tbuckley/cabot-search huggingface dataset:
Telomere Length Is a Determinant of Emphysema Susceptibility
Authors: Jonathan K. Alder, Nini Guo, Frant Kembou, Erin M. Parry, Collin J. Anderson, Amany I. Gorgy, Michael F. Walsh, Thomas Sussan, Shyam Biswal, Wayne Mitzner, Rubin M. Tuder, Mary Armanios
Journal: American Journal of Respiratory and Critical Care Medicine (2011)

Germline mutations in the enzyme telomerase cause telomere shortening, and have their most common clinical manifestation in age-related lung disease that manifests as idiopathic pulmonary fibrosis. Short telomeres are also a unique heritable trait that is acquired with age.We sought to understand the mechanisms by which telomerase deficiency contributes to lung disease.We studied telomerase null mice with short telomeres.Although they have no baseline histologic defects, when mice with short telomeres are exposed to chronic cigarette smoke, in contrast with controls, they develop emphysematous air space enlargement. The emphysema susceptibility did not depend on circulating cell genotype, because mice with short telomeres developed emphysema even when transplanted with wild-type bone marrow. In lung epithelium, cigarette smoke exposure caused additive DNA damage to telomere dysfunction, which limited their proliferative recovery, and coincided with a failure to down-regulate p21, a mediator of cellular senescence, and we show here, a determinant of alveolar epithelial cell cycle progression. We also report early onset of emphysema, in addition to pulmonary fibrosis, in a family with a germline deletion in the Box H domain of the RNA component of telomerase.Our data indicate that short telomeres lower the threshold of cigarette smoke-induced damage, and implicate telomere length as a genetic susceptibility factor in emphysema, potentially contributing to its age-related onset in humans.
Comparative study of the synovial histology in rheumatoid arthritis, spondyloarthropathy, and osteoarthritis: influence of disease duration and activity
Authors: D Baeten
Journal: Annals of the Rheumatic Diseases (2000)

<h3>OBJECTIVES</h3> To compare the macroscopic and microscopic characteristics of synovial tissue in rheumatoid arthritis (RA), spondyloarthropathy (SpA), and osteoarthritis (OA) after exclusion of possible biases induced by disease duration or activity, or both. <h3>METHODS</h3> Synovial biopsy specimens were obtained by needle arthroscopy in patients with early RA (n=16), late RA (n=14), early SpA (n=23), and OA (n=12). Macroscopic and microscopic features were scored on a four point scale and analysed as a function of disease duration (early versus late RA), local and systemic disease activity, and diagnosis. <h3>RESULTS</h3> Except for the maximal synovial lining thickness, no significant differences were seen between early and late RA. For disease activity, synovial histology was only weakly correlated with C reactive protein in RA, but seemed to be strongly dependent on effusion of the biopsied joint in all disease groups. After stratification for local disease activity, no disease related differences were found in patients without joint effusion. In contrast, important differences were found between patients with RA and SpA with active joint effusion. Synovial vascularity was macroscopically increased in SpA versus RA (p=0.017). A straight vessel pattern was only seen in RA, while tortuous vessels were preferentially seen in SpA. Vascularity was also microscopically increased in SpA compared with RA (p=0.031), and correlated with the macroscopic vascularity (<i>r<sub>s</sub></i>=0.36, p=0.036). CD3+ (p=0.008), CD4+ (p=0.008), and CD20+ (p=0.024) lymphocytes were overrepresented in RA compared with SpA. The integrin expression in RA was characterised by a decrease of αVβ3 in the synovial lining (p=0.006) and an increase of αVβ5 in the sublining (p&lt;0.001). <h3>CONCLUSIONS</h3> The immune architecture of the synovial membrane is more dependent on local disease activity than on disease duration. Synovium obtained from clinically affected joints shows important histological differences between RA and SpA.
<i>TERT</i> Promoter Mutations Occur Early in Urothelial Neoplasia and Are Biomarkers of Early Disease and Disease Recurrence in Urine
Authors: Isaac Kinde, Enrico Munari, Sheila F. Faraj, Ralph H. Hruban, Mark Schoenberg, Trinity Bivalacqua, Mohamad Allaf, Simeon Springer, Yuxuan Wang, Luis A. Diaz, Kenneth W. Kinzler, Bert Vogelstein, Nickolas Papadopoulos, George J. Netto
Journal: Cancer Research (2013)

Abstract Activating mutations occur in the promoter of the telomerase reverse transcriptase (TERT) gene in 66% of muscle-invasive urothelial carcinomas. To explore their role in bladder cancer development and to assess their utility as urine markers for early detection, we sequenced the TERT promoter in 76 well-characterized papillary and flat noninvasive urothelial carcinomas, including 28 pTa low-grade transitional cell carcinomas (TCC), 31 pTa high-grade TCCs, and 17 pTis carcinoma in situ lesions. We also evaluated the sequence of the TERT promoter in a separate series of 14 early bladder neoplasms and matched follow-up urine samples to determine whether urine TERT status was an indicator of disease recurrence. A high rate of TERT promoter mutation was observed in both papillary and flat lesions, as well as in low- and high-grade noninvasive urothelial neoplasms (mean: 74%). In addition, among patients whose tumors harbored TERT promoter mutations, the same mutations were present in follow-up urines in seven of eight patients that recurred but in none of the six patients that did not recur (P &amp;lt; 0.001). TERT promoter mutations occur in both papillary and flat lesions, are the most frequent genetic alterations identified to date in noninvasive precursor lesions of the bladder, are detectable in urine, and seem to be strongly associated with bladder cancer recurrence. These provocative results suggest that TERT promoter mutations may offer a useful urinary biomarker for both early detection and monitoring of bladder neoplasia. Cancer Res; 73(24); 7162–7. ©2013 AACR.
Detection of Preformed Venous Thrombi in Dogs by Means of I <sup>131</sup> -Labeled Antibodies to Dog Fibrinogen
Authors: IRVING L. SPAR, RUTH L. GOODLAND, SEYMOUR I. SCHWARTZ
Journal: Circulation Research (1965)

Dogs with thrombin-induced thrombi received I 131 rabbit antibody to dog fibrinogen and a day later were given antiserum to the rabbit gamma globulin. Scintillation scanning techniques successfully detected the site of thrombosis. Excision of the thrombi and surrounding blood vessels demonstrated deposition of radioactivity in the lesion. The immunologic removal of the gamma globulin from the circulating blood increased the difference between the radioactivity deposited in the lesion and that present in the blood. This accentuates the lesion and offers potential diagnostic advantage.
Expression and Functional Analysis of Human Leukocyte Antigen Class I Antigen-Processing Machinery in Medulloblastoma
Authors: Lizzia Raffaghello, Paolo Nozza, Fabio Morandi, Marta Camoriano, Xinhui Wang, Maria Luisa Garrè, Armando Cama, Giuseppe Basso, Soldano Ferrone, Claudio Gambini, Vito Pistoia
Journal: Cancer Research (2007)

Abstract Defects in the expression and/or function of the human leukocyte antigen (HLA) class I antigen-processing machinery (APM) components are found in many tumor types. These abnormalities may have a negative impact on the interactions of tumor cells with host's immune system and on the outcome of T cell–based immunotherapy. To the best of our knowledge, no information is available about APM component expression and functional characteristics in human medulloblastoma cells (Mb). Therefore, in the present study, we have initially compared the expression of APM components in Mb, an embryonal pediatric brain tumor with a poor prognosis, with that in noninfiltrating astrocytic pediatric tumors, a group of differentiated brain malignancies with favorable prognosis. LMP2, LMP7, calnexin, β2-microglobulin–free heavy chain (HC) and β2-microglobulin were down-regulated or undetectable in Mb lesions, but not in astrocytic tumors or normal fetal cerebellum. Two Mb cell lines (DAOI and D283) displayed similar but not superimposable defects in APM component expression as compared with primary tumors. To assess the functional implications of HLA class I APM component down-regulation in Mb cell lines, we tested their recognition by HLA class I antigen-restricted, tumor antigen (TA)–specific CTL, generated by stimulations with dendritic cells that had been transfected with Mb mRNA. The Mb cell lines were lysed by TA-specific CTL in a HLA-restricted manner. Thus, defective expression of HLA class I–related APM components in Mb cells does not impair their ability to present TA to TA-specific CTL. In conclusion, these results can contribute to optimize T cell–based immunotherapeutic strategies for Mb treatment. [Cancer Res 2007;67(11):5471–8]
Negativity bias, emotion targets, and emotion systems
Authors: Patrick Colm Hogan
Journal: Behavioral and Brain Sciences (2014)

Hibbing et al.'s article isolates a plausible psychological factor contributing to differences in political orientation. However, there are two potential difficulties. Both the nature of negativity and the liberal-conservative opposition are ambiguous. A possible way of treating these problems enhances the theoretical framework through fuller reference to emotion systems and categories of triggers for those systems.
HMGB1 release induced by liver ischemia involves Toll-like receptor 4–dependent reactive oxygen species production and calcium-mediated signaling
Authors: Allan Tsung, John R. Klune, Xianghong Zhang, Geetha Jeyabalan, Zongxian Cao, Ximei Peng, Donna B. Stolz, David A. Geller, Matthew R. Rosengart, Timothy R. Billiar
Journal: The Journal of Experimental Medicine (2007)

Ischemic tissues require mechanisms to alert the immune system of impending cell damage. The nuclear protein high-mobility group box 1 (HMGB1) can activate inflammatory pathways when released from ischemic cells. We elucidate the mechanism by which HMGB1, one of the key alarm molecules released during liver ischemia/reperfusion (I/R), is mobilized in response to hypoxia. HMGB1 release from cultured hepatocytes was found to be an active process regulated by reactive oxygen species (ROS). Optimal production of ROS and subsequent HMGB1 release by hypoxic hepatocytes required intact Toll-like receptor (TLR) 4 signaling. To elucidate the downstream signaling pathways involved in hypoxia-induced HMGB1 release from hepatocytes, we examined the role of calcium signaling in this process. HMGB1 release induced by oxidative stress was markedly reduced by inhibition of calcium/calmodulin-dependent kinases (CaMKs), a family of proteins involved in a wide range of calcium-linked signaling events. In addition, CaMK inhibition substantially decreased liver damage after I/R and resulted in accumulation of HMGB1 in the cytoplasm of hepatocytes. Collectively, these results demonstrate that hypoxia-induced HMGB1 release by hepatocytes is an active, regulated process that occurs through a mechanism promoted by TLR4-dependent ROS production and downstream CaMK-mediated signaling.
The (Pro)renin Receptor/ATP6AP2 is Essential for Vacuolar H <sup>+</sup> -ATPase Assembly in Murine Cardiomyocytes
Authors: Kenichiro Kinouchi, Atsuhiro Ichihara, Motoaki Sano, Ge-Hong Sun-Wada, Yoh Wada, Asako Kurauchi-Mito, Kanako Bokuda, Tatsuya Narita, Yoichi Oshima, Mariyo Sakoda, Yoshitaka Tamai, Hiromu Sato, Keiichi Fukuda, Hiroshi Itoh
Journal: Circulation Research (2010)

Rationale : The (pro)renin receptor [(P)RR], encoded in ATP6AP2 , plays a key role in the activation of local renin-angiotensin system (RAS). A truncated form of (P)RR, termed M8.9, was also found to be associated with the vacuolar H + -ATPase (V-ATPase), implicating a non–RAS-related function of ATP6AP2. Objective : We investigated the role of (P)RR/ATP6AP2 in murine cardiomyocytes. Methods and Results : Cardiomyocyte-specific ablation of Atp6ap2 resulted in lethal heart failure; the cardiomyocytes contained RAB7- and lysosomal-associated membrane protein 2 (LAMP2)-positive multivesicular vacuoles, especially in the perinuclear regions. The myofibrils and mitochondria remained at the cell periphery. Cardiomyocyte death was accompanied by numerous autophagic vacuoles that contained undigested cellular constituents, as a result of impaired autophagic degradation. Notably, ablation of Atp6ap2 selectively suppressed expression of the V O subunits of V-ATPase, resulting in deacidification of the intracellular vesicles. Furthermore, the inhibition of intracellular acidification by treatment with bafilomycin A1 or chloroquine reproduced the phenotype observed for the (P)RR/ATP6AP2-deficient cardiomyocytes. Conclusions : Genetic ablation of Atp6ap2 created a loss-of-function model for V-ATPase. The gene product of ATP6AP2 is considered to act as in 2 ways: (1) as (P)RR, exerting a RAS-related function; and (2) as the V-ATPase-associated protein, exerting a non–RAS-related function that is essential for cell survival.
The Sphingosine Kinase 1/Sphingosine-1-Phosphate Pathway in Pulmonary Arterial Hypertension
Authors: Jiwang Chen, Haiyang Tang, Justin R. Sysol, Liliana Moreno-Vinasco, Krystyna M. Shioura, Tianji Chen, Irina Gorshkova, Lichun Wang, Long Shuang Huang, Peter V. Usatyuk, Saad Sammani, Guofei Zhou, J. Usha Raj, Joe G. N. Garcia, Evgeny Berdyshev, Jason X.-J. Yuan, Viswanathan Natarajan, Roberto F. Machado
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

Sphingosine kinases (SphKs) 1 and 2 regulate the synthesis of the bioactive sphingolipid sphingosine-1-phosphate (S1P), an important lipid mediator that promotes cell proliferation, migration, and angiogenesis.We aimed to examine whether SphKs and their product, S1P, play a role in the development of pulmonary arterial hypertension (PAH).SphK1(-/-), SphK2(-/-), and S1P lyase heterozygous (Sgpl1(+/-)) mice, a pharmacologic SphK inhibitor (SKI2), and a S1P receptor 2 (S1PR2) antagonist (JTE013) were used in rodent models of hypoxia-mediated pulmonary hypertension (HPH). S1P levels in lung tissues from patients with PAH and pulmonary arteries (PAs) from rodent models of HPH were measured.mRNA and protein levels of SphK1, but not SphK2, were significantly increased in the lungs and isolated PA smooth muscle cells (PASMCs) from patients with PAH, and in lungs of experimental rodent models of HPH. S1P levels were increased in lungs of patients with PAH and PAs from rodent models of HPH. Unlike SphK2(-/-) mice, SphK1(-/-) mice were protected against HPH, whereas Sgpl1(+/-) mice were more susceptible to HPH. Pharmacologic SphK1 and S1PR2 inhibition prevented the development of HPH in rodent models of HPH. Overexpression of SphK1 and stimulation with S1P potentially via ligation of S1PR2 promoted PASMC proliferation in vitro, whereas SphK1 deficiency inhibited PASMC proliferation.The SphK1/S1P axis is a novel pathway in PAH that promotes PASMC proliferation, a major contributor to pulmonary vascular remodeling. Our results suggest that this pathway is a potential therapeutic target in PAH.
Administrative Data for Public Health Surveillance and Planning
Authors: Beth A Virnig, Marshall McBean
Journal: Annual Review of Public Health (2001)

▪ Abstract Electronically available administrative data are increasingly used by public health researchers and planners. The validity of the data source has been established, and its strengths and weaknesses relative to data abstracted from medical records and obtained via survey are documented. Administrative data are available from a variety of state, federal, and private sources and can, in many cases, be combined. As a tool for planning and surveillance, administrative data show great promise: They contain consistent elements, are available in a timely manner, and provide information about large numbers of individuals. Because they are available in an electronic format, they are relatively inexpensive to obtain and use. In the United States, however, there is no administrative data set covering the entire population. Although Medicare provides health care for an estimated 96% of the elderly, age 65 years and older, there is no comparable source for those under 65.
Posttransplantation Anemia at 12 Months in Kidney Recipients Treated with Mycophenolate Mofetil
Authors: Anikphe E. Imoagene-Oyedeji, Sylvia E. Rosas, Alden M. Doyle, Simin Goral, Roy D. Bloom
Journal: Journal of the American Society of Nephrology (2006)

Although posttransplantation anemia (PTA) is common in the mycophenolate mofetil era, its impact on patient survival is unknown. This retrospective cohort study characterized factors that are associated with PTA 12 mo after transplantation in mycophenolate mofetil-treated kidney recipients and explored whether 12-mo PTA affects outcomes. The records of 626 kidney recipients were examined for presence of anemia (hemoglobin <12 g/dl). Multivariate regression models, fit with covariates that had unadjusted relationships, investigated both risk factors for 12-mo PTA and whether 12-mo PTA contributes to mortality. Anemia prevalence was 72, 40, and 20.3% at 1, 3, and 12 mo, respectively. By multivariate logistic regression, anemia at 3 mo (odds ratio [OR] 10.0; 95% confidence interval [CI] 5.3 to 17.1; P = 0.0001), donor age (OR 1.0; 95% CI 1.1 to 1.3; P = 0.005), and 3-mo creatinine (OR 2.0; 95% CI 1.2 to 3.3; P = 0.044) were associated with 12-mo PTA. The PTA cohort had inferior patient survival (P = 0.02, log rank) and a higher proportion of cardiovascular deaths (6.3 versus 2.2%; P = 0.017) than nonanemic patients. By Cox regression, 12-mo PTA (hazard ratio [HR] 3.0; 95% CI 1.3 to 6.7; P = 0.009), 12-mo creatinine (HR 1.3; 95% CI 1.1 to 1.4; P = 0.008), age at transplantation (HR 1.1; 95% CI 1.1 to 1.2; P = 0.004), and hepatitis C seropositivity (HR 2.8; 95% CI 1.1 to 7.0; P = 0.03) were associated with mortality. There was no interaction between 12-mo PTA and serum creatinine. In conclusion, 12-mo PTA is associated with an increased risk for patient death. The presence of anemia 3 mo after kidney transplantation is a major determinant of 12-mo PTA. PTA in kidney recipients therefore should be defined by its persistence or occurrence beyond the third posttransplantation month.
Outcomes of hip arthroscopy. A prospective analysis and comparison between patients under 25 and over 25 years of age
Authors: Anthony Philip Cooper, Sheba Z Basheer, Rajan Maheshwari, Laura Regan, Sanjeev S Madan
Journal: British Journal of Sports Medicine (2012)

Objective To compare the results of hip arthroscopy in patients under the age of 25 with those over 25 years. Design From March 2006 until May 2010, data were collected on all patients who underwent hip arthroscopy for symptomatic intra-articular hip pathology. The patients were divided into two groups based on age (less than 25 years and over 25 years). Patients completed the modified Harris hip score (MHHS), non-arthritic hip score (NAHS) and hip dysfunction and osteoarthritis outcome score (HOOS) questionnaires at baseline then at 6 weeks, 6 months, 12 months and at latest follow-up. Participants 88 patients who underwent 94 hip arthroscopies by the senior author. Mean age was 24.3 (range 11–57 years). Results The mean NAHS and HOOS subscales for pain and activities of daily living were worse at baseline in over 25 groups. Follow-up ranged from 9 to 68 months. 45 hips had greater than 3 year follow-up. The MHHS improved in both groups with a mean difference in the under-25 group of 16.22, and 20.88 in the over 25s. Improvements in the NAHS and HOOS subscales were also of a similar magnitude. There was no statistically significant difference between outcome scores of the two groups at the latest follow-up visit. Conclusions We found a comparable improvement in outcome between those patients under 25 years and those over 25 years. We propose that hip arthroscopy is of potential benefit to patients with symptoms of femoroacetabular impingement regardless of age.
International Union of Pharmacology. LI. Nomenclature and Structure-Function Relationships of Cyclic Nucleotide-Regulated Channels
Authors: Franz Hofmann, Martin Biel, U. Benjamin Kaupp
Journal: Pharmacological Reviews (2005)

The family of cyclic nucleotide-regulated channels comprises two groups: the cyclic nucleotide-gated (CNG[1][1]) channels and the hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels. CNG cation channels are ion channels whose activation is mediated by the direct binding of cGMP or
Melanotic Macules in Albright's Syndrome and in Neurofibromatosis
Authors: Patricia H. Benedict
Journal: JAMA (1968)

The clinical features of the pigmentation in 27 cases of Albright's syndrome and 19 cases of neurofibromatosis were indistinguishable. Microscopic study of split-skin preparations showed giant pigment granules in malpighian cells or in melanocytes, or in both, in normal skin and in cafe-au-lait spots of 19 patients with neurofibromatosis but in only one of ten patients with Albright's syndrome. This difference was statistically significant ( P =
PHARMACOLOGY AND FUNCTIONS OF METABOTROPIC GLUTAMATE RECEPTORS
Authors: P. Jeffrey Conn, Jean-Philippe Pin
Journal: The Annual Review of Pharmacology and Toxicology (1997)

▪ Abstract In the mid to late 1980s, studies were published that provided the first evidence for the existence of glutamate receptors that are not ligand-gated cation channels but are coupled to effector systems through GTP-binding proteins. Since those initial reports, tremendous progress has been made in characterizing these metabotropic glutamate receptors (mGluRs), including cloning and characterization of cDNA that encodes a family of eight mGluR subtypes, several of which have multiple splice variants. Also, tremendous progress has been made in developing new highly selective mGluR agonists and antagonists and toward determining the physiologic roles of the mGluRs in mammalian brain. These findings have exciting implications for drug development and suggest that the mGluRs provide a novel target for development of therepeutic agents that could have a significant impact on neuropharmacology.
Guidelines versus clinical practice in the treatment of chronic obstructive pulmonary disease
Authors: M. Miravitlles
Journal: European Respiratory Journal (2002)

To the Editor:

Chronic obstructive pulmonary disease (COPD) is a very prevalent disease in developed countries. It is estimated that between 7–10% of the adult population may be affected 1. In recent years, many scientific societies have published guidelines for the treatment of these patients, one of the most ambitious of which is the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2. However, management patterns of the disease in both primary care and specialised settings differ from those proposed by experts. In a recent issue of the European Respiratory Journal , Roche et al. 3 presented data on the treatment of COPD …