tbuckley/cabot-search huggingface dataset:
Sensitivity and Specificity of a Single Emergency Department Measurement of Urinary Neutrophil Gelatinase–Associated Lipocalin for Diagnosing Acute Kidney Injury
Authors: Thomas L. Nickolas, Matthew J. O'Rourke, Jun Yang, Meghan E. Sise, Pietro A. Canetta, Nicholas Barasch, Charles Buchen, Faris Khan, Kiyoshi Mori, James Giglio, Prasad Devarajan, Jonathan Barasch
Journal: Annals of Internal Medicine (2008)

Background: A single serum creatinine measurement cannot distinguish acute kidney injury from chronic kidney disease or prerenal azotemia. Objective: To test the sensitivity and specificity of a single measurement of urinary neutrophil gelatinase–associated lipocalin (NGAL) and other urinary proteins to detect acute kidney injury in a spectrum of patients. Design: Prospective cohort study. Setting: Emergency department of Columbia University Medical Center, New York, New York. Participants: 635 patients admitted to the hospital with acute kidney injury, prerenal azotemia, chronic kidney disease, or normal kidney function. Measurements: Diagnosis of acute kidney injury was based on the RIFLE (risk, injury, failure, loss, and end-stage) criteria and assigned by researchers who were blinded to experimental measurements. Urinary NGAL was measured by immunoblot, N-acetyl-β-d-glucosaminidase (NAG) by enzyme measurement, α1-microglobulin and α1-acid glycoprotein by immunonephelometry, and serum creatinine by Jaffe kinetic reaction. Experimental measurements were not available to treating physicians. Results: Patients with acute kidney injury had a significantly elevated mean urinary NGAL level compared with the other kidney function groups (416 µg/g creatinine [SD, 387]; P = 0.001). At a cutoff value of 130 µg/g creatinine, sensitivity and specificity of NGAL for detecting acute injury were 0.900 (95% CI, 0.73 to 0.98) and 0.995 (CI, 0.990 to 1.00), respectively, and positive and negative likelihood ratios were 181.5 (CI, 58.33 to 564.71) and 0.10 (CI, 0.03 to 0.29); these values were superior to those for NAG, α1-microglobulin, α1-acid glycoprotein, fractional excretion of sodium, and serum creatinine. In multiple logistic regression, urinary NGAL level was highly predictive of clinical outcomes, including nephrology consultation, dialysis, and admission to the intensive care unit (odds ratio, 24.71 [CI, 7.69 to 79.42]). Limitations: All patients came from a single center. Few kidney biopsies were performed. Conclusion: A single measurement of urinary NGAL helps to distinguish acute injury from normal function, prerenal azotemia, and chronic kidney disease and predicts poor inpatient outcomes.
Activating Transcription Factor 3 and Early Growth Response 1 Are the Novel Targets of LY294002 in a Phosphatidylinositol 3-Kinase–Independent Pathway
Authors: Kiyoshi Yamaguchi, Seong-Ho Lee, Jong-Sik Kim, Jay Wimalasena, Shigetaka Kitajima, Seung Joon Baek
Journal: Cancer Research (2006)

Abstract LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor, has been widely used to study the function of PI3K in cellular responses. Based on its inhibitory effect on PI3K, LY294002 has been shown to exert antitumorigenic effect in vivo and in vitro. Here, we report that LY294002 alters early growth response 1 (EGR-1) phosphorylation and subsequently enhances activating transcription factor 3 (ATF3) expression independently of PI3K inhibition. This pathway may be, in part, responsible for the antitumorigenic effect of LY294002 in human colorectal cancer cells. ATF3 expression was increased by LY294002, followed by the induction of apoptosis in several colorectal cancer cell lines. This is consistent with results showing that the down-regulation of the ATF3 gene by small interfering RNA suppressed LY294002-induced apoptosis in HCT-116 cells. On the other hand, ATF3 expression was not affected by another PI3K inhibitor, wortmannin, as well as phosphatase and tensin homologue or dominant-negative Akt overexpression. We also found that LY294002 increases ATF3 promoter activity and the transactivation is partly mediated by a GC-rich sequence located in the promoter. EGR-1 binds to the ATF3 promoter as assessed by gel shift assay. Furthermore, phosphorylated EGR-1 was highly increased in LY294002-treated cells, indicating that EGR-1 phosphorylation induced by LY294002 may facilitate ATF3 transactivation. Our data suggest that EGR-1 acts as a mediator in LY294002-induced ATF3 expression via a PI3K-independent pathway. ATF3 and EGR-1 may provide a novel explanation for the antitumorigenic properties of LY294002 in human colorectal cancer cells. (Cancer Res 2006; 66(4): 2376-84)
Function of immunoglobulin A in immunity
Authors: M A KERR
Journal: Gut (2000)

Despite the well-recognized involvement of immunoglobulin (Ig) A in mucosal immunity, the function of its receptor, Fc RI (CD89), is poorly understood.The ability of Fc RI to activate leukocytes seems to conflict with the proposed anti-inflammatory activity of secretory IgA.We show here that in a transgenic mouse model, inflammatory mediators induced expression of Fc RI on KupVer cells, which enabled eYcient phagocytosis in vivo of bacteria coated with serum IgA.Secretory IgA did not initiate phagocytosis.Therefore, interactions between serum IgA and Fc RI on KupVer cells may provide a 'second line of defense' in mucosal immunity, by eliminating invasive bacteria entering through the portal circulation and thus preventing disease.
THE POLITICS OF PUBLIC HEALTH POLICY
Authors: Thomas R. Oliver
Journal: Annual Review of Public Health (2005)

Politics, for better or worse, plays a critical role in health affairs. The purpose of this article is to articulate a role for political analysis of public health issues, ranging from injury and disease prevention to health care reform. It begins by examining how health problems make it onto the policy agenda. Perceptions regarding the severity of the problem, responsibility for the problem, and affected populations all influence governmental responses. Next, it considers how bounded rationality, fragmented political institutions, resistance from concentrated interests, and fiscal constraints usually lead political leaders to adopt incremental policy changes rather than comprehensive reforms even when faced with serious public health problems. It then identifies conditions under which larger-scale transformation of health policy can occur, focusing on critical junctures in policy development and the role of policy entrepreneurs in seizing opportunities for innovation. Finally, it reviews the challenges confronting officials and agencies who are responsible for implementing and administering health policies. Public health professionals who understand the political dimensions of health policy can conduct more realistic research and evaluation, better anticipate opportunities as well as constraints on governmental action, and design more effective policies and programs.
Insulin Degludec in Type 1 Diabetes
Authors: Kåre I. Birkeland, Philip D. Home, Ulrich Wendisch, Robert E. Ratner, Thue Johansen, Lars A. Endahl, Karsten Lyby, Johan H. Jendle, Anthony P. Roberts, J. Hans DeVries, Luigi F. Meneghini
Journal: Diabetes Care (2011)

Insulin degludec (IDeg) is a basal insulin that forms soluble multihexamers after subcutaneous injection, resulting in an ultra-long action profile. We assessed the efficacy and safety of IDeg formulations administered once daily in combination with mealtime insulin aspart in people with type 1 diabetes.In this 16-week, randomized, open-label trial, participants (mean: 45.8 years old, A1C 8.4%, fasting plasma glucose [FPG] 9.9 mmol/L, BMI 26.9 kg/m(2)) received subcutaneous injections of IDeg(A) (600 μmol/L; n = 59), IDeg(B) (900 μmol/L; n = 60), or insulin glargine (IGlar; n = 59), all given once daily in the evening. Insulin aspart was administered at mealtimes. RESULTS At 16 weeks, mean A1C was comparable for IDeg(A) (7.8 ± 0.8%), IDeg(B) (8.0 ± 1.0%), and IGlar (7.6 ± 0.8%), as was FPG (8.3 ± 4.0, 8.3 ± 2.8, and 8.9 ± 3.5 mmol/L, respectively). Estimated mean rates of confirmed hypoglycemia were 28% lower for IDeg(A) compared with IGlar (rate ratio [RR]: 0.72 [95% CI 0.52-1.00]) and 10% lower for IDeg(B) compared with IGlar (RR: 0.90 [0.65-1.24]); rates of nocturnal hypoglycemia were 58% lower for IDeg(A) (RR: 0.42 [0.25-0.69]) and 29% lower for IDeg(B) (RR: 0.71 [0.44-1.16]). Mean total daily insulin dose was similar to baseline. The frequency and pattern of adverse events was similar between insulin treatments.In this clinical exploratory phase 2 trial in people with type 1 diabetes, IDeg is safe and well tolerated and provides comparable glycemic control to IGlar at similar doses, with reduced rates of hypoglycemia.
Reactivation of cutaneous leishmaniasis after surgery
Authors: R.T. Czechowicz, T.P. Millard, H.R. Smith, R.E. Ashton, S.B. Lucas, R.J. Hay
Journal: British Journal of Dermatology (1999)

Cutaneous leishmaniasis (CL) is caused by a parasite from the genus Leishmania. Infection is transmitted to humans from the bite of sandflies. We describe an 85‐year‐old man who developed CL on his face after recent cutaneous surgery in that site. The case is also unusual because the most likely source of exposure to the infection occurred over 50 years previously. Polymerase chain reaction, slit‐skin smear, serology and the leishmanin test were not helpful in diagnosis, which was confirmed by histopathological demonstration of the parasite.
Associations Among Volatile Organic Compounds, Allergic Sensitization, and Respiratory Illness In Children With Asthma Enrolled In a Study Of Low-Income, Green Eco-Friendly Housing (The Green Housing Study)
Authors: Joy Hsu, Sandra Chaves, Marika Iwane, Yang Qiu, Christopher Schaffer, Marty Alvarez-Reeves, Tiina Reponen, Gary Adamkiewicz, Patrick Ryan, Doug Brugge, David Turcotte, Fuyuen Yip, Kanta Sircar, Benjamin Blount, K. Udeni Alwis, Connie Sosnoff, Peter Ashley, Curtis Hedman, Steve Strebel, Behrooz Behbod, Matthew Lozier, Ginger L. Chew
Journal: Journal of Allergy and Clinical Immunology (2014)
Hydrogen Peroxide-Mediated Cytosolic Acidification Is a Signal for Mitochondrial Translocation of Bax during Drug-Induced Apoptosis of Tumor Cells
Authors: Kashif A. Ahmad, Kartini B. Iskandar, Jayshree L. Hirpara, Marie-Veronique Clement, Shazib Pervaiz
Journal: Cancer Research (2004)

Abstract Absence of the proapoptotic protein Bax renders tumor cells resistant to drug-induced apoptosis. We have shown that hydrogen peroxide (H2O2)-mediated cytosolic acidification is an effector mechanism during drug-induced apoptosis of tumor cells. Here, we report that Bax is critical in determining the sensitivity of tumor cells to H2O2-induced apoptosis. More importantly, exposure of colorectal carcinoma (HCT116) and leukemia cells (HL60 and CEM) to H2O2 or its intracellular production during drug-induced apoptosis is a signal for mitochondrial translocation of Bax. Furthermore, we provide evidence that drug-induced H2O2-mediated Bax translocation in tumor cells is caspase independent but involves cytosolic acidification. Inhibiting cytosolic acidification prevents Bax translocation, and contrarily enforced acidification of the intracellular milieu results in mitochondrial recruitment of Bax, even in the absence of a trigger. These findings provide a novel mechanism for mitochondrial translocation of Bax and directly implicate H2O2-mediated cytosolic acidification in the recruitment of the mitochondrial pathway during drug-induced apoptosis of tumor cells.
An Endoplasmic Reticulum Retention Function for the Cytoplasmic Tail of the Human Pre–T Cell Receptor (Tcr) α Chain
Authors: Yolanda R. Carrasco, Almudena R. Ramiro, César Trigueros, Virginia G. de Yébenes, Marina García-Peydró, María L. Toribio
Journal: The Journal of Experimental Medicine (2001)

The pre-T cell receptor (TCR), which consists of a TCR-β chain paired with pre–TCR-α (pTα) and associated with CD3/ζ components, is a critical regulator of T cell development. For unknown reasons, extremely low pre-TCR levels reach the plasma membrane of pre-T cells. By transfecting chimeric TCR-α–pTα proteins into pre-T and mature T cell lines, we show here that the low surface expression of the human pre-TCR is pTα chain dependent. Particularly, the cytoplasmic domain of pTα is sufficient to reduce surface expression of a conventional TCR-α/β to pre-TCR expression levels. Such reduced expression cannot be attributed to qualitative differences in the biochemical composition of the CD3/ζ modules associated with pre-TCR and TCR surface complexes. Rather, evidence is provided that the pTα cytoplasmic tail also causes a reduced surface expression of individual membrane molecules such as CD25 and CD4, which are shown to be retained in the endoplasmic reticulum (ER). Native pTα is also observed to be predominantly ER localized. Finally, sequential truncations along the pTα cytoplasmic domain revealed that removal of the COOH-terminal 48 residues is sufficient to release a CD4-pTα chimera from ER retention, and to restore native CD4 surface expression levels. As such a truncation in pTα also correlates with enhanced pre-TCR expression, the observed pTα ER retention function may contribute to the regulation of surface pre-TCR expression on pre-T cells.
Genome-wide Association Identifies the <i>T</i> Gene as a Novel Asthma Pharmacogenetic Locus
Authors: Kelan G. Tantisira, Amy Damask, Stanley J. Szefler, Brooke Schuemann, Amy Markezich, Jessica Su, Barbara Klanderman, Jody Sylvia, Rongling Wu, Fernando Martinez, Homer A. Boushey, Vernon M. Chinchilli, Dave Mauger, Scott T. Weiss, Elliot Israel
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

To date, most studies aimed at discovering genetic factors influencing treatment response in asthma have focused on biologic candidate genes. Genome-wide association studies (GWAS) can rapidly identify novel pharmacogenetic loci.To investigate if GWAS can identify novel pharmacogenetic loci in asthma.Using phenotypic and GWAS genotype data available through the NHLBI-funded Single-nucleotide polymorphism Health association-Asthma Resource Project, we analyzed differences in FEV(1) in response to inhaled corticosteroids in 418 white subjects with asthma. Of the 444,088 single nucleotide polymorphisms (SNPs) analyzed, the lowest 50 SNPs by P value were genotyped in an independent clinical trial population of 407 subjects with asthma.The lowest P value for the GWAS analysis was 2.09 × 10(-6). Of the 47 SNPs successfully genotyped in the replication population, three were associated under the same genetic model in the same direction, including two of the top four SNPs ranked by P value. Combined P values for these SNPs were 1.06 × 10(-5) for rs3127412 and 6.13 × 10(-6) for rs6456042. Although these two were not located within a gene, they were tightly correlated with three variants mapping to potentially functional regions within the T gene. After genotyping, each T gene variant was also associated with lung function response to inhaled corticosteroids in each of the trials associated with rs3127412 and rs6456042 in the initial GWAS analysis. On average, there was a twofold to threefold difference in FEV(1) response for those subjects homozygous for the wild-type versus mutant alleles for each T gene SNP.Genome-wide association has identified the T gene as a novel pharmacogenetic locus for inhaled corticosteroid response in asthma.
Efficacy and Safety of Varenicline for Smoking Cessation in Patients With Cardiovascular Disease
Authors: Nancy A. Rigotti, Andrew L. Pipe, Neal L. Benowitz, Carmen Arteaga, Dahlia Garza, Serena Tonstad
Journal: Circulation (2010)

Background— Smoking cessation is a key component of secondary cardiovascular disease prevention. Varenicline, a partial α4β2 nicotinic acetylcholine receptor agonist, is effective for smoking cessation in healthy smokers, but its efficacy and safety in smokers with cardiovascular disease are unknown. Methods and Results— A multicenter, randomized, double-blind, placebo-controlled trial compared the efficacy and safety of varenicline with placebo for smoking cessation in 714 smokers with stable cardiovascular disease. Participants received varenicline (1 mg twice daily) or placebo, along with smoking-cessation counseling, for 12 weeks. Follow-up lasted 52 weeks. The primary end point was carbon monoxide-confirmed continuous abstinence rate for weeks 9 through 12 (last 4 weeks of treatment). The continuous abstinence rate was higher for varenicline than placebo during weeks 9 through 12 (47.0% versus 13.9%; odds ratio, 6.11; 95% confidence interval [CI], 4.18 to 8.93) and weeks 9 through 52 (19.2% versus 7.2%; odds ratio, 3.14; 95% CI, 1.93 to 5.11). The varenicline and placebo groups did not differ significantly in cardiovascular mortality (0.3% versus 0.6%; difference, −0.3%; 95% CI, −1.3 to 0.7), all-cause mortality (0.6% versus 1.4%; difference, −0.8%; 95% CI, −2.3 to 0.6), cardiovascular events (7.1% versus 5.7%; difference, 1.4%; 95% CI, −2.3 to 5.0), or serious adverse events (6.5% and 6.0%; difference, 0.5%; 95% CI, −3.1 to 4.1). As a result of adverse events, 9.6% of varenicline and 4.3% of placebo participants discontinued study drug. Conclusions— Varenicline is effective for smoking cessation in smokers with cardiovascular disease. It was well tolerated and did not increase cardiovascular events or mortality; however, trial size and duration limit definitive conclusions about safety. Clinical Trial Registration Information— URL: http://www.clinicaltrials.gov/ct2/show/NCT00282984. Unique identifier: NCT00282984.
Preventive therapy for breast cancer: a consensus statement
Authors: Jack Cuzick, Andrea DeCensi, Banu Arun, Powel H Brown, Monica Castiglione, Barbara Dunn, John F Forbes, Agnes Glaus, Anthony Howell, Gunter von Minckwitz, Victor Vogel, Heinz Zwierzina
Journal: The Lancet Oncology (2011)
mRNA deadenylation and telomere disease
Authors: Philip J. Mason, Monica Bessler
Journal: Journal of Clinical Investigation (2015)

Dyskeratosis congenita (DC) is an inherited BM failure disorder that is associated with mutations in genes involved with telomere function and maintenance; however, the genetic cause of many instances of DC remains uncharacterized. In this issue of the JCI, Tummala and colleagues identify mutations in the gene encoding the poly(A)-specific ribonuclease (PARN) in individuals with a severe form of DC in three different families. PARN deficiency resulted in decreased expression of genes required for telomere maintenance and an aberrant DNA damage response, including increased levels of p53. Together, the results of this study support PARN as a DC-associated gene and suggest a potential link between p53 and telomere shortening.
Hepatic intra-arterial versus intravenous fotemustine in patients with liver metastases from uveal melanoma (EORTC 18021): a multicentric randomized trial
Authors: S. Leyvraz, S. Piperno-Neumann, S. Suciu, J.F. Baurain, M. Zdzienicki, A. Testori, E. Marshall, M. Scheulen, T. Jouary, S. Negrier, J.B. Vermorken, E. Kaempgen, X. Durando, D. Schadendorf, R. Karra Gurunath, U. Keilholz
Journal: Annals of Oncology (2014)
Reduction in Myocardial Infarct Size by Basic Fibroblast Growth Factor After Temporary Coronary Occlusion in a Canine Model
Authors: Mark C.G. Horrigan, Andrew I. MacIsaac, Francesca A. Nicolini, D. Geoffrey Vince, Philmo Lee, Stephen G. Ellis, Eric J. Topol
Journal: Circulation (1996)

Background Basic fibroblast growth factor (bFGF) has been shown to reduce infarct size in canine acute myocardial infarction; however, the mechanism of tissue salvage remains uncertain. We evaluated the effect of bFGF on infarct size in a model of acute infarction in which coronary occlusion was followed by prolonged reperfusion and sought to determine whether reperfusion attenuates the stimulus for myocardial neovascularization. Methods and Results Anesthetized dogs undergoing 4-hour balloon occlusion of the left anterior descending coronary artery were treated with intracoronary bFGF (n=8) or vehicle (n=6). Ten-microgram doses of bFGF were administered 10 minutes after occlusion and again immediately before reperfusion. Left ventriculograms were obtained before occlusion, after reperfusion, and preceding euthanasia on day 7. Infarct size, expressed as a percentage of the area at risk, was reduced in bFGF-treated dogs (13.7±2.1% versus 28±3.4%; P =.002). Changes in left ventricular ejection fraction, capillary density, and cellular proliferation—assessed immunohistochemically with factor VIII and proliferating cell nuclear antigen antibodies—were similar in both groups. To assess coronary vasomotor responses to bFGF, a separate hemodynamic study was performed in five anesthetized nonischemic dogs in which incremental bFGF doses up to 100 μg induced no vasodilator response. Conclusions Treatment with bFGF was associated with a reduction in infarct size without hemodynamic effects or evidence of neovascularization. These data suggest that bFGF mediates myocardial salvage independently of angiogenesis and that reperfusion after infarction may attenuate the stimulus for neovascularization.
PAROTID GLAND SECRETIONS IN MANIC-DEPRESSIVE PATIENTS
Authors: Edward I. Strongin, Leland E. Hinsie
Journal: American Journal of Psychiatry (1938)

An attempt has been made to determine the rate of parotid gland secretion on a group of manic-depressive patients while they were awake in the absence of marked extro-stimulation. Some hydrogen ion determinations were also made. The parotid gland secretion on one side for five minutes over a one hour period shows an average secretion with A. Normal subjects of .07 c. c., the range being from .02 to .15 c. c. B. Manic patients of .065 c. c., the range being from .03 to .09 c. c., this falling within the normal secretory range. C. Depressed patients of .005 c. c., the range being from .001 to .01 c. c., this rate being definitely below the normal secretory rate. Preliminary findings on the hydrogen ion concentration of the parotid gland secretions indicate a correlation between the secretory rate and the hydrogen ion concentration, namely, the higher the secretory rate the higher the pH. In other words the depressed patient has a more acid secretion than the average normal individual while the parotid gland secretion of the deteriorated præcox is less acid than that of the other groups.