tbuckley/cabot-search huggingface dataset:
Brain ‘Ouabain’ Mediates Sympathetic Hyperactivity in Congestive Heart Failure
Authors: Frans H. H. Leenen, Bing S. Huang, Huilian Yu, Baoxue Yuan
Journal: Circulation Research (1995)

Abstract In congestive heart failure (CHF), endogenous compounds with ouabainlike activity (OLA) may contribute to the maintenance of the circulatory homeostasis by peripheral as well as central effects. In the present study, we assessed changes in peripheral (plasma and left ventricle) and central (pituitary, hypothalamus, pons, and cortex) OLA in two animal models of CHF and determined whether brain OLA mediates sympathetic hyperactivity in CHF. Cardiomyopathic hamsters with their controls were studied at 9 months of age for tissue OLA. Rats were studied 4 weeks after acute coronary artery ligation for tissue OLA and sympathetic activity. In both models, left ventricular end-diastolic pressure was markedly increased. CHF was associated with significant increases in both plasma and tissue OLA in both models. In the brain, the most marked (twofold to threefold) increases occurred in the hypothalamus. In vitro, all OLA measured could be blocked by antibody Fab fragments (Digibind). Conscious rats with CHF showed elevated plasma catecholamines and enhanced responses of mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) to air stress and to intracerebroventricular (ICV) injection of the α 2 -adrenergic receptor agonist guanabenz compared with sham-operated rats. ICV administration of the Fab fragments did not change resting RSNA or responses to air stress at 1 hour. However, 18 hours after injection of the Fab fragments, resting RSNA levels had significantly decreased compared with the control values, and plasma catecholamine levels had decreased to control values. Moreover, the magnitudes of the increases or decreases in MAP, HR, and RSNA to air stress or ICV guanabenz had markedly decreased as well and were now similar to those observed in sham-operated control animals. The present results show that the development of CHF in two animal models is associated with marked increases in both peripheral and brain OLA. Brain OLA appears to mediate the increase in resting sympathetic tone and enhanced sympathoexcitatory responses to stress.
Hemoglobin function in stored blood
Authors: H. Franklin Bunn, Mary H. May, Walter F. Kocholaty, Charles E. Shields
Journal: Journal of Clinical Investigation (1969)

Serial oxygen dissociation curves were performed on blood units preserved in acid-citrate-dextrose (ACD), ACD-adenine, and ACD-adenine-inosine. Dividing blood from a single donor into two or more bags allowed direct comparison between preservatives. During the 1st wk of storage in ACD, a progressive increase in oxygen affinity was observed. Thereafter, little further change was noted. Oxygen affinity increased even more rapidly during initial storage in ACD-adenine. However, with the inclusion of inosine as a preservative, oxygen affinity remained unaltered during the first 2 wk. Increases in oxygen affinity correlated well with falling levels of red cell 2,3-diphosphoglycerate (2,3-DPG) during storage. No significant changes in glutathione, reduced form (GSH), or A3 (A(I)) hemoglobin levels were noted during the first 3 wk of storage. No significant accumulation of ferrihemoglobin was detected. When blood stored 20 days in ACD or ACD-adenine was incubated with inosine for 60 min at 37 degrees C, 2,3-DPG and adenosine triphosphate (ATP) were resynthesized, and oxygen affinity was decreased. The distribution of 2,3-DPG in fresh and stored red cells appeared to influence experimental values for Hill's n, a measure of heme-heme interaction.
Mechanisms of Cardiovascular Disease in Accelerated Aging Syndromes
Authors: Brian C. Capell, Francis S. Collins, Elizabeth G. Nabel
Journal: Circulation Research (2007)

In the past several years, remarkable progress has been made in the understanding of the mechanisms of premature aging. These rare, genetic conditions offer valuable insights into the normal aging process and the complex biology of cardiovascular disease. Many of these advances have been made in the most dramatic of these disorders, Hutchinson–Gilford progeria syndrome. Although characterized by features of normal aging such as alopecia, skin wrinkling, and osteoporosis, patients with Hutchinson–Gilford progeria syndrome are affected by accelerated, premature arteriosclerotic disease that leads to heart attacks and strokes at a mean age of 13 years. In this review, we highlight recent advances in the biology of premature aging uncovered in Hutchinson–Gilford progeria syndrome and other accelerated aging syndromes, advances that provide insight into the mechanisms of cardiovascular diseases ranging from atherosclerosis to arrhythmias.
Fast-evolving noncoding sequences in the human genome
Authors: Christine P Bird, Barbara E Stranger, Maureen Liu, Daryl J Thomas, Catherine E Ingle, Claude Beazley, Webb Miller, Matthew E Hurles, Emmanouil T Dermitzakis
Journal: Genome biology (2007)

Gene regulation is considered one of the driving forces of evolution. Although protein-coding DNA sequences and RNA genes have been subject to recent evolutionary events in the human lineage, it has been hypothesized that the large phenotypic divergence between humans and chimpanzees has been driven mainly by changes in gene regulation rather than altered protein-coding gene sequences. Comparative analysis of vertebrate genomes has revealed an abundance of evolutionarily conserved but noncoding sequences. These conserved noncoding (CNC) sequences may well harbor critical regulatory variants that have driven recent human evolution.Here we identify 1,356 CNC sequences that appear to have undergone dramatic human-specific changes in selective pressures, at least 15% of which have substitution rates significantly above that expected under neutrality. The 1,356 'accelerated CNC' (ANC) sequences are enriched in recent segmental duplications, suggesting a recent change in selective constraint following duplication. In addition, single nucleotide polymorphisms within ANC sequences have a significant excess of high frequency derived alleles and high F(ST) values relative to controls, indicating that acceleration and positive selection are recent in human populations. Finally, a significant number of single nucleotide polymorphisms within ANC sequences are associated with changes in gene expression. The probability of variation in an ANC sequence being associated with a gene expression phenotype is fivefold higher than variation in a control CNC sequence.Our analysis suggests that ANC sequences have until very recently played a role in human evolution, potentially through lineage-specific changes in gene regulation.
P123 Opiate Smokers have a High Prevalence of Respiratory Symptoms Irrespective of Airflow Obstruction: Abstract P123 Table 1.
Authors: N Lewis-Burke, O Wooding, K McKinnell, L Davies, PP Walker
Journal: Thorax (2013)

<h3></h3> In the 1990s inhalation (‘chasing the dragon’) became the predominant method of recreational opiate (heroin and crack cocaine) consumption as it was perceived to have fewer detrimental health effects than injection. Although clinicians encounter individuals with COPD associated with opiate smoking (‘heroin lung’) the airway effects and symptoms resulting from opiate smoking are not established. We recruited 145 current and past opiate users from a local community drug service and recorded demographics. They completed spirometry pre and post salbutamol and questionnaires addressing drug use, symptoms and health status. Lower limit of normal was used to define airflow obstruction. Ten subjects failed to produce adequate spirometry, 26 had only injected and never smoked opiates while 6 subjects had marked bronchodilator (BD) reversibility consistent with asthma. Thirty six subjects appeared to have COPD and these were compared with 67 opiate smokers with normal post-BD spirometry and the 26 subjects who only injected opiates. The results from the 3 groups are shown in the table. The COPD group was a little older and necessarily had a lower FEV1 and post-BD airflow obstruction. There was little difference in length of drug use when the opiate smokers with COPD were compared to those without and the frequency of cough and phlegm differed little. Opiate smokers with COPD had modestly higher rates of wheeze and breathlessness; hence, higher CAT and MRC dyspnoea scores, but respiratory symptoms and use of respiratory medication were common in the non-COPD groups. Heroin and crack cocaine smoking is a risk factor for the development of irreversible airflow obstruction at a very young age. Respiratory symptoms are common in opiate smokers irrespective of the presence of COPD and not uncommon in those who have only injected opiates. In many, this is associated with a reduced health status despite normal spirometry; hence, symptoms are not a useful way to ‘diagnose’ COPD and spirometry is essential.
Association between radiographic damage of the spine and spinal mobility for individual patients with ankylosing spondylitis: can assessment of spinal mobility be a proxy for radiographic evaluation?
Authors: A Wanders
Journal: Annals of the Rheumatic Diseases (2005)

To demonstrate the association between various measures of spinal mobility and radiographic damage of the spine in individual patients with ankylosing spondylitis, and to determine whether the assessment of spinal mobility can be a proxy for the assessment of radiographic damage.Radiographic damage was assessed by the mSASSS. Cumulative probability plots combined the radiographic damage score of an individual patient with the corresponding score for nine spinal mobility measures. Receiver operating characteristic analysis was performed to determine the cut off level of every spinal mobility measure that discriminates best between the presence and absence of radiographic damage. Three arbitrary cut off levels for radiographic damage were investigated. Likelihood ratios were calculated to explore further the diagnostic properties of the spinal mobility measures.Cumulative probability plots showed an association between spinal mobility measures and radiographic damage for the individual patient. Irrespective of the chosen cut off level for radiographic progression, lateral spinal flexion and BASMI discriminated best between patients with and those without structural damage. Even the best discriminatory spinal mobility assessments misclassified a considerable proportion of patients (up to 20%). Intermalleolar distance performed worst (up to 30% misclassifications). Lateral spinal flexion best predicted the absence of radiographic damage, and a modified Schober test best predicted the presence of radiographic damage.This study unequivocally demonstrated a relationship between spinal mobility and radiographic damage. However, spinal mobility cannot be used as a proxy for radiographic evaluation in an individual patient.
ABL Regulation by AXL Promotes Cisplatin Resistance in Esophageal Cancer
Authors: Jun Hong, DunFa Peng, Zheng Chen, Vikas Sehdev, Abbes Belkhiri
Journal: Cancer Research (2012)

Abstract Esophageal adenocarcinoma (EAC) is characterized by resistance to chemotherapy and poor outcome. Although cisplatin (CDDP) has been used as a first-line therapy in patients with EAC, resistance remains a major clinical problem. The AXL receptor tyrosine kinase, originally isolated as a transforming gene from leukemia, is overexpressed in several solid tumors. Herein, we assessed AXL protein expression in human EACs and examined its role in CDDP resistance in human EAC cells. AXL overexpression was detected in more than 50% of tumors examined. Elevating AXL in nonoverexpressing cells doubled the CDDP IC50 and increased cell survival three-fold, while attenuating AXL in overexpressing cells reduced survival two-fold. The effects of AXL modulation on cell survival were associated with changes in cellular and molecular markers of apoptosis. Mechanistic investigations revealed that AXL blocked CDDP-induced activation of endogenous p73β (TP73), reducing its protein half-life, and inhibited CDDP-induced levels of p-c-ABL(Y412) and p-p73β(Y99). These changes were associated with a disruption of c-ABL/p73β protein interactions due to association with c-ABL in the cytoplasm, thereby blocking nuclear accumulation of c-ABL and phosphorylation of p73β in response to DNA damage. Together, our results establish that AXL promotes CDDP resistance in esophageal adenocarcinoma and argue that therapeutic targeting of AXL may sensitize these cancers to DNA-damaging drugs. Cancer Res; 73(1); 331–40. ©2012 AACR.
Ecological priming: Convergent evidence for the link between ecology and psychological processes
Authors: Michele J. Gelfand, Janetta Lun
Journal: Behavioral and Brain Sciences (2013)

Abstract This commentary describes the use of ecological priming methods to address the limitations of the correlational research discussed in the target article. We provide examples from our own work on cultural tightness–looseness to illustrate how we can bring ecological and societal conditions into the laboratory in order to study the impact of ecological threats on psychological processes experimentally.
Patterns and Correlates of Patient Referral to Surgeons for Treatment of Breast Cancer
Authors: Steven J. Katz, Timothy P. Hofer, Sarah Hawley, Paula M. Lantz, Nancy K. Janz, Kendra Schwartz, Lihua Liu, Dennis Deapen, Monica Morrow
Journal: Journal of Clinical Oncology (2007)

Purpose Characteristics of surgeons and their hospitals have been associated with cancer treatments and outcomes. However, little is known about factors that are associated with referral pathways. Methods We analyzed tumor registry and survey data from women with breast cancer diagnosed in 2002 and reported to the Detroit and Los Angeles Surveillance, Epidemiology, and End Results registries (n = 1,844; response rate, 77.4%) and their attending surgeons (n = 365; response rate 80.0%). Results About half of the patients (54.3%) reported that they were referred to the surgeon by another provider or health plan; 20.3% reported that they selected the surgeon; and 21.9% reported that they both were referred and were involved in selecting the surgeon. Patients who selected the surgeon based on reputation were more likely to have received treatment from a high-volume surgeon (adjusted odds ratio [OR], 2.2; 95% CI, 1.5 to 3.4) and more likely to have been treated in an American College of Surgeons–approved cancer program or a National Cancer Institute (NCI) –designated cancer center (adjusted OR, 2.0; 95% CI, 1.3 to 3.1; adjusted OR, 3.4; 95% CI, 1.9 to 6.2, respectively). Patients who were referred to the surgeon were less likely to be treated in an NCI-designated cancer center (adjusted OR, 0.5; 95% CI, 0.3 to 0.9). Conclusion Women with breast cancer who actively participate in the surgeon selection process are more likely to be treated by more experienced surgeons and in hospitals with cancer programs. Patients should be aware that provider or health plan–based referral may not connect them with the most experienced surgeon or comprehensive practice setting in their community.
A pilot study examining changes in dust lead loading on walls and ceilings after lead hazard control interventions.
Authors: E Tohn, S Dixon, R Rupp, S Clark
Journal: Environmental Health Perspectives (2000)

The U.S. Department of Housing and Urban Development (HUD) guidelines on lead hazard control instruct contractors to clean floors, windows, walls, ceilings, and other horizontal surfaces to remove lead-contaminated dust and debris after lead interventions are conducted. This dust removal activity adds costs to each project. The need to clean floors and windows is well documented in the HUD guidelines. However, there is substantially less documentation to support the recommendation to clean walls and ceilings. We examined whether it is necessary to clean walls and ceilings after lead hazard control (LHC) interventions by comparing dust lead loadings measured on these surfaces before an LHC intervention to dust lead loadings after the intervention. Twenty-two dwelling units undergoing substantial LHC measures consistent with the HUD guidelines were enrolled in the study. There was a significant increase in dust lead loading on walls and ceilings between the pre- and postintervention. The change in wall dust lead loading was substantial and created potentially harmful lead exposures. Although statistically significant, the change in ceiling dust lead loading was minimal and the postintervention dust lead loadings were far below the existing federal floor dust lead clearance standard. These results strongly support the recommendations in the HUD guidelines to clean walls after LHC interventions and do not provide sufficient justification to alter the current recommendation to clean ceilings after lead work.
Aerobic training reverses airway inflammation and remodelling in an asthma murine model
Authors: R. A. Silva, R. P. Vieira, A. C. S. Duarte, F. D. T. Q. S. Lopes, A. Perini, T. Mauad, M. A. Martins, C. R. F. Carvalho
Journal: European Respiratory Journal (2009)

Aerobic training (AT) decreases dyspnoea and exercise-induced bronchospasm, and improves aerobic capacity and quality of life; however, the mechanisms for such benefits remain poorly understood. The aim of the present study was to evaluate the AT effects in a chronic model of allergic lung inflammation in mice after the establishment of airway inflammation and remodelling. Mice were divided into the control group, AT group, ovalbumin (OVA) group or OVA+AT group and exposed to saline or OVA. AT was started on day 28 for 60 min five times per week for 4 weeks. Respiratory mechanics, specific immunoglobulin (Ig)E and IgG 1 , collagen and elastic fibres deposition, smooth muscle thickness, epithelial mucus, and peribronchial density of eosinophils, CD3+ and CD4+, IL-4, IL-5, IL-13, interferon-γ, IL-2, IL-1ra, IL-10, nuclear factor (NF)-κB and Foxp3 were evaluated. The OVA group showed an increase in IgE and IgG 1 , eosinophils, CD3+, CD4+, IL-4, IL-5, IL-13, NF-κB, collagen and elastic, mucus synthesis, smooth muscle thickness and lung tissue resistance and elastance. The OVA+AT group demonstrated an increase of IgE and IgG 1 , and reduction of eosinophils, CD3+, CD4+, IL-4, IL-5, IL-13, NF-κB, airway remodelling, mucus synthesis, smooth muscle thickness and tissue resistance and elastance compared with the OVA group (p&lt;0.05). The OVA+AT group also showed an increase in IL-10 and IL-1ra (p&lt;0.05), independently of Foxp3. AT reversed airway inflammation and remodelling and T-helper cell 2 response, and improved respiratory mechanics. These results seem to occur due to an increase in the expression of IL-10 and IL-1ra and a decrease of NF-κB.
The Akt Inhibitor ISC-4 Activates Prostate Apoptosis Response Protein-4 and Reduces Colon Tumor Growth in a Nude Mouse Model
Authors: Arun K. Sharma, Christina L. Kline, Arthur Berg, Shantu Amin, Rosalyn B. Irby
Journal: Clinical Cancer Research (2011)

Prostate apoptosis response protein-4 (Par-4) sensitizes cells to chemotherapy; however, Akt1 inactivates Par-4. Previously we showed that Par-4-overexpressing colon cancer cells responded more readily to 5-fluorouracil (5-FU) than their wild-type counterparts. In this study we investigated (i) the effects of the Akt inhibitor, phenylbutyl isoselenocyanate (ISC-4), on tumor growth in nude mice and (ii) bystander effect of Par-4-overexpressing cells on wild-type tumor growth.Mice (n = 80) were injected with wild-type HT29 human colon cancer cells in the right flank. Forty of the mice were also injected in the left flank with HT29 cells engineered to overexpress Par-4. The mice were treated with 5-FU, ISC-4, a combination, or vehicle.ISC-4 reduced tumor growth, with or without 5-FU. When Par-4-overexpressing tumors were present, wild-type tumors grew more slowly compared to when no Par-4-overexpressing tumors were present. The level of Par-4 protein as well as the Par-4 binding protein, GRP78, was increased in wild-type cells growing in the same mouse as Par-4-overexpressing tumors compared with wild-type tumors growing without Par-4-overexpressing tumors.Par-4-overexpressing tumors exhibited a bystander effect on wild-type tumors growing distally in the same mouse. This suggests that gene therapy need not achieve total penetration to have a positive effect on tumor treatment. Inhibition of Akt with ISC-4 inhibited tumor growth and had a greater effect on cells overexpressing Par-4. The data indicate ISC-4 alone or in combination with Par-4 can greatly reduce tumor growth.
Severe acute respiratory syndrome (SARS)
Authors: N L Muller
Journal: Thorax (2003)

The radiological manifestations of severe acute respiratory syndrome (SARS) typically consist of focal unilateral or bilateral areas of hazy increased density (ground glass opacities) or airspace consolidation (fig 1A).1 In most patients the abnormalities gradually improve over several days following treatment. Approximately 20–25% of patients, however, show …
Sustained desensitization to bacterial Toll-like receptor ligands after resolutionof respiratory influenza infection
Authors: Arnaud Didierlaurent, John Goulding, Seema Patel, Robert Snelgrove, Lionel Low, Magali Bebien, Toby Lawrence, Leonie S. van Rijt, Bart N. Lambrecht, Jean-Claude Sirard, Tracy Hussell
Journal: The Journal of Experimental Medicine (2008)

The World Health Organization estimates that lower respiratory tract infections (excluding tuberculosis) account for ∼35% of all deaths caused by infectious diseases. In many cases, the cause of death may be caused by multiple pathogens, e.g., the life-threatening bacterial pneumonia observed in patients infected with influenza virus. The ability to evolve more efficient immunity on each successive encounter with antigen is the hallmark of the adaptive immune response. However, in the absence of cross-reactive T and B cell epitopes, one lung infection can modify immunity and pathology to the next for extended periods of time. We now report for the first time that this phenomenon is mediated by a sustained desensitization of lung sentinel cells to Toll-like receptor (TLR) ligands; this is an effect that lasts for several months after resolution of influenza or respiratory syncytial virus infection and is associated with reduced chemokine production and NF-κB activation in alveolar macrophages. Although such desensitization may be beneficial in alleviating overall immunopathology, the reduced neutrophil recruitment correlates with heightened bacterial load during secondary respiratory infection. Our data therefore suggests that post-viral desensitization to TLR signals may be one possible contributor to the common secondary bacterial pneumonia associated with pandemic and seasonal influenza infection.