenberry, feijoa, pomegranate, rosehip and strawberry, which all contain ellagitannins, known inhibitors of kinases. These fruits are in the Rosales and Myrtales plant orders. No other foods gave >1% of the maximal JAK2 inhibitory activities of these fruits. AMPK, a sensor and regulator of energy metabolism in cells, is a serine-threonine kinase which is reported to be activated by various flavonoid phytochemicals. Using a TR-FRET assay, we tested various fruit extracts for AMPK activation and inhibition. Ellagitannin containing foods scored highly as AMPK inhibitors. Despite several reports of AMPK activation in whole cells by phytochemicals, no extracts or pure compounds activated AMPK in our assay.

Purpose: Reports of the use of whole-exome sequencing in clinical practice are limited. We report our experience with whole-exome sequencing in 115 patients in a single center and evaluate its feasibility and clinical usefulness in clinical care., Methods: Whole-exome sequencing was utilized based on the judgment of three clinical geneticists. We describe age, gender, ethnicity, consanguinity, indication for testing, family history, insurance, laboratory results, clinician interpretation of results, and impact on patient care., Results: Most patients were children (78.9%). The most common indications for testing were birth defects (24.3%) and developmental delay (25.2%). We identified four new candidate human disease genes and possibly expanded the disease phenotypes associated with five different genes. Establishing a diagnosis led to discontinuation of additional planned testing in all patients, screening for additional manifestations in eight, altered management in fourteen, novel therapy in two, identification of other familial mutation carriers in five, and reproductive planning in six., Conclusion: Our results show that whole-exome sequencing is feasible, has clinical usefulness, and allows timely medical interventions, informed reproductive choices, and avoidance of additional testing. Our results also suggest phenotype expansion and identification of new candidate disease genes that would have been impossible to diagnose by other targeted testing methods.

Dysregulated neurodevelopment with altered structural and functional connectivity is believed to underlie many neuropsychiatric disorders, and 'a disease of synapses' is the major hypothesis for the biological basis of schizophrenia. Although this hypothesis has gained indirect support from human post-mortem brain analyses and genetic studies, little is known about the pathophysiology of synapses in patient neurons and how susceptibility genes for mental disorders could lead to synaptic deficits in humans. Genetics of most psychiatric disorders are extremely complex due to multiple susceptibility variants with low penetrance and variable phenotypes. Rare, multiply affected, large families in which a single genetic locus is probably responsible for conferring susceptibility have proven invaluable for the study of complex disorders. Here we generated induced pluripotent stem (iPS) cells from four members of a family in which a frameshift mutation of disrupted in schizophrenia 1 (DISC1) co-segregated with major psychiatric disorders and we further produced different isogenic iPS cell lines via gene editing. We showed that mutant DISC1 causes synaptic vesicle release deficits in iPS-cell-derived forebrain neurons. Mutant DISC1 depletes wild-type DISC1 protein and, furthermore, dysregulates expression of many genes related to synapses and psychiatric disorders in human forebrain neurons. Our study reveals that a psychiatric disorder relevant mutation causes synapse deficits and transcriptional dysregulation in human neurons and our findings provide new insight into the molecular and synaptic etiopathology of psychiatric disorders.

Rationale: Pulmonary venoocclusive disease (PVOD) is an uncommon cause of pulmonary arterial hypertension (PAH). However, unlike PAH, treatment options for PVOD are usually quite limited. The impact of the lung allocation score on access to transplantation for patients with PVOD and the clinical course of these patients have not been well-described., Objectives: To examine the association between the diagnosis of PVOD and lung transplantation for patients on the transplant waiting list., Methods: Patients with a diagnosis of PVOD and PAH registered on the United Network for Organ Sharing wait list for transplantation from May 4, 2005 to May 3, 2013 were included. Lung transplantation was the primary outcome measure. Multivariable analyses were performed to determine the odds of dying or receiving a lung transplant after listing. Survival was compared using Kaplan-Meier and competing risks methods., Results: Of 12,251 patients listed for lung transplantation, 49 with PVOD and 647 with PAH were identified. There were no significant differences in the lung allocation score between patients with PVOD and PAH at listing, transplant, or wait list removal for death/too sick for transplant. By 6 months, 22.6% of patients with PVOD had been removed from the wait list due to death, compared with 11.0% of patients with PAH (Chi-square P = 0.03). Patients with PVOD who died or were considered too sick for transplant were removed from the waiting list sooner after listing (22 vs. 105 d, P = 0.08). There was no difference in the proportion of patients with PVOD and PAH transplanted (50.0 vs. 47.6%, P = 0.60)., Conclusions: In the lung allocation score era, patients with PVOD may be at higher risk for death while on the transplant waiting list. After wait list registration, close monitoring for disease progression is advised.

Chronic obstructive pulmonary disease (COPD), one of the most common chronic diseases and a leading cause of death, has historically been considered a disease of men. However, there has been a rapid increase in the prevalence, morbidity, and mortality of COPD in women over the last two decades. This has largely been attributed to historical increases in tobacco consumption among women. But the influence of sex on COPD is complex and involves several other factors, including differential susceptibility to the effects of tobacco, anatomic, hormonal, and behavioral differences, and differential response to therapy. Interestingly, nonsmokers with COPD are more likely to be women. In addition, women with COPD are more likely to have a chronic bronchitis phenotype, suffer from less cardiovascular comorbidity, have more concomitant depression and osteoporosis, and have a better outcome with acute exacerbations. Women historically have had lower mortality with COPD, but this is changing as well. There are also differences in how men and women respond to different therapies. Despite the changing face of COPD, care providers continue to harbor a sex bias, leading to underdiagnosis and delayed diagnosis of COPD in women. In this review, we present the current knowledge on the influence of sex on COPD risk factors, epidemiology, diagnosis, comorbidities, treatment, and outcomes, and how this knowledge may be applied to improve clinical practices and advance research.

In humans and mice, γδ T cells represent <5% of the total circulating lymphocytes. In contrast, the γδ T cell compartment in ruminants accounts for 15-60% of the total circulating mononuclear lymphocytes. Despite the existence of CD4(+)CD25(high) Foxp3(+) T cells in the bovine system, these are neither anergic nor suppressive. We present evidence showing that bovine γδ T cells are the major regulatory T cell subset in peripheral blood. These γδ T cells spontaneously secrete IL-10 and proliferate in response to IL-10, TGF-β, and contact with APCs. IL-10-expressing γδ T cells inhibit Ag-specific and nonspecific proliferation of CD4(+) and CD8(+) T cells in vitro. APC subsets expressing IL-10 and TFG-β regulate proliferation of γδ T cells producing IL-10. We propose that γδ T cells are a major regulatory T cell population in the bovine system., (Copyright © 2014 The Authors.)

Bovine respiratory syncytial virus (BRSV) causes inflammation and obstruction of the small airways, leading to severe respiratory disease in young calves. The virus is closely related to human (H)RSV, a major cause of bronchiolitis and pneumonia in young children. The ability to manipulate the genome of RSV has provided opportunities for the development of stable, live attenuated RSV vaccines. The role of the SH protein in the pathogenesis of BRSV was evaluated in vitro and in vivo using a recombinant (r)BRSV in which the SH gene had been deleted. Infection of bovine epithelial cells and monocytes with rBRSVΔSH, in vitro, resulted in an increase in apoptosis, and higher levels of TNF-α and IL-1β compared with cells infected with parental, wild-type (WT) rBRSV. Although replication of rBRSVΔSH and WT rBRSV, in vitro, were similar, the replication of rBRSVΔSH was moderately reduced in the lower, but not the upper, respiratory tract of experimentally infected calves. Despite the greater ability of rBRSVΔSH to induce pro-inflammatory cytokines, in vitro, the pulmonary inflammatory response in rBRSVΔSH-infected calves was significantly reduced compared with that in calves inoculated with WT rBRSV, 6 days previously. Virus lacking SH appeared to be as immunogenic and effective in inducing resistance to virulent virus challenge, 6 months later, as the parental rBRSV. These findings suggest that rBRSVΔSH may be an ideal live attenuated virus vaccine candidate, combining safety with a high level of immunogenicity.

Academic health centers (AHCs) are at the forefront of delivering care to the diverse medically underserved and uninsured populations in the United States, as well as training the majority of the health care workforce, who are professionally obligated to serve all patients regardless of race or immigration status. Despite AHCs' central leadership role in these endeavors, few consolidated efforts have emerged to resolve potential conflicts between national, state, and local policies that exclude certain classifications of immigrants from receiving federal public assistance and health professionals' social missions and ethical oath to serve humanity. For instance, whereas the 2010 Patient Protection and Affordable Care Act provides a pathway to insurance coverage for more than 30 million Americans, undocumented immigrants and legally documented immigrants residing in the United States for less than five years are ineligible for Medicaid and excluded from purchasing any type of coverage through state exchanges. To inform this debate, the authors describe their experience at the University of New Mexico Hospital (UNMH) and discuss how the UNMH has responded to this challenge and overcome barriers. They offer three recommendations for aligning AHCs' social missions and professional ethics with organizational policies: (1) that AHCs determine eligibility for financial assistance based on residency rather than citizenship, (2) that models of medical education and health professions training provide students with service-learning opportunities and applied community experience, and (3) that frontline staff and health care professionals receive standardized training on eligibility policies to minimize discrimination towards immigrant patients.

Purpose: Inhibition of VEGF is widely used in patients to control neovascularization and decrease vascular permeability. To date, the effect of VEGF inhibition has not been evaluated in the developing retina such as that seen in premature infants. The goal of this study was to address the effect of anti-VEGF treatment on retinal development of a mouse model of retinopathy., Methods: C57BL/6J mice were evaluated using a model of oxygen-induced retinopathy. Test animals were treated at postnatal day (P) 14 with intravitreal injections of the VEGF inhibitor aflibercept (2.5 or 10 μg) in one eye. Control animals were treated with injection of PBS in one eye. The noninjected fellow eyes were used as internal controls. Areas of avascular retina and neovascular tufts in injected (treated) eyes and noninjected fellow eyes were determined at P17, and the difference related to these characteristics was obtained among them. To evaluate the effect of VEGF inhibition on neurogenesis, focal ERG was performed at P21 and P42. Histologic evaluation of the retinal structure was also evaluated at P42., Results: Aflibercept treatment reduced the amount of neovascular tufts but significantly increased the area of avascular retina (low dose and high dose) at P17. The delayed vascular growth corresponded to decreased ERG amplitudes (at P21 and P42) and structural changes in the retinal layers that persisted (at P42), despite vascular recovery., Conclusions: Inhibition of VEGF in developing eyes has the short-term effect of delayed vascular growth and the long-term effects of decreased function with persistent changes in the neuroretinal structures.

Major nonprimate-primate differences in cortico-genesis include the dimensions, precursor lineages, and developmental timing of the germinal zones (GZs). microRNAs (miRNAs) of laser-dissected GZ compartments and cortical plate (CP) from embryonic E80 macaque visual cortex were deep sequenced. The CP and the GZ including ventricular zone (VZ) and outer and inner subcompartments of the outer subventricular zone (OSVZ) in area 17 displayed unique miRNA profiles. miRNAs present in primate, but absent in rodent, contributed disproportionately to the differential expression between GZ subregions. Prominent among the validated targets of these miRNAs were cell-cycle and neurogenesis regulators. Coevolution between the emergent miRNAs and their targets suggested that novel miRNAs became integrated into ancient gene circuitry to exert additional control over proliferation. We conclude that multiple cell-cycle regulatory events contribute to the emergence of primate-specific cortical features, including the OSVZ, generated enlarged supragranular layers, largely responsible for the increased primate cortex computational abilities., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Chronic obstructive pulmonary disease (COPD) represents one of the main causes of morbidity and mortality worldwide. According to the World Health Organization, approximately 3 million people in the world die as a consequence of COPD every year. Tobacco use remains the main factor associated with development of disease in the industrialized world, but other risk factors are important and preventable causes of COPD, particularly in the developing world. The purpose of this review is to summarize the literature on the subject and to provide an update of the most recent advances in the field., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Guillain-Barré syndrome (GBS) has been described after solid organ and bone marrow transplantation mostly due to viral infections and possibly calcineurin inhibitors. Incidence after bone marrow transplant is 0.3-0.7%, though incidence in other transplants is not well known. We present the first description of tacrolimus associated GBS in lung transplant recipients in the English language literature. The pathophysiology of tacrolimus-induced polyneuropathy is not known, but some have hypothesized that tacrolimus induces an inflammatory phenomenon by differential effects on T cell subsets. Diagnosis of association may be challenging and requires high index of suspicion. The optimal treatment of GBS-associated with tacrolimus after lung transplantation is unknown, although drug discontinuation may result in improvement in some patients, while some reports suggest that the use of IVIG and/or plasmapheresis may be helpful and safe in organ transplant recipients with severe symptoms.

We tested the hypothesis that mutant tau proteins that cause neurodegeneration and dementia differentially alter kinesin translocation along microtubules (MTs) relative to normal tau in vitro. We employed complementary in vitro motility assays using purified recombinant kinesin, purified recombinant tau, and purified bovine brain α:β tubulin to isolate interactions among these components without any contribution by cellular regulatory mechanisms. We found that kinesin translocates slower along MTs assembled by any of three independent tau mutants (4-repeat P301L tau, 4-repeat ΔN296 tau, and 4-repeat R406W tau) relative to its translocation rate along MTs assembled by normal, 4-repeat wild type (WT) tau. Moreover, the R406W mutation exhibited isoform specific effects; while kinesin translocation along 4-repeat R406W tau assembled MTs is slower than along MTs assembled by 4-repeat WT tau, the R406W mutation had no effect in the 3-repeat tau context. These data provide strong support for the notion that aberrant modulation of kinesin translocation is a component of tau-mediated neuronal cell death and dementia. Finally, we showed that assembling MTs with taxol before coating them with mutant tau obscured effects of the mutant tau that were readily apparent using more physiologically relevant MTs assembled with tau alone, raising important issues regarding the use of taxol as an experimental reagent and novel insights into therapeutic mechanisms of taxol action.

The biogeochemical cycles of carbon (C), nitrogen (N) and phosphorus (P) are interlinked by primary production, respiration and decomposition in terrestrial ecosystems. It has been suggested that the C, N and P cycles could become uncoupled under rapid climate change because of the different degrees of control exerted on the supply of these elements by biological and geochemical processes. Climatic controls on biogeochemical cycles are particularly relevant in arid, semi-arid and dry sub-humid ecosystems (drylands) because their biological activity is mainly driven by water availability. The increase in aridity predicted for the twenty-first century in many drylands worldwide may therefore threaten the balance between these cycles, differentially affecting the availability of essential nutrients. Here we evaluate how aridity affects the balance between C, N and P in soils collected from 224 dryland sites from all continents except Antarctica. We find a negative effect of aridity on the concentration of soil organic C and total N, but a positive effect on the concentration of inorganic P. Aridity is negatively related to plant cover, which may favour the dominance of physical processes such as rock weathering, a major source of P to ecosystems, over biological processes that provide more C and N, such as litter decomposition. Our findings suggest that any predicted increase in aridity with climate change will probably reduce the concentrations of N and C in global drylands, but increase that of P. These changes would uncouple the C, N and P cycles in drylands and could negatively affect the provision of key services provided by these ecosystems.

Chronic obstructive lung disease (COPD) is one of the most prevalent health conditions, and a major cause of morbidity and mortality around the globe. Once thought of primarily as a disease of men, COPD is now known to be increasingly prevalent among women. Although increasing tobacco consumption among women during the past several decades might explain some of this increase, the relationship may be more complex, including factors such as differential susceptibility to tobacco, anatomic and hormonal differences, behavioral differences, and differences in response to available therapeutic modalities. Moreover, women with COPD may present differently, may have a different pattern of comorbidities, and may have a better survival after acute exacerbations. Care providers continue to have a gender bias that may affect both diagnosis and treatment. Future work should focus on factors that lead to gender differences in COPD as well as gender-specific treatment strategies., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Background: Most current classification schemes for COPD use lung function as the primary way of classifying disease severity and monitoring disease progression. This approach misses important components of the disease process., Methods: We evaluated existing data to develop a classification scheme for COPD using measures beyond lung function, including respiratory symptoms, exacerbation history, quality-of-life assessment, comorbidity, and BMI. We then applied this scheme to data from the Lung Health Study, calculating a score for study subjects in year 1 and year 5 of the study, along with the difference between year 1 and year 5., Results: We developed a four-point scale ranging from 1.00 (mild) to 4.00 (very severe). In year 1 of the study, the mean COPD score was 1.76; in year 5 it was 1.82. The mean difference from year 1 to year 5 was an increase (worsening) of 0.06 and a range from -1.0 to 1.6. The COPD score at year 1, year 5, and the difference between these scores were all predictive of mortality at follow-up. For example, the 14.0% of subjects whose score improved by at least 0.25 between year 1 and 5 had decreased mortality compared with those with stable scores (between -0.25 and 0.25; hazard ratio, 0.6; 95% CI, 0.4, 0.8)., Conclusions: A COPD severity score that includes components in addition to lung function and allows for both improvement and worsening of disease may provide additional guidance to COPD classification, management, and prognosis.

Over two dozen mutations in the gene encoding the microtubule associated protein tau cause a variety of neurodegenerative dementias known as tauopathies, including frontotemporal dementia (FTD), PSP, CBD and Pick's disease. The vast majority of these mutations map to the C-terminal region of tau possessing microtubule assembly and microtubule dynamics regulatory activities as well as the ability to promote pathological tau aggregation. Here, we describe a novel and non-conservative tau mutation (G55R) mapping to an alternatively spliced exon encoding part of the N-terminal region of the protein in a patient with the behavioral variant of FTD. Although less well understood than the C-terminal region of tau, the N-terminal region can influence both MT mediated effects as well as tau aggregation. The mutation changes an uncharged glycine to a basic arginine in the midst of a highly conserved and very acidic region. In vitro, 4-repeat G55R tau nucleates microtubule assembly more effectively than wild-type 4-repeat tau; surprisingly, this effect is tau isoform specific and is not observed in a 3-repeat G55R tau versus 3-repeat wild-type tau comparison. In contrast, the G55R mutation has no effect upon the abilities of tau to regulate MT growing and shortening dynamics or to aggregate. Additionally, the mutation has no effect upon kinesin translocation in a microtubule gliding assay. Together, (i) we have identified a novel tau mutation mapping to a mutation deficient region of the protein in a bvFTD patient, and (ii) the G55R mutation affects the ability of tau to nucleate microtubule assembly in vitro in a 4-repeat tau isoform specific manner. This altered capability could markedly affect in vivo microtubule function and neuronal cell biology. We consider G55R to be a candidate mutation for bvFTD since additional criteria required to establish causality are not yet available for assessment.

Objective: Cardiac neonatal lupus (cardiac-NL), initiated by surface binding of anti-Ro60 autoantibodies to apoptotic cardiocytes during development, activates the urokinase plasminogen activator/urokinase plasminogen activator receptor (uPA/uPAR) system. Subsequent accumulation of apoptotic cells and plasmin generation facilitates increased binding of anti-Ro60 by disrupting and cleaving circulating β2-glycoprotein I (β2GPI) thereby eliminating its protective effect. The association of soluble levels of components of the uPA/uPAR system with cardiac-NL was examined., Methods: Levels of the uPA/uPAR system were assessed by ELISA in cord blood and immunohistological evaluation of autopsies., Results: uPA, uPAR and plasminogen levels were each significantly higher in cord blood from cardiac-NL (n = 35) compared with non-cardiac-NL (n = 26) anti-Ro-exposed neonates: 3.3 ± 0.1 vs 1.9 ± 0.05 ng/ml (P < 0.0001), 6.6 ± 0.3 vs 2.1 ± 0.2 ng/ml (P < 0.0001) and 435 ± 34 vs 220 ± 19 ng/ml (P < 0.0001), respectively. In three twin pairs discordant for cardiac-NL, the twin with cardiac-NL had higher levels of uPA, uPAR and plasminogen than the unaffected twin (3.1 ± 0.1 vs 1.9 ± 0.05 ng/ml; P = 0.0086, 6.2 ± 1.4 vs 2.2 ± 0.7 ng/ml; P = 0.147 and 412 ± 61 vs 260 ± 27 ng/ml; P = 0.152, respectively). Immunohistological evaluation of three hearts from fetuses dying with cardiac-NL revealed macrophages and giant cells expressing uPA and plasminogen in the septal region., Conclusion: Increased soluble uPA, uPAR and plasminogen in cord blood and expression in affected tissue of fetuses with cardiac-NL supports the hypothesis that fetal cardiac injury is in part mediated by plasmin generation initiated by anti-Ro binding to the apoptotic cardiocyte.

Objective: To determine whether epigenetic changes occur during cyclophosphamide-induced chronic bladder inflammation in mice., Materials and Methods: Epigenetic changes play a role in the regulation of inflammatory genes in noncancer diseases such as asthma and chronic obstructive pulmonary disease. However, epigenetic (deoxyribonucleic acid [DNA] methylation) changes during chronic bladder inflammation have not been previously described. Chronic cystitis was induced in 3 groups of adult CD-1 male mice using multiple weight-based intraperitoneal cyclophosphamide injections during a 3-month period. Histopathologic and MethyLight assays were performed on specimens with chronic bladder inflammation at multiple points to monitor cystitis progression and DNA methylation changes compared with the control specimens., Results: Histopathologic analysis showed the most extensive edema and urothelial sloughing at the 1-month point. MethyLight analyses revealed statistically significant changes in DNA methylation associated with the Calca, Timp3, Mmp2, and Igf2r genes in the chronic bladder injury model. The changes in DNA methylation associated with chronic cystitis were DNA hypomethylation of the Calca gene in the control tissue and DNA hypermethylation for the Calca, Timp3, Mmp2, and Igf2r genes compared with that in the control tissue., Conclusion: DNA methylation changes were noted in the Calca, Timp3, Mmp2, and Igf2r genes during chronic cystitis in a murine model. Epigenetic changes appear to play a role in the regulation of inflammatory bladder genes during chronic cystitis; however, additional studies are needed to elucidate the pathways associated with these genes., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Surveys are being used increasingly in health-care research to answer questions that may be difficult to answer using other methods. While surveys depend on data that may be influenced by self-report bias, they can be powerful tools as physicians seek to enhance the quality of care delivered or the health care systems they work in. The purpose of this article is to provide readers with a basic framework for understanding survey research, with a goal of creating well-informed consumers. The importance of validation, including pretesting surveys before launch, will be discussed. Highlights from published surveys are offered as supplementary material.

Objective: Acute clinical deterioration preceding death is a common observation in patients with advanced interstitial lung disease and secondary pulmonary hypertension. Patients with pulmonary arterial hypertension refractory to medical therapy are also at risk of sudden cardiac death (cor pulmonale). The treatment of these patients remains complex, and the findings from retrospective studies have suggested that intubation and mechanical ventilation are inappropriate given the universally poor outcomes. Extracorporeal support technologies have received limited attention because of the presumed inability to either recover cardiopulmonary function in the patient with end-stage disease or the presumed inability to proceed to definitive therapy with transplantation., Methods: A retrospective review was performed of 31 patients from 2 institutions placed on extracorporeal membrane oxygenation as a bridge to lung transplantation compared with similar patients without extracorporeal membrane oxygenation at the same institutions and comparison groups queried from the United Network for Organ Sharing database., Results: We have transplanted 31 patients with refractory lung disease from mechanical artificial lung support. Of the 31 patients, 19 were ambulatory at transplantation. Pulmonary fibrosis (42%), cystic fibrosis (20%), and pulmonary hypertension (16%) were the most common diagnostic codes and acute cor pulmonale (48%) and hypoxia (39%) were the most common indications for device deployment. The average duration of extracorporeal membrane oxygenation support was 13.7 days (range, 2-53 days), and the mean survival of all patients bridged to pulmonary transplantation was 26 months (range, 54 days to 95 months). The 1-, 3-, and 5-year survival was 93%, 80%, and 66%, respectively. The duration of in-house postoperative transplant care ranged from 12 to 86 days (mean, 31 days). Patients requiring an extracorporeal membrane oxygenation bridge had comparable survival to that of the high acuity patients transplanted without extracorporeal membrane oxygenation support in the Scientific Registry of Transplant Recipients database but were at a survival disadvantage compared with the high-acuity patients (lung allocation score, >50) transplanted at the same center who did not require mechanical support (P < .001)., Conclusions: These observations challenge current assumptions about the treatment of selected patients with end-stage lung disease and suggest that "salvage transplant" is both technically feasible and logistically viable. Widespread adoption of artificial lung technology in lung transplant will require the design of clinical trials that establish the most effective circumstances in which to use these technologies. A discussion of a clinical trial and reconsideration of current allocation policy is warranted., (Copyright © 2013 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Objective: High variability has been observed in type 1 diabetes mellitus (DM1) incidence rates (IRs) in childhood. The aim of this study was to characterize DM1 in Aragón and to identify variations in the geographical pattern by gender., Methods: A descriptive and ecological study was conducted to determine geographical variations in the DM1 incidence for the period 1991-2009. The source of information was the registry of DM1. To determine data completeness, a capture-recapture analysis was performed. Cases were georeferenced according to the Basic Healthcare Area (BHA) of residence. IRs for both genders, age group, 5 yr of diagnosis, and 95% confidence intervals (95% CIs) were calculated. Geographical pattern was studied applying Bayesian statistical model. The standardized incidence ratios (SIRs), smoothed SIR, and the posteriori risk probability (PRP) were represented cartographically for BHA stratified by gender., Results: The completeness was 93.5%. The global IR was 19.2 cases/10(5) person-years (95% CI: 17.6-20.8), boys 21.4 (95% CI: 19.0-23.8) and girls 16.8 (95% CI: 14.7-19.1). The age-specific rates were significantly lower in the 0-4 year age group with respect to the groups of 5-9 and 10-14 years. For boys, areas with a statistically significant excess of risk were found in the north [smoothed SIR: 118-167.9 and PRP of what the smoothed SIR would be greater than 100 (PRP) above 0.8] and below average risk in the south (smoothed SIR: 65.9-79.1 and PRP less than 0.2)., Conclusions: DM1 IR presented a north-south geographical pattern in boys. This pattern was not observed in girls or when both genders were considered together. Later studies should include gender as an essential variable., (© 2012 John Wiley & Sons A/S.)

The use of ventricular assist devices in patients with complex congenital heart disease has not been well described. We present a case of successful ventricular assist device support in a 38-year-old man with congenitally corrected transposition of the great arteries and severe secondary pulmonary hypertension., (Copyright © 2013 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Leri-Weill syndrome (LWS) is a genetic disorder caused by deletions or mutations in the SHOX gene or by deletions downstream of the gene and is classically characterized by short stature, mesomelic shortening of forearms and legs, and Madelung deformity. Correct identification of short stature homeobox-containing gene (SHOX) deficiency in children with growth problems is vital for appropriate initiation of growth hormone therapy., Method: We report a phenotypically normal 23 day old male infant born to a father diagnosed with Leri-Weill syndrome at age 12 years with a documented SHOX deletion on his X chromosome. The patient's fetal long bones had been found to be about three weeks delayed in growth on prenatal ultrasound during the second trimester., Results: The infant underwent genetic evaluation at 23 days of life and was found to have a SHOX deletion on Yp11.32 identified using single nucleotide polymorphism microarray (SNP) analysis and confirmed by FISH using a SHOX gene probe., Conclusion: We report the case of a male infant diagnosed with Leri-Weill syndrome with an unusual documented inheritance between father and son due to crossover between X and Y chromosomes during paternal meiosis. Our case is the youngest patient in literature documented by FISH analysis to have an X to Y chromosome transfer and the first of these patients diagnosed prior to onset of short stature or Madelung deformity. Our patient was identified prior to growth failure and can now be monitored for growth abnormalities with the ability to implement growth augmentation therapy without delay. Our case highlights the importance of advising affected SHOX patients of risks to future offspring and supports screening off-spring of parents carrying SHOX abnormalities regardless of sex.

Ghrelin is a growth hormone (GH) secretagogue (GHS) and GHRP-6 is a synthetic peptide analogue; both act through the GHS receptor. GH secretion depends directly on the intracellular concentration of Ca(2+); this is determined from the intracellular reserves and by the entrance of Ca(2+) through the voltage-dependent calcium channels, which are activated by the membrane depolarization. Membrane potential is mainly determined by K(+) channels. In the present work, we investigated the effect of ghrelin (10 nM) or GHRP-6 (100 nM) for 96 h on functional expression of voltage-dependent K(+) channels in rat somatotropes: GC cell line. Physiological patch-clamp whole-cell recording was used to register the K(+) currents. With Cd(2+) (1 mM) and tetrodotoxin (1  μ m) in the bath solution recording, three types of currents were characterized on the basis of their biophysical and pharmacological properties. GC cells showed a K(+) current with a transitory component (I A) sensitive to 4-aminopyridine, which represents ~40% of the total outgoing current; a sustained component named delayed rectifier (I K), sensitive to tetraethylammonium; and a third type of K(+) current was recorded at potentials more negative than -80 mV, permitting the entrance of K(+) named inward rectifier (KIR). Chronic treatment with ghrelin or GHRP-6 did not modify the functional expression of K(+) channels, without significant changes (P < 0.05) in the amplitudes of the three currents observed; in addition, there were no modifications in their biophysical properties and kinetic activation or inactivation.

Background: Lung transplantation is an evolving specialty with the number of transplants growing annually., Purpose: A structured lung transplant curriculum was developed for Pulmonary/Critical Care (Pulm/CC) fellows., Methods: Scores on pulmonary in-training examinations (ITE) 2 years prior to and 3 years after implementation were reviewed as well as completion of satisfaction surveys., Results: The mean pulmonary ITE score of 1st-year fellows increased from 54.2 ± 2.5 to 63.6 ± 1.2 (M ± SD), p = .002, whereas mean pulmonary ITE score for 2nd-year fellows increased from 63.0 ± 3.0 to 70.7 ± 1.2, p = .019. The combined mean pulmonary ITE score increased from 58.6 ± 2.3 to 67.1 ± 1.2, p = .001. Satisfaction surveys revealed that fellow perception of the curriculum was that the experience contributed to an overall improvement in their knowledge base and clinical skills while opportunity to perform transbronchial biopsies was available., Conclusions: A structured educational lung transplant curriculum was associated with improved performance on the pulmonary ITE and was perceived by fellows to be beneficial in their education and training while providing opportunities for fellows to perform transbronchial biopsies.

The use of extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplantation was reported for the first time more than three decades ago; nevertheless, its use in lung transplantation was largely abandoned because of poor patient survival and frequent complications. The outcomes of patients bridged to lung transplantation using ECMO have substantially improved in the last 5 years. Recent advances in extracorporeal life support technology now allow patients with end-stage lung disease to be successfully supported for prolonged periods of time, preventing the use of mechanical ventilation and facilitating physical rehabilitation and ambulation while the patients awaits lung transplantation. This review briefly describes the evolution of ECMO use in lung transplantation and summarizes the available technology and current approaches to provide ECMO support.

Chronic obstructive pulmonary disease represents a major cause of morbidity and mortality in industrialized and nonindustrialized countries. Although tobacco use remains the main factor associated with development of the disease, occupational risk factors represent an important and preventable cause. The most common occupationally related factors include exposure to organic dusts, metallic fumes, and a variety of other mineral gases and/or vapors. This article summarizes the literature on the subject and provides an update of the most recent advances in the field., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: To evaluate whether increasing body mass index (BMI) alters the efficacy of ultrasound-directed cerclage in women with a history of preterm birth., Methods: This was a planned secondary analysis of a multicenter trial in which women with a singleton gestation and prior spontaneous preterm birth (17 to 33 + 6 weeks' gestation) were screened for a short cervix by serial transvaginal ultrasound evaluations between 16 and 22 + 6 weeks. Women with a short cervix (cervical length < 25 mm) were randomly assigned to cerclage or not. Linear and logistic regression were used to assess the relationship between BMI and continuous and categorical variables, respectively., Results: Overall, in the screened women (n = 986), BMI was not associated with cervical length (P = 0.68), gestational age at delivery (P = 0.12) or birth at < 35 weeks (P = 0.68). For the cerclage group (n = 148), BMI had no significant effect. For the no-cerclage group (n = 153), BMI was associated with a decrease in gestational age at delivery, with an estimated slope of - 0.14 weeks per kg/m(2) (P = 0.03; including adjustment for cervical length). This result was driven primarily by several women with BMI > 47 kg/m(2) ., Conclusion: In women at high risk for recurrent preterm birth, BMI was not associated with cervical length or gestational age at birth. BMI did not appear to adversely affect ultrasound-indicated cerclage., (Copyright © 2012 ISUOG. Published by John Wiley & Sons, Ltd.)

Objectives/hypothesis: Orofacial clefts are the most common craniofacial birth defects in humans, with the majority of orofacial clefts occurring as nonsyndromic cleft lip with or without cleft palate (NSCLP). We previously demonstrated associations between single-nucleotide polymorphisms (SNPs) in the IRF6 gene and NSCLP in the Honduran population. Here we investigated other candidate genes and chromosomal regions associated with NSCLP identified from genome-wide association studies (GWAS), including MAFB, ABCA4, 8q24, 9q22, 10q25, and 17q22 in two independent Hispanic populations., Study Design: Case-control and family-based association testing., Methods: Honduran families with two or more members with NSCLP (multiplex) were identified. DNA was collected from affected and unaffected family members (488) and 99 gender-matched controls. NSCLP Colombian families were identified; DNA was collected from 26 proband-parent trios. All participants were genotyped for 17 SNPs in six chromosomal regions. Case-control association and family-based association testing (FBAT) analyses were conducted., Results: Seven SNPs demonstrated association in at least one model in the Honduran population. In the Colombian families, five SNPs demonstrated significance in FBAT when patients with isolated cleft palate (CP) were included; four overlapped with SNPs demonstrating significance in the Honduran population, two with the same allele. One SNP retained significance with CP excluded., Conclusions: This study supports the previous GWAS findings and is the first to suggest a role for FOXE1, ABCA4, and MAFB in orofacial clefting in two separate Hispanic populations., (Copyright © 2012 The American Laryngological, Rhinological, and Otological Society, Inc.)

The use of atrial septostomy for refractory pulmonary hypertension and right ventricular failure results in an adequate left ventricular preload and improved cardiac output at the expense of a profound hypoxic shunt. Combined dual-lumen venovenous extracorporeal membrane oxygenation and atrial septostomy provides extracorporeal gas exchange of venous return before the directional right atrial to left atrial shunt, can be deployed percutaneously, and results in an ambulatory patient with stable hemodynamics., (Copyright © 2012 Elsevier Inc. All rights reserved.)