tbuckley/cabot-search huggingface dataset:
Long-term Exposure to Black Carbon and Carotid Intima-Media Thickness: The Normative Aging Study
Authors: Elissa H. Wilker, Murray A. Mittleman, Brent A. Coull, Alexandros Gryparis, Michiel L. Bots, Joel Schwartz, David Sparrow
Journal: Environmental Health Perspectives (2013)

Background: Evidence suggests that air pollution is associated with atherosclerosis and that traffic-related particles are a particularly important contributor to the association.Objectives: We investigated the association between long-term exposure to black carbon, a correlate of traffic particles, and intima-media thickness of the common carotid artery (CIMT) in elderly men residing in the greater Boston, Massachusetts, area.Methods: We estimated 1-year average exposures to black carbon at the home addresses of Normative Aging Study participants before their first CIMT measurement. The association between estimated black carbon levels and CIMT was estimated using mixed effects models to account for repeated outcome measures. In secondary analyses, we examined whether living close to a major road or average daily traffic within 100 m of residence was associated with CIMT.Results: There were 380 participants (97% self-reported white race) with an initial visit between 2004 and 2008. Two or three follow-up CIMT measurements 1.5 years apart were available for 340 (89%) and 260 (68%) men, respectively. At first examination, the average ± SD age was 76 ± 6.4 years and the mean ± SD CIMT was 0.99 ± 0.18 mm. A one-interquartile range increase in 1-year average black carbon (0.26 µg/m3) was associated with a 1.1% higher CIMT (95% CI: 0.4, 1.7%) based on a fully adjusted model.Conclusions: Annual mean black carbon concentration based on spatially resolved exposure estimates was associated with CIMT in a population of elderly men. These findings support an association between long-term air pollution exposure and atherosclerosis.Citation: Wilker EH, Mittleman MA, Coull BA, Gryparis A, Bots ML, Schwartz J, Sparrow D. 2013. Long-term exposure to black carbon and carotid intima-media thickness: the Normative Aging Study. Environ Health Perspect 121:1061–1067; http://dx.doi.org/10.1289/ehp.1104845 [Online 2 July 2013]
Successful Aging: Focus on Cognitive and Emotional Health
Authors: Colin Depp, Ipsit V. Vahia, Dilip Jeste
Journal: Annual Review of Clinical Psychology (2010)

We review the definitions, predictors, and biobehavioral determinants of successful aging, as well as the evidence for and mechanisms of underlying selected interventions to enhance cognitive and emotional health in older adults. Defining successful aging has proven difficult, with discrepancies seen among biomedical, psychological, and lay perspectives. Although consensus is lacking, a number of studies have examined the genetic, lifestyle, and social determinants of operationalized determinants of successful aging; qualitative examinations of the meaning of the construct have also been conducted. The determinants coincide with fundamental aspects of aging. Recent clinical trials suggest that caloric restriction, physical activity, cognitive intervention, stress reduction, and social programs may enhance cognitive and emotional health in older people.
Determinants and Outcomes of Accelerated Arteriosclerosis
Authors: Alexandre Loupy, Dewi Vernerey, Denis Viglietti, Olivier Aubert, Jean-Paul Duong Van Huyen, Jean-Philippe Empana, Patrick Bruneval, Denis Glotz, Christophe Legendre, Xavier Jouven, Carmen Lefaucheur
Journal: Circulation Research (2015)

Rationale: The role of circulating antibodies in addition to traditional cardiovascular risk factors in the development of accelerated arteriosclerosis and their long-term clinical consequences have not been demonstrated. Objective: We investigated the role of circulating antibodies in accelerated arteriosclerosis and the role of immune-associated arteriosclerosis in graft and patient survival and the occurrence of major adverse cardiovascular events. Methods and Results: This was an observational prospective cohort study that included 1065 kidney transplant patients (principal cohort, n=744; validation cohort, n=321) between 2004 and 2010. Participants were assessed for traditional cardiovascular risk factors and circulating anti–human leukocyte antigen (HLA) antibodies. All patients underwent allograft biopsies to assess arteriosclerotic lesions and endothelial activation, endarteritis, and complement deposition. In the principal cohort, 250 (33.6%) patients had severe arteriosclerosis (luminal narrowing &gt;25% via fibrointimal arterial thickening). Circulating donor-specific anti-HLA antibodies were significantly associated with severe allograft arteriosclerosis (hazard ratio, 2.9; P &lt;0.0001), independently of traditional risk factors. Patients with severe arteriosclerosis and anti-HLA antibodies (n=91, 12.2%) demonstrated allograft endothelial activation, endarteritis, and complement deposition. High levels of anti-HLA antibodies and their complement binding capacity were associated with increased severity of arteriosclerosis. Patients with antibody-associated severe arteriosclerosis had decreased allograft survival and increased mortality ( P &lt;0.0001); they exhibited a 2.5- and 4.1-fold increased risk of major adverse cardiovascular events compared with patients who had severe arteriosclerosis without antibodies and patients with minimal arteriosclerosis, respectively ( P &lt;0.0005). Circulating donor-specific anti-HLA antibodies were significantly associated with occurrence of major adverse cardiovascular events (hazard ratio, 2.4; P =0.0004), independently of traditional risk factors. Conclusions: Circulating antibodies are major determinants of severe arteriosclerosis and major adverse cardiovascular events, independent of traditional cardiovascular risk factors.
Classifying an unpredictable disease: the revised Atlanta classification of acute pancreatitis
Authors: Markus M Lerch
Journal: Gut (2012)

Pancreatitis is among the most variable diseases known to us, and is the number 1 benign disorder leading to hospital admission.1 Its natural history ranges from complete recovery after a single episode, to chronic debilitating disease over decades, to rapid death. In acute pancreatitis, the problem of unpredictability is compounded because 80% of patients with mild pancreatitis require only short hospital admissions and little in terms of resources. The remaining 20% with severe pancreatitis will have to be triaged to either aggressive early treatment, transfer to intensive care, or referral to tertiary specialist centres. When evidence emerged that certain clinical and diagnostic imaging characteristics allow to distinguish mild from severe pancreatitis on hospital admission, severity classifications of pancreatitis were introduced. The earliest such efforts date back half a century,2 but a better understanding of the natural history and refinements in diagnostic tools required updates roughly every decade. The most widely accepted such systems were the Marseille classification of 19843 and the Atlanta classification of 1992.4 A revision of the Atlanta classification has now been accomplished and appears in this issue of Gut .5

The genesis of pancreatitis is interesting. Rather than withdrawing to a secluded but sunny location for a meeting of world experts, or using the established instruments of evidence-based medicine with their formalised literature search and consensus-finding tools, the authors have chosen a web-based consensus-building approach. They first considered required revisions to the original Atlanta classification, composed an initial draft, and distributed it through the email lists of 11 international pancreas societies. Their initial call for suggestions and corrections was answered by 40 respondents, the second call by 57 and the third by 58 more. When the draft was put on the internet, while falling short of going viral, it not only led …
The Translational Research Working Group Developmental Pathway for Lifestyle Alterations
Authors: Ernest T. Hawk, Addison Greenwood, Ellen R. Gritz, Anne McTiernan, Thomas Sellers, Stephen D. Hursting, Scott Leischow, Oren Grad
Journal: Clinical Cancer Research (2008)

Abstract The Translational Research Working Group (TRWG) was created as a national initiative to evaluate the current status of National Cancer Institute's investment in translational research and envision its future. The TRWG conceptualized translational research as a set of six developmental processes or pathways focused on various clinical goals. One of those pathways describes the development of lifestyle alterations, which can, variously, be recommended to prevent cancer, modify a patient's adherence and response to cancer treatment, ameliorate side effects of cancer treatments, or improve prognosis and quality of life in cancer patients and survivors. The lifestyle alteration pathway was conceived not as a comprehensive description of the corresponding real-world processes, but rather as a tool designed to facilitate movement of a candidate lifestyle alteration through the translational process up to the point where it could be handed off for definitive testing, when appropriate. This article discusses key issues associated with the development of lifestyle alterations in light of the pathway.
The ubiquitin-proteasome system in cardiac proteinopathy: a quality control perspective
Authors: H. Su, X. Wang
Journal: Cardiovascular Research (2009)

Protein quality control (PQC) depends on elegant collaboration between molecular chaperones and targeted proteolysis in the cell. The latter is primarily carried out by the ubiquitin-proteasome system, but recent advances in this area of research suggest a supplementary role for the autophagy-lysosomal pathway in PQC-related proteolysis. The (patho)physiological significance of PQC in the heart is best illustrated in cardiac proteinopathy, which belongs to a family of cardiac diseases caused by expression of aggregation-prone proteins in cardiomyocytes. Cardiac proteasome functional insufficiency (PFI) is best studied in desmin-related cardiomyopathy, a bona fide cardiac proteinopathy. Emerging evidence suggests that many common forms of cardiomyopathy may belong to proteinopathy. This review focuses on examining current evidence, as it relates to the hypothesis that PFI impairs PQC in cardiomyocytes and contributes to the progression of cardiac proteinopathies to heart failure.
Tumor-Specific Activation of an EGFR-Targeting Probody Enhances Therapeutic Index
Authors: Luc R. Desnoyers, Olga Vasiljeva, Jennifer H. Richardson, Annie Yang, Elizabeth E. M. Menendez, Tony W. Liang, Chihunt Wong, Paul H. Bessette, Kathy Kamath, Stephen J. Moore, Jason G. Sagert, Daniel R. Hostetter, Fei Han, Jason Gee, Jeanne Flandez, Kate Markham, Margaret Nguyen, Michael Krimm, Kenneth R. Wong, Shouchun Liu, Patrick S. Daugherty, James W. West, Henry B. Lowman
Journal: Science Translational Medicine (2013)

A proteolytically activatable EGFR Probody demonstrates antitumor efficacy while alleviating toxicity.
Association between C-reactive protein levels and outcome in acute lung injury in children
Authors: Martijn Bruijn, Eva Jansen, Thom Klapwijk, Johanna van der Lee, Rick van Rijn, Job van Woensel, Albert Bos
Journal: European Respiratory Journal (2011)

Background: Acute lung injury (ALI) is a life threatening condition affecting both children and adults. High plasma C-reactive protein (CRP) levels are associated with favorable outcome in adults with ALI, suggesting a protective physiological effect of high CRP levels. The association between CRP levels and outcome has not been studied in ALI in children.

Aim: We hypothesized that increased plasma CRP levels are associated with favorable outcome in ALI in children in terms of 28-day mortality and ventilator free days (VFD).

Methods: We performed a historical cohort study in 98 mechanically ventilated children (0-18 years) with ALI. The CRP level within 48 hours of disease onset was tested for association with mortality and VFD. Clinical parameters and ventilator settings were evaluated for possible confounding.

Results: Fourteen patients (14%) died within 28 days. The median (Q1;Q3) CRP level in non-survivors was 126 mg/L (64;187) compared to 56 mg/L (20;105) in survivors (p=0.01). For every 10 mg/L rise in CRP level, the unadjusted odds for mortality increased 8.7% (95% CI 2.1%-15.8%). Cardiovascular organ failure (CVOF) at onset of ALI was the strongest predictor for mortality (OR 30.5, 95% CI 6.2-152.5). After adjustment for CVOF, for every 10 mg/L rise in CRP level, the odds for mortality increased 5.0% (95% CI -2.7%-12.6%). Increased CRP levels were associated with a decrease in VFD (ρ -0.26, p=0.01).

Conclusion: We conclude that increased plasma CRP levels are not associated with favorable outcome in ALI in children. Based on our findings and existing evidence that pathophysiology in ALI in adults and children differ, we suggest future research should take these differences into consideration.
Prolonged Single-Agent Versus Combination Chemotherapy in Indolent Follicular Lymphomas: A Study of the Cancer and Leukemia Group B
Authors: Bruce A. Peterson, Gina R. Petroni, Glauco Frizzera, Maurice Barcos, Clara D. Bloomfield, Nis I. Nissen, David D. Hurd, Edward S. Henderson, George P. Sartiano, Jeffrey L. Johnson, James F. Holland, Arlan J. Gottlieb
Journal: Journal of Clinical Oncology (2002)

Purpose: The array of options for the initial management of follicular small cleaved lymphoma (FSCL) and follicular mixed lymphoma (FML) ranges from little or no therapy to the use of intensive combinations of drugs. The Cancer and Leukemia Group B (CALGB) compared two contrasting approaches: a single agent, and combination chemotherapy capable of curing diffuse aggressive lymphomas. Patients and Methods: A total of 228 patients with stage III or IV FSCL or FML were randomized to cyclophosphamide or the combination of cyclophosphamide, doxorubicin, vincristine, prednisone, and bleomycin (CHOP-B). Treatment was continued in responders for 2 years beyond maximal response. The primary end point was survival in the most common subtype, FSCL. Results: Ninety-one percent of all patients responded; complete responses were seen in 66% of those treated with cyclophosphamide and in 60% treated with CHOP-B (P = .36). At 10 years with either cyclophosphamide or CHOP-B, respectively, overall time to failure (25% failure free v 33%; P = .107) and survival (44% alive v 46%; P = .79) were similar by treatment. Outcomes in FSCL also were similar. In 46 patients with FML, at 10 years the combination was associated with better failure-free (9% v 48%; P = .005) and overall (25% v 61%; P = .024) survival. Acute toxic effects were more common with combination chemotherapy. Second malignancies, which might be attributed to treatment, were seen with both approaches. Conclusion: There is no advantage to the initial use of the relatively intensive combination, CHOP-B, for patients with FSCL compared with the less toxic single agent, cyclophosphamide. However, in an unplanned subgroup analysis, patients with FML who received the combination experienced improved disease control and survival.
The temporal evolution of antidrug antibodies in patients with inflammatory bowel disease treated with infliximab
Authors: Bella Ungar, Yehuda Chowers, Miri Yavzori, Orit Picard, Ella Fudim, Ofir Har-Noy, Uri Kopylov, Rami Eliakim, Shomron Ben-Horin
Journal: Gut (2013)

<h3>Objective</h3> To characterise the temporal evolution of antibodies to infliximab (ATI). <h3>Design</h3> Prospective observational study of infliximab-treated patients with inflammatory bowel disease between 2009 and 2012. <h3>Interventions</h3> Trough levels of infliximab and ATI were measured before each infusion by anti-λ ELISA. Patients were monitored for disease activity by clinical activity indexes and for dose-intensification or infliximab cessation. The occurrence of transient ATI disappearing spontaneously without intervention was recorded separately. <h3>Results</h3> 125 patients were included (98 Crohn9s disease, 27 ulcerative colitis, median follow-up 11.5±22 months) and 1119 sera were analysed for infliximab and ATI levels. Kaplan-Meier analysis showed that 42% of patients remained ATI-free by 4 years of treatment. Most (90%) of the patients who developed ATI did so within the first 12 months of therapy, whereas transient ATI were detected throughout the duration of infliximab therapy (p&lt;0.001). ATI incidence was similar between patients who received infliximab previously (episodic/interrupted therapy patients, n=14) and scheduled-therapy patients (n=111). In the scheduled group, combination immunomodulator+infliximab resulted in longer ATI-free survival compared with monotherapy (p=0.003, logrank test). Survival free of clinical loss of response was enjoyed by 51% of patients, and serial measurements showed that ATI development often preceded the onset of clinical flare. <h3>Conclusions</h3> When followed prospectively, most patients who develop ATI do so within the first 12 months of therapy. This incidence is reduced by concomitant immunomodulator even in scheduled-therapy patients. In contrast, transient ATI, which are of little clinical significance, can appear haphazardly at any time during treatment. The onset of clinical loss of response may lag behind the appearance of anti-infliximab antibodies.
653 IMPROVEMENT OF LIPID AND GLUCOSE HOMEOSTASIS IN HEPATITIS C BY BRANCHED CHAIN AMINO ACIDS (BCAA): ANALYSIS USING ANIMAL MODEL
Authors: K. Moriya, H. Miyoshi, S. Shinzawa, T. Tsutsumi, H. Fujie, Y. Shintani, K. Goto, H. Fujinaga, H. Yotsuyanagi, K. Koike
Journal: Journal of Hepatology (2010)
Nerve growth factor enhances cough and airway obstruction via TrkA receptor- and TRPV1-dependent mechanisms
Authors: A Z El-Hashim, S M Jaffal
Journal: Thorax (2009)

<h3>Background:</h3> Nerve growth factor (NGF) is an important mediator of airway hyper-responsiveness and hyperalgesia but its role in cough is unknown. <h3>Objectives:</h3> In this study the effects of NGF on the cough reflex and airway calibre were investigated in guinea pigs. The involvement of the tropomyosin-related kinase A (TrkA) receptor and transient receptor potential vanilloid-1 (TRPV1), and the p38 mitogen-activated protein kinase (MAPK)-dependent pathway in any NGF-induced effects on cough and airway obstruction was also assessed. <h3>Methods:</h3> Guinea pigs were placed in a transparent whole-body plethysmograph box. Cough was assessed visually, acoustically and by analysis of the airflow signal. Airway obstruction was measured using enhanced pause (Penh) as an index. <h3>Results:</h3> Exposure of guinea pigs to NGF did not induce a cough response nor a significant airway obstruction. However, exposure of guinea pigs to NGF immediately before citric acid inhalation resulted in a significant increase in the citric acid-induced cough and airway obstruction compared with vehicle-treated animals. Pretreatment with the TrkA receptor antagonist, K252a, or the TRPV1 antagonist, iodoresiniferatoxin, significantly inhibited the NGF-enhanced cough and airway obstruction. Exposure to NGF also increased p38 MAPK phosphorylation, but pretreatment with the p38 MAPK inhibitor, SB203580, did not affect either the NGF-enhanced cough or airway obstruction despite preventing the NGF-induced elevation in p38 MAPK phosphorylation. <h3>Conclusions:</h3> The data show that NGF can enhance both cough and airway obstruction via a mechanism that involves the activation of the TrkA receptor and TRPV1 but not the p38 MAPK-dependent pathway.
Shigella enterotoxin 1: an enterotoxin of Shigella flexneri 2a active in rabbit small intestine in vivo and in vitro.
Authors: A Fasano, F R Noriega, D R Maneval, S Chanasongcram, R Russell, S Guandalini, M M Levine
Journal: Journal of Clinical Investigation (1995)

Culture filtrates of Shigella flexneri 2a strain M4243 grown in iron-depleted medium, caused significant fluid accumulation in rabbit ileal loops. Also, when tested in Ussing chambers, a greater rise in potential difference and short circuit current was seen with such filtrates compared with the medium control. Analogous filtrates from two M4243 derivatives lacking the 140-MD invasiveness plasmid (either M4243avir or BS103) retained 60-65% of the wild-type enterotoxic activity. Ultrafiltration and gel exclusion size fractionation of M4243 filtrate revealed that the activity was approximately 60 kD. SDS-PAGE performed on this fraction showed 18 bands, 5 of which reacted with human convalescent sera. Genes encoding this enterotoxin, named ShET1 for Shigella enterotoxin 1, were cloned from the S. flexneri 2a chromosome, and two separate open reading frames of 534 and 186 bp were sequenced. These observations suggest that S. flexneri 2a elaborates two distinct enterotoxins: ShET1, encoded by genes located on the chromosome, and ShET2, encoded by a gene on the 140-MD invasiveness plasmid. ShET1, which is composed of two distinct subunits and is elaborated in vivo, where it elicits an immune response, may be important in the pathogenesis of diarrheal illness due to S. flexneri 2a.
Intracellular pH in human arterial smooth muscle. Regulation by Na+/H+ exchange and a novel 5-(N-ethyl-N-isopropyl)amiloride-sensitive Na(+)- and HCO3(-)-dependent mechanism.
Authors: C B Neylon, P J Little, E J Cragoe, A Bobik
Journal: Circulation Research (1990)

We investigated in a physiological salt solution (PSS) containing HCO3- the intracellular pH (pHi) regulating mechanisms in smooth muscle cells cultured from human internal mammary arteries, using the pH-sensitive dye 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF) and 22Na+ influx rates. The recovery of pHi from an equivalent intracellular acidosis was more rapid when the cells were incubated in CO2/HCO3(-)-buffered PSS than in HEPES-buffered PSS. Recovery of pHi was dependent on extracellular Na+ (Km, 13.1 mM); however, it was not attenuated by 4-acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic acid (SITS), indicating the absence of SITS-sensitive HCO3(-)-dependent mechanisms. Recovery instead appeared mostly dependent on processes sensitive to 5-(N-ethyl-N-isopropyl)amiloride (EIPA), indicating the involvement of Na+/H+ exchange and a previously undescribed EIPA-sensitive Na(+)- and HCO3(-)-dependent mechanism. Differentiation between this HCO3(-)-dependent mechanism and Na+/H+ exchange was achieved after depletion of cellular ATP. Under these conditions, the NH4Cl-induced 22Na+ influx rate stimulated by intracellular acidosis was markedly attenuated in HEPES-buffered PSS but not in CO2/HCO3(-)-buffered PSS. EIPA also appeared to inhibit the two mechanisms differentially. In HEPES-buffered PSS containing 20 mM Na+, the EIPA inhibition curve for the intracellular acidosis-induced 22Na+ influx was monophasic (IC50, 39 nM), whereas in an identical CO2/HCO3(-)-buffered PSS, the inhibition curve exhibited biphasic characteristics (IC50, 37.3 nM and 312 microM). Taken together, the results indicate that Na+/H+ exchange and a previously undescribed EIPA-sensitive Na(+)- and HCO3(-)-dependent mechanism play an important role in regulating the pHi of human vascular smooth muscle. The involvement of the latter mechanism depends on the severity of the intracellular acidosis, varying from approximately 25% in severe intracellular acidosis up to 50% at lesser, more physiological, levels of induced acidosis.