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1.  Effect of progressive horizontal resistive force on the comfortable walking speed of individuals post-stroke 
Individuals post-stroke select slow comfortable walking speeds (CWS) and the major factors used to select their CWS is unknown.
To determine the extent to which slow CWS post-stroke is achieved through matching a relative force output or targeting a particular walking speed.
Ten neurologically nonimpaired individuals and fourteen chronic stroke survivors with hemiplegia were recruited. Participants were instructed to “walk at the speed that feels most comfortable” on a treadmill against 12 progressively increasing horizontal resistive force levels applied at the pelvis using a robotic system that allowed participant to self-select their walking speed. We compared slope coefficients of the simple linear regressions between the observed normalized force vs. normalized speed relationship in each group to a slope of -1.0 (i.e. ideal slope for a constant relative force output) and 0.0 (i.e. ideal slope for a constant relative speed). We also compared slope coefficients between groups.
The slope coefficients were significantly greater than -1.0 (p < 0.001 for both) and significantly less than 0 (p < 0.001 for both). However, compared with nonimpaired individuals, people post-stroke were less able to maintain their walking speed (p = 0.003).
The results of this study provide evidence for a complex interaction between the regulation of relative force output and intention to move at a particular speed in the selection of the CWS for individuals post-stroke. This would suggest that therapeutic interventions should not only focus on task specific lower-limb strengthening exercises (e.g. walking against resistance), but should also focus on increasing the range of speeds at which people can safely walk.
PMCID: PMC4329221
Locomotion; Post-stroke; Force generation; Comfortable walking speed
2.  Disentangling the relative effects of bushmeat availability on human nutrition in central Africa 
Scientific Reports  2015;5:8168.
We studied links between human malnutrition and wild meat availability within the Rainforest Biotic Zone in central Africa. We distinguished two distinct hunted mammalian diversity distributions, one in the rainforest areas (Deep Rainforest Diversity, DRD) containing taxa of lower hunting sustainability, the other in the northern rainforest-savanna mosaic, with species of greater hunting potential (Marginal Rainforest Diversity, MRD). Wild meat availability, assessed by standing crop mammalian biomass, was greater in MRD than in DRD areas. Predicted bushmeat extraction was also higher in MRD areas. Despite this, stunting of children, a measure of human malnutrition, was greater in MRD areas. Structural equation modeling identified that, in MRD areas, mammal diversity fell away from urban areas, but proximity to these positively influenced higher stunting incidence. In DRD areas, remoteness and distance from dense human settlements and infrastructures explained lower stunting levels. Moreover, stunting was higher away from protected areas. Our results suggest that in MRD areas, forest wildlife rational use for better human nutrition is possible. By contrast, the relatively low human populations in DRD areas currently offer abundant opportunities for the continued protection of more vulnerable mammals and allow dietary needs of local populations to be met.
PMCID: PMC4313087  PMID: 25639588
3.  Cholinergic Afferent Stimulation Induces Axonal Function Plasticity in Adult Hippocampal Granule Cells 
Neuron  2015;85(2):346-363.
Acetylcholine critically influences hippocampal-dependent learning. Cholinergic fibers innervate hippocampal neuron axons, dendrites, and somata. The effects of acetylcholine on axonal information processing, though, remain unknown. By stimulating cholinergic fibers and making electrophysiological recordings from hippocampal dentate gyrus granule cells, we show that synaptically released acetylcholine preferentially lowered the action potential threshold, enhancing intrinsic excitability and synaptic potential-spike coupling. These effects persisted for at least 30 min after the stimulation paradigm and were due to muscarinic receptor activation. This caused sustained elevation of axonal intracellular Ca2+ via T-type Ca2+ channels, as indicated by two-photon imaging. The enhanced Ca2+ levels inhibited an axonal KV7/M current, decreasing the spike threshold. In support, immunohistochemistry revealed muscarinic M1 receptor, CaV3.2, and KV7.2/7.3 subunit localization in granule cell axons. Since alterations in axonal signaling affect neuronal firing patterns and neurotransmitter release, this is an unreported cellular mechanism by which acetylcholine might, at least partly, enhance cognitive processing.
•Cholinergic fiber stimulation caused a persistent reduction in the spike threshold•Post-synaptic muscarinic receptor activation enhanced axonal CaV3.2 channel activity•The sustained Ca2+ entry inhibited axonal KV7 channels, lowering the spike threshold•The lower spike threshold increased the propensity for action potential generation
Acetylcholine is thought to influence cognitive processing by affecting somato-dendritic excitability and neurotransmitter release. Here, Martinello et al. show that endogenous acetylcholine acts on axonal muscarinic receptors to significantly influence action potential initiation and information processing in hippocampal granule cells.
PMCID: PMC4306544  PMID: 25578363
4.  Multiple failed intubation attempts are associated with decreased success rates on the first rescue intubation in the emergency department: a retrospective analysis of multicentre observational data 
Although the international guidelines emphasize early and systematic use of rescue intubation techniques, there is little evidence to support this notion. We aimed to test the hypothesis that preceding multiple failed intubation attempts are associated with a decreased success rate on the first rescue intubation in emergency departments (EDs).
We analysed data from two multicentre prospective registries designed to characterize current ED airway management in Japan between April 2010 and June 2013. All patients who underwent a rescue intubation after a failed attempt or a series of failed attempts were included for the analysis. Multiple failed intubation attempts were defined as ≥2 consecutive failed intubation attempts before a rescue intubation. Primary outcome measure was success rate on the first rescue intubation attempt.
Of 6,273 consecutive patients, 1,151 underwent a rescue intubation. The success rate on the first rescue intubation attempt declined as the number of preceding failed intubation attempts increased (81% [95% CI, 79%-84%] after one failed attempt; 71% [95% CI, 66%-76%] after two failed attempts; 67% [95% CI, 55%-78%] after three or more failed attempts; Ptrend <0.001). In the multivariable analysis adjusting for age, sex, principal indication, change in methods, devices, and intubator specialty, and clustering of patients within EDs, success rate on the first rescue intubation after two failed attempts was significantly lower (OR, 0.56; 95% CI, 0.41-0.77) compared to that after one failed attempt. Similarly, success rate on the first rescue intubation attempt after three or more failed attempts was significantly lower (OR, 0.49; 95% CI, 0.25-0.94) compared to that after one failed attempt.
Preceding multiple failed intubation attempts was independently associated with a decreased success rate on the first rescue intubation in the ED.
PMCID: PMC4307194
Intubation; Failed intubation; Rescue intubation; Success rate; Emergency department
5.  MiR-494 Within an Oncogenic MicroRNA Megacluster Regulates G1/S Transition in Liver Tumorigenesis Through Suppression of MCC 
Hepatology (Baltimore, Md.)  2013;59(1):10.1002/hep.26662.
Hepatocellular carcinoma (HCC) is associated with poor survival for patients and few effective treatment options, raising the need for novel therapeutic strategies. MicroRNAs (miRNAs) play important roles in tumor development and show deregulated patterns of expression in HCC. Because of the liver’s unique affinity for small nucleic acids, miRNA based therapy has been proposed in the treatment of liver disease. There is thus an urgent need to identify and characterize aberrantly expressed miRNAs in HCC. In our study, we profiled miRNA expression changes in de novo liver tumors driven by MYC and/or RAS, two canonical oncogenes activated in a majority of human HCC. We identified an upregulated miRNA megacluster comprised of 53 miRNAs on mouse chromosome 12qF1 (human homolog 14q32). This miRNA megacluster is upregulated in all three transgenic liver models and in a subset of human HCCs. An unbiased functional analysis of all miRNAs within this cluster was performed.
We found that miR-494 is overexpressed in human HCC, and aids in transformation by regulating the G1/S cell cycle transition through targeting of the Mutated in Colorectal Cancer (MCC) tumor suppressor. miR-494 inhibition in human HCC cell lines decreases cellular transformation and anti-miR-494 treatment of primary MYC-driven liver tumor formation significantly diminishes tumor size. Our findings identify a new therapeutic target, miR-494, for the treatment of HCC.
PMCID: PMC3877416  PMID: 23913442
HCC; cancer; cell cycle; Dlk1-Dio3; miRNA therapy
6.  The Impact of Financial Barriers on Access to Care, Quality of Care and Vascular Morbidity Among Patients with Diabetes and Coronary Heart Disease 
The prevalence and consequences of financial barriers to health care among patients with multiple chronic diseases are poorly understood.
We sought to assess the prevalence of self-reported financial barriers to health care among individuals with diabetes and coronary heart disease (CHD) and to determine their association with access to care, quality of care and clinical outcomes.
The 2007 Centers for Disease Control Behavioral Risk Factor Surveillance Survey.
Diabetic patients with CHD.
Financial barriers to health care were defined by a self-reported time in the past 12 months when the respondent needed to see a doctor but could not because of cost. The primary clinical outcome was vascular morbidity—a composite of stroke, retinopathy, nonhealing foot sores or bilateral foot amputations.
Among the 11,274 diabetics with CHD, 1,541 (13.7 %) reported financial barriers to health care. Compared to individuals without financial barriers, those with financial barriers had significantly reduced rates of medical assessments within the past 2 years, hemoglobin (Hgb) A1C measurements in the past year, cholesterol measurements at any time, eye and foot examinations within the past year, diabetic education, antihypertensive treatment, aspirin use and a higher prevalence of vascular morbidity. In multivariable analyses, financial barriers to health care were independently associated with reduced odds of medical checkups (Odds Ratio [OR], 0.61; 95 % Confidence Intervals [CI], 0.55–0.67), Hgb A1C measurement (OR, 0.85; 95 % CI, 0.77–0.94), cholesterol measurement (OR, 0.76; 95 % CI, 0.67–0.86), eye (OR, 0.85; 95 % CI, 0.79–0.92) and foot (OR, 0.92; 95 % CI, 0.84–1.00) examinations, diabetic education (OR, 0.93; 95 % CI, 0.87–0.99), aspirin use (OR, 0.88; 95 % CI, 0.81–0.96) and increased odds of vascular morbidity (OR, 1.23; 95 % CI, 1.14–1.33).
In diabetic adults with CHD, financial barriers to health care were associated with impaired access to medical care, inferior quality of care and greater vascular morbidity. Eliminating financial barriers and adherence to guideline-based recommendations may improve the health of individuals with multiple chronic diseases.
PMCID: PMC3889957  PMID: 24078406
7.  Temporal Trends in Emergency Department Visits for Bronchiolitis in the United States, 2006-2010 
To examine temporal trends in emergency departments (ED) visits for bronchiolitis among US children between 2006 and 2010.
Serial, cross-sectional analysis of the Nationwide Emergency Department Sample, a nationally-representative sample of ED patients. We used ICD-9-CM code 466.1 to identify children <2 years of age with bronchiolitis. Primary outcome measures were rate of bronchiolitis ED visits, hospital admission rate, and ED charges.
Between 2006 and 2010, weighted national discharge data included 1,435,110 ED visits with bronchiolitis. There was a modest increase in the rate of bronchiolitis ED visits, from 35.6 to 36.3 per 1000 person-years (2% increase; Ptrend=0.008), due to increases in the ED visit rate among children from 12 months to 23 months (24% increase; Ptrend<0.001). By contrast, there was a significant decline in the ED visit rate among infants (4% decrease; Ptrend<0.001) Although unadjusted admission rate did not change between 2006 and 2010 (26% in both years), admission rate declined significantly after adjusting for potential patient- and ED-level confounders (adjusted OR for comparison of 2010 with 2006, 0.84; 95%CI, 0.76-0.93; P<0.001). Nationwide ED charges for bronchiolitis increased from $337 million to $389 million (16% increase; Ptrend<0.001), adjusted for inflation. This increase was driven by a rise in geometric mean of ED charges per case from $887 to $1059 (19% increase; Ptrend<0.001).
Between 2006 and 2010, we found a divergent temporal trend in the rate of bronchiolitis ED visits by age group. Despite a significant increase in associated ED charges, ED-associated hospital admission rates for bronchiolitis significantly decreased over this same period.
PMCID: PMC3984903  PMID: 23934206
bronchiolitis; emergency department; incidence; hospitalization; charge
8.  Reduction of early reperfusion injury with the mitochondria-targeting peptide Bendavia 
We recently showed that Bendavia, a novel mitochondria-targeting peptide, reduced infarction and no-reflow across several experimental models. The purpose of this study was to determine the therapeutic timing and mechanism of action that underlie Bendavia’s cytoprotective property. In rabbits exposed to in vivo ischemia/reperfusion (30/180 min), Bendavia administered 20 min prior to reperfusion (0.05mg/kg/hr, i.v.) reduced myocardial infarct size by ~50% when administered for either 1 or 3 hours of reperfusion. However, when Bendavia perfusion began just 10 min after the onset of reperfusion, the protection against infarction and no–reflow was completely lost, indicating that the mechanism of protection is occurring early in reperfusion. Experiments in isolated mouse liver mitochondria found no discernible effect of Bendavia on blocking the permeability transition pore, and studies in isolated heart mitochondria showed no effect of Bendavia on respiratory rates. As Bendavia significantly lowered reactive oxygen species (ROS) levels in isolated heart mitochondria, the ROS-scavenging capacity of Bendavia was compared to well-known ROS scavengers using in vitro (cell-free) systems that enzymatically generate ROS. Across doses ranging from 1nM to 1mM, Bendavia showed no discernible ROS-scavenging properties, clearly differentiating itself from prototypical scavengers. In conclusion, Bendavia is a promising candidate to reduce cardiac injury when present at onset of reperfusion, but not after reperfusion has already commenced. Given that both infarction and no-reflow are related to increased cellular ROS, Bendavia’s protective mechanism of action likely involves reduced ROS generation (as opposed to augmented scavenging) by endothelial and myocyte mitochondria.
PMCID: PMC4103197  PMID: 24288396
mitochondria; reactive oxygen species; reperfusion; heart; peptide
10.  Mucosally-directed adrenergic nerves and sympathomimetic drugs enhance non-intimate adherence of Escherichia coli O157:H7 to porcine cecum and colon 
European journal of pharmacology  2006;539(0):116-124.
The sympathetic neurotransmitter norepinephrine has been found to increase mucosal adherence of enterohemorrhagic Escherichia coli O157:H7 in explants of murine cecum and porcine distal colon. In the present study, we tested the hypothesis that norepinephrine augments the initial, loose adherence of this important pathogen to the intestinal mucosa. In mucosal sheets of porcine cecum or proximal, spiral and distal colon mounted in Ussing chambers, norepinephrine (10 µM, contraluminal addition) increased mucosal adherence of wild-type E. coli O157:H7 strain 85–170; in the cecal mucosa, this effect occurred within 15 – 90 min after bacterial inoculation. In addition, norepinephrine transiently increased short-circuit current in cecal and colonic mucosal sheets, a measure of active anion transport. Norepinephrine was effective in promoting cecal adherence of a non-O157 E. coli strain as well as E. coli O157:H7 eae or espA mutant strains that are incapable of intimate mucosal attachment. Nerve fibers immunoreactive for the norepinephrine synthetic enzyme dopamine β-hydroxylase appeared in close proximity to the cecal epithelium, and the norepinephrine reuptake blocker cocaine, like norepinephrine and the selective α2-adrenoceptor agonist UK-14,304, increased E. coli O157:H7 adherence. These results suggest that norepinephrine, acting upon the large bowel mucosa, modulates early, non-intimate adherence of E. coli O157:H7 and probably other mucosa-associated bacteria. Sympathetic nerves innervating the cecocolonic mucosa may link acute stress exposure or psychostimulant abuse with an increased microbial colonization of the intestinal surface. This in turn may alter host susceptibility to enteric infections.
PMCID: PMC4277206  PMID: 16687138
Intimin; Type III secretion system; Mucosa-adherent bacteria; Norepinephrine; Cocaine; Enteric nervous system
11.  Mediation of neurogenic ion transport by acetylcholine, prostanoids and 5-hydroxytryptamine in porcine ileum 
European journal of pharmacology  2005;519(3):285-289.
Enteric neural activity modulates active transepithelial ion transport in the intestine. We investigated the neural circuits mediating neurogenic secretion in mucosal explants from porcine ileum. Transmural electrical stimulation increased short-circuit current, a measure of active ion transport, by 35 ± 2 µA/cm2. The neuronal Na+ channel blocker saxitoxin, the muscarinic cholinergic receptor antagonist atropine, the 5-hydroxytryptamine3 receptor antagonist tropisetron, and the cyclooxygenase inhibitor indomethacin inhibited this response. In addition, tropisetron inhibited the atropine-resistant portion of the response, and both atropine and indomethacin attenuated the saxitoxin-resistant component. Neurogenic secretion in porcine ileum appears to be mediated by tryptaminergic and prostanoid-sensitive cholinergic pathways.
PMCID: PMC4277208  PMID: 16135363
Transmural electrical stimulation; Short-circuit current; 5-hydroxytryptamine 3 receptor; Muscarinic cholinergic receptor; Intestinal mucosa
12.  Unplanned reinterventions are associated with postoperative mortality in neonates with critical congenital heart disease 
Neonates with critical congenital heart disease remain at risk of adverse outcomes after cardiac surgery. Residual or undiagnosed anatomic lesions might be contributory. The present study aimed to describe the incidence and type of cardiac lesions that lead to early, unplanned cardiac reintervention, identify the risk factors for unplanned reintervention, and explore the associations between unplanned reinterventions and hospital mortality.
The present single-center retrospective cohort study included 943 consecutive neonates with critical congenital heart disease who underwent cardiac surgery from 2002 to 2008. An unplanned cardiac reintervention was defined as a cardiac reoperation or interventional cardiac catheterization performed during the same hospitalization as the initial operation. Multivariate logistic regression analyses were used to identify the risk factors for unplanned cardiac reintervention and hospital mortality.
Of the 943 neonates, 104 (11%) underwent an unplanned cardiac reintervention. The independent predictors of unplanned reintervention included prenatal diagnosis, lower birth weight, need for mechanical ventilation before the initial cardiac operation, lower attending surgeon experience, and greater Risk Adjustment in Congenital Heart Surgery, version 1, category. Those who underwent reintervention had increased hospital mortality (n = 33/104, 32%) relative to those who did not (n = 31/839, 4%; adjusted odds ratio, 8.6; 95% confidence interval, 4.7 to 15.6; P < .001). The mortality rates among patients undergoing surgical reintervention (23/66, 35%) or transcatheter reintervention (4/16, 25%), or both (6/22, 27%) were similar (P = .66).
The need for unplanned cardiac reintervention in neonates with critical congenital heart disease is strongly associated with increased mortality. Early unplanned reinterventions might be an important covariate in outcomes studies and useful as a quality improvement measure.
PMCID: PMC4256957  PMID: 22578897
13.  Expression of the Myosin Heavy Chain IIB Gene in Porcine Skeletal Muscle: The Role of the CArG-Box Promoter Response Element 
PLoS ONE  2014;9(12):e114365.
Due to its similarity to humans, the pig is increasingly being considered as a good animal model for studying a range of human diseases. Despite their physiological similarities, differential expression of the myosin heavy chain (MyHC) IIB gene (MYH4) exists in the skeletal muscles of these species, which is associated with a different muscle phenotype. The expression of different MyHC isoforms is a critical determinant of the contractile and metabolic characteristics of the muscle fibre. We aimed to elucidate whether a genomic mechanism was responsible for the drastically different expression of MYH4 between pigs and humans, thus improving our understanding of the pig as a model for human skeletal muscle research. We utilized approximately 1 kb of the MYH4 promoter from a domestic pig and a human (which do and do not express MYH4, respectively) to elucidate the role of the promoter sequence in regulating the high expression of MYH4 in porcine skeletal muscle. We identified a 3 bp genomic difference within the proximal CArG and E-box region of the MYH4 promoter of pigs and humans that dictates the differential activity of these promoters during myogenesis. Subtle species-specific genomic differences within the CArG-box region caused differential protein-DNA interactions at this site and is likely accountable for the differential MYH4 promoter activity between pigs and humans. We propose that the genomic differences identified herein explain the differential activity of the MYH4 promoter of pigs and humans, which may contribute to the differential expression patterns displayed in these otherwise physiologically similar mammals. Further, we report that both the pig and human MYH4 promoters can be induced by MyoD over-expression, but the capacity to activate the MYH4 promoter is largely influenced by the 3 bp difference located within the CArG-box region of the proximal MYH4 promoter.
PMCID: PMC4255089  PMID: 25469802
14.  Standardizing Nasal Nitric Oxide Measurement as a Test for Primary Ciliary Dyskinesia 
Rationale: Several studies suggest that nasal nitric oxide (nNO) measurement could be a test for primary ciliary dyskinesia (PCD), but the procedure and interpretation have not been standardized.
Objectives: To use a standard protocol for measuring nNO to establish a disease-specific cutoff value at one site, and then validate at six other sites.
Methods: At the lead site, nNO was prospectively measured in individuals later confirmed to have PCD by ciliary ultrastructural defects (n = 143) or DNAH11 mutations (n = 6); and in 78 healthy and 146 disease control subjects, including individuals with asthma (n = 37), cystic fibrosis (n = 77), and chronic obstructive pulmonary disease (n = 32). A disease-specific cutoff value was determined, using generalized estimating equations (GEEs). Six other sites prospectively measured nNO in 155 consecutive individuals enrolled for evaluation for possible PCD.
Measurements and Main Results: At the lead site, nNO values in PCD (mean ± standard deviation, 20.7 ± 24.1 nl/min; range, 1.5–207.3 nl/min) only rarely overlapped with the nNO values of healthy control subjects (304.6 ± 118.8; 125.5–867.0 nl/min), asthma (267.8 ± 103.2; 125.0–589.7 nl/min), or chronic obstructive pulmonary disease (223.7 ± 87.1; 109.7–449.1 nl/min); however, there was overlap with cystic fibrosis (134.0 ± 73.5; 15.6–386.1 nl/min). The disease-specific nNO cutoff value was defined at 77 nl/minute (sensitivity, 0.98; specificity, >0.999). At six other sites, this cutoff identified 70 of the 71 (98.6%) participants with confirmed PCD.
Conclusions: Using a standardized protocol in multicenter studies, nNO measurement accurately identifies individuals with PCD, and supports its usefulness as a test to support the clinical diagnosis of PCD.
PMCID: PMC3960971  PMID: 24024753
primary ciliary dyskinesia; Kartagener syndrome; ciliopathy; axoneme
15.  Transcription mediated insulation and interference direct gene cluster expression switches 
eLife  null;3:e03635.
In yeast, many tandemly arranged genes show peak expression in different phases of the metabolic cycle (YMC) or in different carbon sources, indicative of regulation by a bi-modal switch, but it is not clear how these switches are controlled. Using native elongating transcript analysis (NET-seq), we show that transcription itself is a component of bi-modal switches, facilitating reciprocal expression in gene clusters. HMS2, encoding a growth-regulated transcription factor, switches between sense- or antisense-dominant states that also coordinate up- and down-regulation of transcription at neighbouring genes. Engineering HMS2 reveals alternative mono-, di- or tri-cistronic and antisense transcription units (TUs), using different promoter and terminator combinations, that underlie state-switching. Promoters or terminators are excluded from functional TUs by read-through transcriptional interference, while antisense TUs insulate downstream genes from interference. We propose that the balance of transcriptional insulation and interference at gene clusters facilitates gene expression switches during intracellular and extracellular environmental change.
eLife digest
A DNA double helix is made up of two DNA strands, which in turn are made of molecules that are each known by a single letter—A, T, C, or G. The sequence of these ‘letters’ in each DNA strand contains biological information.
Genes are sections of DNA that can be ‘expressed’ to produce proteins and RNA molecules. To express a gene, the DNA strands in the double helix must first be partially separated so that one of them can be used as a template to build an RNA molecule in a process called transcription. Either of the DNA strands in a helix can be used as an RNA template, but contain different genes and are read in opposite directions. One of the two strands is called the ‘sense’ strand, the other the ‘antisense’ strand.
The RNA molecule does not transcribe a whole DNA strand; instead, it transcribes a section of DNA, known as a transcription unit, which contains at least one gene. The end of a transcription unit is marked by certain signals that stop transcription. However, some transcription units in a DNA strand overlap, so there must be some way that the transcription machinery can sometimes ignore these stop signals.
The activity of some genes is linked to the activity of their immediate neighbours. Furthermore, some genes are expressed in different amounts in response to changes in environmental conditions. Researchers have previously suggested that there must be some form of switch that controls when these genes are expressed.
Nguyen et al. now engineer start and stop signals at a neighbouring pair of genes, called HMS2 and BAT2, in yeast. When one gene is switched on, the other is switched off and which gene is active depends on the diet of the yeast cells.
On the antisense DNA strand opposite to HMS2 is another gene, SUT650. Nguyen et al. show that when this gene is transcribed, the transcription of HMS2 on the other DNA strand is blocked. This has the knock-on effect of turning on BAT2. Conversely, transcribing HMS2 switches off SUT650 and BAT2 because the end of HMS2 overlaps with the beginning of both SUT650 and BAT2. Switching between different genes relies on loops that physically link the start and stop signals of the gene to be transcribed while ignoring the start and stop signals for neighbouring genes.
Proteins called transcription factors can bind to DNA and affect whether a gene is transcribed. Nguyen et al. found that a transcription factor that binds near the start of the HMS2 gene helps to control which DNA strand is transcribed. When transcription factors do not bind to the start of HMS2, antisense transcription—and the expression of SUT650—occurs instead.
Overall, Nguyen et al. show that the transcription process itself makes up part of a switch that can control the expression of several genes on both the sense and antisense strands of a DNA double helix. This may also explain how many other, more complex, gene networks are activated in response to changes in the environment.
PMCID: PMC4275577  PMID: 25407679
transcription interference; yeast metabolic cycle; HMS2:BAT2; transcription insulation; cycling transcripts; gene clusters; S. cerevisiae
16.  What is the Clinical Utility of Routine Cardiac Catheterization Before a Fontan Operation? 
Pediatric cardiology  2010;31(7):977-985.
Patients with single-ventricle circulation presenting for Fontan completion routinely undergo cardiac catheterization despite ongoing debate concerning its additive value. Increasing interest in noninvasive preoperative evaluation alone led the authors to analyze the utility of routine pre-Fontan catheterization and to determine whether a subset of patients could avoid this invasive procedure. Patients younger than 5 years referred for pre-Fontan evaluation were retrospectively reviewed. Medical records and catheter angiograms were examined, and catheterizations were categorized as “additive” based on predetermined criteria. Associations between precatheterization variables, catheterization findings, and short-term postoperative outcomes were evaluated. Cardiac catheterization was clinically nonadditive for 89 of 175 patients undergoing pre-Fontan evaluation (51%). There were no robust precatheterization predictors of a nonadditive catheterization. Echocardiography did not fully demonstrate the relevant anatomy of 115 patients (66%), most frequently due to inadequate visualization of the pulmonary arteries, and 22 patients had additive catheterizations due to new diagnostic findings alone. Interventions at catheterization were frequent and deemed “important” for 64 patients (37%). Catheterization hemodynamic data were not associated with early postoperative outcomes. Minor catheterization complications occurred for 51 patients (29%) and major complications for 4 patients (2%). Although at least 50% of the patients presenting for Fontan completion may be able to avoid routine catheterization safely, an echocardiography-based imaging strategy alone is insufficient to allow proper identification of those who could be evaluated noninvasively. A more comprehensive imaging strategy not based solely on echocardiography should be considered.
PMCID: PMC4237011  PMID: 20503042
Cardiac catheterization; CHD; Echocardiography; Fontan; Imaging; Univentricular heart
17.  Predictors of Technical Success and Postnatal Biventricular Outcome After In Utero Aortic Valvuloplasty for Aortic Stenosis With Evolving Hypoplastic Left Heart Syndrome 
Circulation  2009;120(15):1482-1490.
Aortic stenosis in the midgestation fetus with a normal-sized or dilated left ventricle predictably progresses to hypoplastic left heart syndrome when associated with certain physiological findings. Prenatal balloon aortic valvuloplasty may improve left heart growth and function, possibly preventing evolution to hypoplastic left heart syndrome.
Methods and Results
Between March 2000 and October 2008, 70 fetuses underwent attempted aortic valvuloplasty for critical aortic stenosis with evolving hypoplastic left heart syndrome. We analyzed this experience to determine factors associated with procedural and postnatal outcome. The median gestational age at intervention was 23 weeks. The procedure was technically successful in 52 fetuses (74%). Relative to 21 untreated comparison fetuses, subsequent prenatal growth of the aortic and mitral valves, but not the left ventricle, was improved after intervention. Nine pregnancies (13%) did not reach a viable term or preterm birth. Seventeen patients had a biventricular circulation postnatally, 15 from birth. Larger left heart structures and higher left ventricular pressure at the time of intervention were associated with biventricular outcome. A multivariable threshold scoring system was able to discriminate fetuses with a biventricular outcome with 100% sensitivity and modest positive predictive value.
Technically successful aortic valvuloplasty alters left heart valvar growth in fetuses with aortic stenosis and evolving hypoplastic left heart syndrome and, in a subset of cases, appeared to contribute to a biventricular outcome after birth. Fetal aortic valvuloplasty carries a risk of fetal demise. Fetuses undergoing in utero aortic valvuloplasty with an unfavorable multivariable threshold score at the time of intervention are very unlikely to achieve a biventricular circulation postnatally.
PMCID: PMC4235336  PMID: 19786635
fetus; heart defects, congenital; hypoplastic left heart syndrome; stenosis; valvuloplasty
18.  Cerebral Blood Flow Characteristics and Biometry in Fetuses Undergoing Prenatal Intervention for Aortic Stenosis with Evolving Hypoplastic Left Heart Syndrome 
Children with hypoplastic left heart syndrome (HLHS) are at risk for neurodevelopmental dysfunction; prenatal factors may play a role in this predilection. Cerebral blood flow profiles are abnormal in fetuses with HLHS, raising the possibility that cerebral hemodynamics in utero may be related to neurodevelopmental abnormalities. Prenatal aortic valvuloplasty for fetal aortic stenosis with evolving HLHS is technically feasible and improves left heart hemodynamics. This study aimed to assess the effects of prenatal intervention on cerebral blood flow profiles and head circumference in fetuses with evolving HLHS. Seventy fetuses underwent prenatal aortic valvuloplasty for evolving HLHS (median 23 weeks gestation). Among 46 fetuses that had successful valvuloplasty and available data, middle cerebral artery (MCA) pulsatility (PI) and resistive (RI) indices were abnormal (Z-scores −1.7 ± 1.1 and −2.2 ± 1.4, p < 0.001). Early post-valvuloplasty (n = 33) and at late gestation follow-up (n = 28), MCA PI and RI Z-scores remained low with no difference from pre- or early postintervention. Fetal head circumference was normal, as were umbilical artery PI and RI Z-scores. Cerebral blood flow characteristics are abnormal in mid-gestation fetuses with evolving HLHS, suggesting low cerebral vascular impedance. The mechanisms and significance of these abnormalities are unknown. Prenatal aortic valvuloplasty did not have a major impact on these indices.
PMCID: PMC4230573  PMID: 19931971
Fetal surgery; Balloon aortic valvuloplasty; Brain sparing effect; Congenital heart disease; Hypoplastic left heart syndrome; Microcephaly
19.  Using Lean-Based Systems Engineering to Increase Capacity in the Emergency Department 
While emergency department (ED) crowding has myriad causes and negative downstream effects, applying systems engineering science and targeting throughput remains a potential solution to increase functional capacity. However, the most effective techniques for broad application in the ED remain unclear. We examined the hypothesis that Lean-based reorganization of Fast Track process flow would improve length of stay (LOS), percent of patients discharged within one hour, and room use, without added expense.
This study was a prospective, controlled, before-and-after analysis of Fast Track process improvements in a Level 1 tertiary care academic medical center with >95,000 annual patient visits. We included all adult patients seen during the study periods of 6/2010–10/2010 and 6/2011–10/2011, and data were collected from an electronic tracking system. We used concurrent patients seen in another care area used as a control group. The intervention consisted of a simple reorganization of patient flow through existing rooms, based in systems engineering science and modeling, including queuing theory, demand-capacity matching, and Lean methodologies. No modifications to staffing or physical space were made. Primary outcomes included LOS of discharged patients, percent of patients discharged within one hour, and time in exam room. We compared LOS and exam room time using Wilcoxon rank sum tests, and chi-square tests for percent of patients discharged within one hour.
Following the intervention, median LOS among discharged patients was reduced by 15 minutes (158 to 143 min, 95%CI 12 to 19 min, p<0.0001). The number of patients discharged in <1 hr increased by 2.8% (from 6.9% to 9.7%, 95%CI 2.1% to 3.5%, p<0.0001), and median exam room time decreased by 34 minutes (90 to 56 min, 95%CI 31 to 38 min, p<0.0001). In comparison, the control group had no change in LOS (265 to 267 min) or proportion of patients discharged in <1 hr (2.9% to 2.9%), and an increase in exam room time (28 to 36 min, p<0.0001).
In this single center trial, a focused Lean-based reorganization of patient flow improved Fast Track ED performance measures and capacity, without added expense. Broad multi-centered application of systems engineering science might further improve ED throughput and capacity.
PMCID: PMC4251218  PMID: 25493117
20.  Case Definitions, Diagnostic Algorithms, and Priorities in Encephalitis: Consensus Statement of the International Encephalitis Consortium 
We present a consensus document that proposes a standardized case definition and diagnostic guidelines for evaluation of adults and children with suspected encephalitis. In addition, areas of research priority, including host genetics and selected emerging infections, are discussed.
Background. Encephalitis continues to result in substantial morbidity and mortality worldwide. Advances in diagnosis and management have been limited, in part, by a lack of consensus on case definitions, standardized diagnostic approaches, and priorities for research.
Methods. In March 2012, the International Encephalitis Consortium, a committee begun in 2010 with members worldwide, held a meeting in Atlanta to discuss recent advances in encephalitis and to set priorities for future study.
Results. We present a consensus document that proposes a standardized case definition and diagnostic guidelines for evaluation of adults and children with suspected encephalitis. In addition, areas of research priority, including host genetics and selected emerging infections, are discussed.
Conclusions. We anticipate that this document, representing a synthesis of our discussions and supported by literature, will serve as a practical aid to clinicians evaluating patients with suspected encephalitis and will identify key areas and approaches to advance our knowledge of encephalitis.
PMCID: PMC3783060  PMID: 23861361
encephalitis; guidelines; viral; autoimmune; host genetics
21.  Childhood Asthma Hospitalizations in the United States, 2000-2009 
The Journal of pediatrics  2013;163(4):1127-1133.e3.
To examine temporal trends in the US incidence of childhood asthma hospitalizations, inhospital mortality, mechanical ventilation use, and hospital charges between 2000 and 2009.
Study design
A serial, cross-sectional analysis of a nationally-representative sample of children hospitalized with acute asthma. The Kids Inpatient Database was used to identify children <18 years of age with asthma by International Classification of Diseases, Ninth Revision, Clinical Modification code 493.xx. Outcome Measures were asthma hospitalization incidence, in-hospital mortality, mechanical ventilation use, and hospital charges. We examined temporal trends of each outcome, accounting for sampling weights. Hospital charges were adjusted for inflation to 2009 US dollars.
The four separated years (2000, 2003, 2006, and 2009) of national discharge data included 592 805 weighted discharges with asthma. Between 2000 and 2009, asthma hospitalization incidence decreased from 21.1 to 18.4 per 10 000 person-years among all US children (13% decrease; Ptrend<.001). Mortality declined significantly after adjusting for confounders (OR for comparison of 2009 with 2000, 0.37; 95%CI, 0.17-0.79). By contrast, there was an increase in mechanical ventilation use (0.8% to 1.0%; 28% increase; Ptrend<.001). Nationwide hospital charges also increased from $1.27 billion to $1.59 billion (26% increase; Ptrend<.001); this increase was driven by a rise in the geometric mean of hospital charges per discharge, from $5940 to $8410 (42% increase; Ptrend<.001).
Between 2000 and 2009, we found significant declines in asthma hospitalization and in-hospital mortality among US children. By contrast, mechanical ventilation use and hospital charges for asthma significantly increased over this same period.
PMCID: PMC3786053  PMID: 23769497
asthma; children; trends; hospitalization; mechanical ventilation; mortality; length of stay; hospital charge
22.  Prevalence, Correlates, and Prognosis of Peripheral Artery Disease in Rural Ecuador—Rationale, Protocol, and Phase I Results of a Population-Based Survey: An Atahualpa Project-Ancillary Study 
Background. Little is known on the prevalence of peripheral artery disease (PAD) in developing countries. Study design. Population-based study in Atahualpa. In Phase I, the Edinburgh claudication questionnaire (ECQ) was used for detection of suspected symptomatic PAD; persons with a negative ECQ but a pulse pressure ≥65 mmHg were suspected of asymptomatic PAD. In Phase II, the ankle-brachial index will be used to test reliability of screening instruments and to determine PAD prevalence. In Phase III, participants will be followed up to estimate the relevance of PAD as a predictor of vascular outcomes. Results. During Phase I, 665 Atahualpa residents aged ≥40 years were enrolled (mean age: 59.5 ± 12.6 years, 58% women). A poor cardiovascular health status was noticed in 464 (70%) persons of which 27 (4%) had a stroke and 14 (2%) had ischemic heart disease. Forty-four subjects (7%) had suspected symptomatic PAD and 170 (26%) had suspected asymptomatic PAD. Individuals with suspected PAD were older, more often women, and had a worse cardiovascular profile than those with nonsuspected PAD. Conclusions. Prevalence of suspected PAD in this underserved population is high. Subsequent phases of this study will determine whether prompt detection of PAD is useful to reduce the incidence of catastrophic vascular diseases in the region.
PMCID: PMC4217317  PMID: 25389500
23.  The “Goldilocks Zone” from a redox perspective—Adaptive vs. deleterious responses to oxidative stress in striated muscle 
Consequences of oxidative stress may be beneficial or detrimental in physiological systems. An organ system's position on the “hormetic curve” is governed by the source and temporality of reactive oxygen species (ROS) production, proximity of ROS to moieties most susceptible to damage, and the capacity of the endogenous cellular ROS scavenging mechanisms. Most importantly, the resilience of the tissue (the capacity to recover from damage) is a decisive factor, and this is reflected in the disparate response to ROS in cardiac and skeletal muscle. In myocytes, a high oxidative capacity invariably results in a significant ROS burden which in homeostasis, is rapidly neutralized by the robust antioxidant network. The up-regulation of key pathways in the antioxidant network is a central component of the hormetic response to ROS. Despite such adaptations, persistent oxidative stress over an extended time-frame (e.g., months to years) inevitably leads to cumulative damages, maladaptation and ultimately the pathogenesis of chronic diseases. Indeed, persistent oxidative stress in heart and skeletal muscle has been repeatedly demonstrated to have causal roles in the etiology of heart disease and insulin resistance, respectively. Deciphering the mechanisms that underlie the divergence between adaptive and maladaptive responses to oxidative stress remains an active area of research for basic scientists and clinicians alike, as this would undoubtedly lead to novel therapeutic approaches. Here, we provide an overview of major types of ROS in striated muscle and the divergent adaptations that occur in response to them. Emphasis is placed on highlighting newly uncovered areas of research on this topic, with particular focus on the mitochondria, and the diverging roles that ROS play in muscle health (e.g., exercise or preconditioning) and disease (e.g., cardiomyopathy, ischemia, metabolic syndrome).
PMCID: PMC4166897  PMID: 25278906
hormesis; carbonyl stress; mitochondria; lipid peroxidation; redox environment; adaptation; heart; skeletal muscle
24.  A Comparative Transcriptomic Analysis Reveals Conserved Features of Stem Cell Pluripotency in Planarians and Mammals 
Stem cells (Dayton, Ohio)  2012;30(8):1734-1745.
Many long-lived species of animals require the function of adult stem cells throughout their lives. However, the transcriptomes of stem cells in invertebrates and vertebrates have not been compared, and consequently, ancestral regulatory circuits that control stem cell populations remain poorly defined. In this study, we have used data from high-throughput RNA sequencing to compare the transcriptomes of pluripotent adult stem cells from planarians with the transcriptomes of human and mouse pluripotent embryonic stem cells. From a stringently defined set of 4,432 orthologs shared between planarians, mice and humans, we identified 123 conserved genes that are ≥5-fold differentially expressed in stem cells from all three species. Guided by this gene set, we used RNAi screening in adult planarians to discover novel stem cell regulators, which we found to affect the stem cell-associated functions of tissue homeostasis, regeneration, and stem cell maintenance. Examples of genes that disrupted these processes included the orthologs of TBL3, PSD12, TTC27, and RACK1. From these analyses, we concluded that by comparing stem cell transcriptomes from diverse species, it is possible to uncover conserved factors that function in stem cell biology. These results provide insights into which genes comprised the ancestral circuitry underlying the control of stem cell self-renewal and pluripotency.
PMCID: PMC4161212  PMID: 22696458
Adult stem cells; Pluripotency; Lophotrochozoan; Flatworm; Mammals; Deep sequencing; Evolution; Planarians; Schmidtea mediterranea
25.  Examining the Effect of a Patient Navigation Intervention on Outpatient Cardiac Rehabilitation Awareness and Enrollment 
Awareness of and enrollment into outpatient cardiac rehabilitation (OCR) following a cardiac event or procedure remains suboptimal. Thus, it is important to identify new approaches to improve these outcomes. The objectives of this study were to identify: (1) the contributions of a patient navigation (PN) intervention and other patient characteristics on OCR awareness; and (2) the contributions of OCR awareness and other patient characteristics on OCR enrollment among eligible cardiac patients up to 12 weeks post-hospitalization.
In this randomized controlled study, 181 eligible and consenting patients were assigned to either PN (n=90) or Usual Care (UC; n=91) prior to hospital discharge. Awareness of OCR was assessed by telephone interview at 12-weeks posthospitalization and OCR enrollment was confirmed by staff at collaborating OCR programs. Of the 181 study participants, 3 died within 1 month of hospital discharge, and 147 completed the 12-week telephone interview.
Participants in the PN intervention arm were nearly 6 times more likely to have at least some awareness of OCR compared to UC participants (OR=5.99; P=.001). Moreover, participants who reported at least some OCR awareness were more than 9 times more likely to enroll in OCR (OR=9.27, P=.034), and participants who were married were less likely to enroll (P=.031).
Lay health advisors have potential to improve cardiac patient awareness of outpatient rehabilitation services, which in turn can yield greater enrollment rates into a program.
PMCID: PMC3759655  PMID: 23823904
awareness; cardiac rehabilitation; cardiovascular diseases; patient participation

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