tbuckley/cabot-search huggingface dataset:
The hidden costs of environmental contamination
Authors: Philip J. Landrigan
Journal: European Respiratory Journal (2012)

Cost is an inevitable, but often overlooked and uncounted, consequence of environmental contamination. Any degradation of the environment, whether it is contamination of air or water, pollution of landfills by toxic waste or exposure of children to hazardous chemicals, carries costs. Among these costs are: 1) direct medical expenses for persons made ill by toxic exposures; 2) indirect health-related costs such as time lost from school or work, costs of rehabilitation and costs of special education; 3) diminished economic productivity in persons whose brains, lungs or other organ systems are permanently damaged by toxic exposures; 4) loss of irreplaceable environmental treasures such as the Everglades or the Black Forest; and 5) the costs of environmental clean-up. A methodology for estimating the costs of diseases caused by environmental contamination was developed in the US in the early 1980s by an expert committee convened by the Institute of Medicine and chaired by Stanford University's Nobel Laureate in Economics, Prof. K. Arrow [1]. The core of this methodology is the calculation of the “fractional contribution” of the environment to causation of a particular disease in a particular population. This environmentally attributable fraction (EAF) is defined as: “the percentage of a particular disease category that would be eliminated if environmental risk factors were reduced to their lowest feasible levels” [2]. The EAF for a particular disease, such as childhood asthma, may be converted to an estimate of the cost of that disease in a particular population using the following equation:![Formula][1]</img> Costs are traditionally divided into direct and indirect health-related costs, and both are included in the calculation. The EAF model has now been used in a series of important cases to assess the costs of environmental and occupational disease. Findings from these analyses have had powerful impacts on the health … [1]: /embed/graphic-1.gif
Aldose Reductase Protects Against Early Atherosclerotic Lesion Formation in Apolipoprotein E-Null Mice
Authors: Sanjay Srivastava, Elena Vladykovskaya, Oleg A. Barski, Matthew Spite, Karin Kaiserova, J. Mark Petrash, Stephen S. Chung, Greg Hunt, Buddhadeb Dawn, Aruni Bhatnagar
Journal: Circulation Research (2009)

Atherosclerotic lesion formation is associated with the accumulation of oxidized lipids. Products of lipid oxidation, particularly aldehydes, stimulate cytokine production and enhance monocyte adhesion; however, their contribution to atherosclerotic lesion formation remains unclear.To test the hypothesis that inhibition of aldehyde removal by aldose reductase (AR), which metabolizes both free and phospholipid aldehydes, exacerbates atherosclerotic lesion formation.In atherosclerotic lesions of apolipoprotein (apo)E-null mice, AR protein was located in macrophage-rich regions and its abundance increased with lesion progression. Treatment of apoE-null mice with AR inhibitors sorbinil or tolrestat increased early lesion formation but did not affect the formation of advanced lesions. Early lesions of AR(-/-)/apoE(-/-) mice maintained on high-fat diet were significantly larger when compared with age-matched AR(+/+)/apoE(-/-) mice. The increase in lesion area attributable to deletion of the AR gene was seen in both male and female mice. Pharmacological inhibition or genetic ablation of AR also increased the lesion formation in male mice made diabetic by streptozotocin treatment. Lesions in AR(-/-)/apoE(-/-) mice exhibited increased collagen and macrophage content and a decrease in smooth muscle cells. AR(-/-)/apoE(-/-) mice displayed a greater accumulation of the AR substrate 4-hydroxy trans-2-nonenal (HNE) in the plasma and protein-HNE adducts in arterial lesions than AR(+/+)/apoE(-/-) mice.These observations indicate that AR is upregulated in atherosclerotic lesions and it protects against early stages of atherogenesis by removing toxic aldehydes generated in oxidized lipids.
Sex Hormones Are Associated with Right Ventricular Structure and Function
Authors: Corey E. Ventetuolo, Pamela Ouyang, David A. Bluemke, Harikrishna Tandri, R. Graham Barr, Emilia Bagiella, Anne R. Cappola, Michael R. Bristow, Craig Johnson, Richard A. Kronmal, Jorge R. Kizer, Joao A. C. Lima, Steven M. Kawut
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Sex hormones have effects on the left ventricle, but hormonal influences on the right ventricle (RV) are unknown.We hypothesized that sex hormones would be associated with RV morphology in a large cohort free of cardiovascular disease.Sex hormones were measured by immunoassay and RV ejection fraction (RVEF), stroke volume (RVSV), mass, end-diastolic volume, and end-systolic volume (RVESV) were measured by cardiac magnetic resonance imaging in 1,957 men and 1,738 postmenopausal women. The relationship between each hormone and RV parameter was assessed by multivariate linear regression.Higher estradiol levels were associated with higher RVEF (β per 1 ln[nmol/L], 0.88; 95% confidence interval [CI], 0.32 to 1.43; P = 0.002) and lower RVESV (β per 1 ln[nmol/L], -0.87; 95% CI, -1.67 to -0.08; P = 0.03) in women using hormone therapy. In men, higher bioavailable testosterone levels were associated with higher RVSV (β per 1 ln[nmol/L], 1.97; 95% CI, 0.20 to 3.73; P = 0.03) and greater RV mass and volumes (P ≤ 0.01). Higher dehydroepiandrosterone levels were associated with higher RVSV (β per 1 ln[nmol/L], 1.37; 95% CI, 0.15 to 2.59; P = 0.03) and greater RV mass (β per 1 ln[nmol/L], 0.25; 95% CI, 0.00 to 0.49; P = 0.05) and volumes (P ≤ 0.001) in women.Higher estradiol levels were associated with better RV systolic function in women using hormone therapy. Higher levels of androgens were associated with greater RV mass and volumes in both sexes.
Relationship between duodenal bile acids and colorectal neoplasia.
Authors: R J Moorehead, G R Campbell, J D Donaldson, S T McKelvey
Journal: Gut (1987)

To investigate a possible relationship between bile acids and colorectal neoplasia duodenal bile acids were analysed in 50 patients with colorectal adenomas and 14 with carcinoma. Using gas liquid and high performance liquid chromatography a small, but significant increase in the proportion of chenodeoxycholic acid was found in the bile of adenoma patients compared with controls (mean % +/- SD 31.0 +/- 10.8, 26.4 +/- 8.3, p = 0.01). The difference in the proportions of chenodeoxycholic acid correlated with increasing malignant potential of the adenomas as determined by increasing size, histological type, degree of dysplasia and number present. In carcinoma patients an increase in the proportion of chenodeoxycholic acid was also observed compared with controls (mean % +/- SD, 47.2 +/- 9.6, 28.0 +/- 4.5, p less than 0.01). The proportions of other bile acids in those with adenoma or carcinoma were normal.
Vascularity in asthmatic airways: relation to inhaled steroid dose
Authors: B. E Orsida, X. Li, B. Hickey, F. Thien, J. W Wilson, E H. Walters
Journal: Thorax (1999)

<h3>BACKGROUND</h3> There is an increase in vascularity in the asthmatic airway. Although inhaled corticosteroids (ICS) are an effective anti-inflammatory treatment in asthma, there are few data on any effects on structural changes. <h3>METHODS</h3> Endobronchial biopsy specimens from seven asthmatic subjects not receiving ICS and 15 receiving 200–1500 μg/day beclomethasone dipropionate (BDP) were immunohistochemically stained with an anti-collagen type IV antibody to outline the endothelial basement membrane of the vessels. These were compared with biopsy tissue from 11 non-asthmatic controls (four atopic and seven non-atopic). <h3>RESULTS</h3> There was a significant increase in the density of vessels (number of vessels/mm<sup>2</sup> of lamina propria) in the asthmatic subjects not on ICS compared with non-asthmatic controls (mean 485 (interquartile range (IQR) 390–597) versus 329 (IQR 248–376) vessels/mm<sup>2</sup>, p&lt;0.05; 95% CI for the difference 48 to 286). There was no significant difference between asthmatic subjects on ICS and those not on ICS or control subjects in the number of vessels/mm<sup>2</sup> (mean 421 (IQR 281–534)). However, patients who received ⩾800 μg/day BDP tended to have a reduced number of vessels/mm<sup>2</sup> compared with patients not on ICS and those receiving ⩽500 μg/day BDP (mean 366 (IQR 153–608) versus 494 (IQR 391–583), p = 0.08; 95% CI for the difference –31 to 288). Similarly, there was an increase in the percentage of lamina propria occupied by vessels in asthmatic patients not on ICS compared with controls (mean 15.6% (IQR 13.1–18.0) versus 10.1% (IQR 8.4–13.3), p&lt;0.01; 95% CI for the difference 2.4 to 9.3) but a significant decrease in the percentage of lamina propria occupied by vessels was detected in asthmatic patients on ICS (mean 11.4% (IQR 9.1–14.9), p&lt;0.01; 95% CI for the difference 0.7 to 7.7) compared with those not on ICS. The density of vessels correlated significantly with both airway hyperresponsiveness and percentage change in forced expiratory volume in one second (FEV<sub>1</sub>) after bronchodilator (<i>r</i> = –0.38 for PD<sub>20</sub> methacholine and <i>r</i> = 0.49 for change in percentage FEV<sub>1</sub> after bronchodilator versus number of vessels/mm<sup>2</sup>, p&lt;0.05). <h3>CONCLUSION</h3> These findings suggest that ICS, especially at higher doses, may reduce airway wall vascularity in asthmatic subjects but further longitudinal intervention studies are required to confirm this suggestion.
GOLD and the fixed ratio
Authors: J. Vestbo, R. Rodriguez-Roisin
Journal: European Respiratory Journal (2011)

to confidently predict which young adult smokers will develop clinically important COPD.Meanwhile, we do not think that assembling a panel of clinicians to attempt a consensus about the diagnosis of COPD in a number of cases will be useful.Establishing a diagnosis is a means to an end: intervention.Apart from smoking cessation, which is effective at any level of FEV1, the cost-effectiveness of COPD interventions when FEV1 is .60%pred remains very poor, and, thus, screening or case-finding for early COPD should not currently be performed [6].We are especially concerned for older persons who are classified as having COPD stage I, as such a designation may lead to inappropriate pharmacotherapy and delays in the consideration of other diagnoses, such as heart failure, which is common in older smokers [7].
Aggressive primary mediastinal non‐Hodgkin′s lymphomas: a study of 29 cases
Authors: B. Etienne, P.-H. Guillaud, R. Loire, B Coiffier, F Berger, J.-F. Cordier
Journal: European Respiratory Journal (1999)

Aggressive primary mediastinal non-Hodgkin's lymphomas (NHL) represent a particular entity among intrathoracic neoplasms. Twenty-nine patients with primary mediastinal aggressive NHL diagnosed and treated in the author's institution were studied. According to the Revised European-American Lymphoma (REAL) classification, there were 15 diffuse large B-cell, eight T-lymphoblastic, four anaplastic, one large T-cell and one Burkitt's lymphomas. The study group consisted of 14 females and 15 males, with a mean age of 38 yrs. Symptoms arose from an aggressive anterior mediastinal mass, with a high prevalence of superior vena caval syndrome, pleural, and pericardial effusions. At the time of diagnosis, disease was confined to supradiaphragmatic areas in 24 patients, while subdiaphragmatic nodal or extranodal involvement was also present in five. All patients received a combination of aggressive chemotherapy regimens, mainly according to the French protocols for the treatment of NHL. A chest radiograph response of <50% after the first course of chemotherapy and failure to achieve a complete remission after the first line of chemotherapy were significantly associated with unfavourable prognosis. Overall 5-yr and 9-yr survival rates were 55 and 48%, respectively. Patients properly diagnosed and treated with a combined modality of chemotherapy can experience prolonged survival.
Rhinitis is an independent risk factor for developing cough apart from colds among adults
Authors: S. Guerra, D. L. Sherrill, S. Baldacci, L. Carrozzi, F. Pistelli, F. Di Pede, G. Viegi
Journal: Allergy (2005)

In cross-sectional clinical studies, rhinitis has been shown to be strongly associated with co-existing chronic cough. However, to date, this association has been poorly delineated from a prospective and epidemiological standpoint.We used data from the 'Pisa Prospective Study', a population-based longitudinal cohort study composed of a baseline and a follow-up survey taken approximately 5 years apart from each other. Information on cough, rhinitis, and other risk factors was collected by standardized questionnaire. Cough apart from colds was defined as either 'chronic' (most days for at least 3 months for at least two consecutive years) or 'occasional' (if the three above temporal conditions were not met). 'Any' cough was defined as the presence of either occasional or chronic cough.Complete information was available for 1670 subjects who were > or =15 years old and had no positive history of cough apart from colds at the baseline survey. Among them, 299 (18%) had rhinitis at baseline. By the follow-up survey, 16% of the subjects with rhinitis had developed any cough apart from colds, as compared with only 10% of the subjects without rhinitis (OR 1.7, 95% CI 1.2-2.5, P < 0.005). After adjustment for age, gender, asthma status, smoking, and occupational exposure, rhinitis remained significantly associated with an increased risk both for any cough (OR 1.8, 95% CI 1.2-2.6) and for occasional and chronic cough separately (OR 2.2, 95% CI 1.1-4.5, and OR 1.7, 95% CI 1.1-2.6, respectively).Rhinitis is a significant and independent risk factor for developing cough among adults. Further research is needed to assess potential implications in terms of prevention.
A small-molecule IAP inhibitor overcomes resistance to cytotoxic therapies in malignant gliomas in vitro and in vivo
Authors: D. S. Ziegler, J. Keating, S. Kesari, E. M. Fast, L. Zawel, N. Ramakrishna, J. Barnes, M. W. Kieran, S. E. M. Veldhuijzen van Zanten, A. L. Kung
Journal: Neuro-Oncology (2011)

We tested the use of the small-molecule Inhibitor of Apoptosis Protein (IAP) inhibitor LBW242 in combination with the standard-of-care therapies of irradiation and temozolomide for malignant gliomas. In vitro assays demonstrated that LBW242 enhanced the cytotoxic activity of radiotherapy, and clonogenic assays showed that the combination therapy led to a synergistic anti-glioma effect in multiple cell lines. Neurosphere assays revealed that the combination of radiation and LBW242 led to a pro-apoptotic effect in these glioma–initiating cell-enriched assays, with a corresponding inhibition of primary tumor cell growth. Athymic mice bearing established human malignant glioma tumor xenografts treated with LBW242 plus radiation and temozolomide demonstrated a synergistic suppression of tumor growth. Taken together, these experiments show that the pro-apoptotic and anti-glioma effects of radiotherapy and chemotherapy can be enhanced by the addition of a small-molecule IAP inhibitor. These results are readily translatable to clinical trial and offer the potential for improved treatment outcomes for patients with glioma.
Comprehensive characterization of the cis-regulatory code responsible for the spatio-temporal expression of olSix3.2 in the developing medaka forebrain
Authors: Ivan Conte, Paola Bovolenta
Journal: Genome biology (2007)

Embryonic development is coordinated by sets of cis-regulatory elements that are collectively responsible for the precise spatio-temporal organization of regulatory gene networks. There is little information on how these elements, which are often associated with highly conserved noncoding sequences, are combined to generate precise gene expression patterns in vertebrates. To address this issue, we have focused on Six3, an important regulator of vertebrate forebrain development. Using computational analysis and exploiting the diversity of teleost genomes, we identified a cluster of highly conserved noncoding sequences surrounding the Six3 gene. Transgenesis in medaka fish demonstrates that these sequences have enhancer, silencer, and silencer blocker activities that are differentially combined to control the entire distribution of Six3. This report provides the first example of the precise regulatory code necessary for the expression of a vertebrate gene, and offers a unique framework for defining the interplay of trans-acting factors that control the evolutionary conserved use of Six3.
Plasma level of tumor necrosis factor in disseminated intravascular coagulation
Authors: Hideo Wada, Michiaki Ohiwa, Toshihiro Kaneko, Shigehisa Tamaki, Motoaki Tanigawa, Mikio Takagi, Yoshitaka Mori, Shigeru Shirakawa
Journal: American Journal of Hematology (1991)

Abstract The plasma level of tumor necrosis factor (TNF) was determined in 20 normal individuals, 52 patients with disseminated intravascular coagulation (DIC), 22 pre‐DIC patients, and 39 non‐DIC patients. TNF was not detected in the normal subjects, and the level was very low in non‐DIC patients. However, the TNF level was significantly elevated in DIC patients, and it was moderately increased in pre‐DIC patients shortly before the onset of DIC. This increase in circulating TNF may be associated with DIC. TNF was higher in DIC associated with solid cancer than in DIC associated with leukemia or sepsis. The increase in plasma TNF level was mildly correlated with DIC score, and it was significantly increased in patients with poor prognosis. However, the plasma TNF level in DIC patients with organ failure was not significantly different from those without organ failure. We conclude that the increase in circulating TNF reflects the pathogenic factors in DIC rather than being a consequence of organ failure due to DIC.
Endothelial cell storage and release of endothelin as a cardioregulatory mechanism.
Authors: G McClellan, A Weisberg, D Rose, S Winegrad
Journal: Circulation Research (1994)

Coronary vascular endothelial cells release substances into the coronary circulation that modify the contractile system of cardiac myocytes, and cardiac myocytes may release factors that modulate the secretion of cardioregulatory substances by endothelial cells. This regulatory loop is sensitive to the rate of coronary flow and tissue oxygen tension. In the present study, coronary venous effluent from isolated perfused hearts and the contents of the coronary vascular endothelial cells have been collected, the latter by disrupting the cells with coronary perfusion at high pressure. The relative amounts of upregulating and downregulating factors in both collections have been estimated by assaying their effects on the contractility of isolated cardiac trabeculas. The amount of upregulating factor stored in the endothelial cells is sensitive to the rate of coronary flow just before disruption of the cells. The quantity of endothelin in the coronary venous effluent and in the vascular endothelial cell contents was measured by radioimmunoassay and compared with the degree of upregulation of contractility produced by the two types of solutions. Upregulation was never produced in the absence of endothelin. The extent of the increase in contractility that was observed with endothelial cell contents correlated with the concentration of endothelin and was approximately the same as the increase in contractility from similar concentrations of endothelin added to standard Krebs' solution. The amount of the increase in contractility from coronary effluent could be accounted for by the concentration of endothelin in the effluent with the additional presence of some downregulating factor as well. The endothelin antagonist BQ123 inhibited the upregulation from coronary perfusate. It appears that endothelin alone can account for all of the upregulation of contractility produced by the vascular endothelial cells. Coronary flow, probably through shear forces, seems to regulate the production of endothelin possibly from an inactive precursor. Tissue oxygen tension appears to modulate the rate of release of the endothelin from endothelial cells though substances released by cardiac myocytes or other cells in the tissue. The downregulating factor is stored to a much smaller extent.
MR imaging techniques for nano-pathophysiology and theranostics
Authors: Kevin M. Bennett, Jun-ichiro Jo, Horacio Cabral, Rumiana Bakalova, Ichio Aoki
Journal: Advanced Drug Delivery Reviews (2014)

The advent of nanoparticle DDSs (drug delivery systems, nano-DDSs) is opening new pathways to understanding physiology and pathophysiology at the nanometer scale. A nano-DDS can be used to deliver higher local concentrations of drugs to a target region and magnify therapeutic effects. However, interstitial cells or fibrosis in intractable tumors, as occurs in pancreatic or scirrhous stomach cancer, tend to impede nanoparticle delivery. Thus, it is critical to optimize the type and size of nanoparticles to reach the target. High-resolution 3D imaging provides a means of "seeing" the nanoparticle distribution and therapeutic effects. We introduce the concept of "nano-pathophysiological imaging" as a strategy for theranostics. The strategy consists of selecting an appropriate nano-DDS and rapidly evaluating drug effects in vivo to guide the next round of therapy. In this article we classify nano-DDSs by component carrier materials and present an overview of the significance of nano-pathophysiological MRI.
Cori cycle activity in man
Authors: Christine Waterhouse, Julian Keilson
Journal: Journal of Clinical Investigation (1969)

12 subjects have been studied after an overnight fast with trace amounts of pyruvate-3-(14)C and glucose-6-(14)C. Blood disappearance curves and incorporation of the pyruvate-3-(14)C label into blood glucose have been determined. By the use of transfer functions which allow processes with many different chemical steps to be examined as a unit, we have determined the per cent of pyruvate and presumably lactate which is regenerated into glucose. 8 of the 12 subjects showed that 7-23 mg/kg per hr are recycled, while 4 subjects fell well outside this range. Correlation of increased activity was not good with any demonstrated metabolic abnormality (diabetes or obesity), and it is suggested from clinical observation of the subjects that anxiety may play a role.