tbuckley/cabot-search huggingface dataset:
Distinct Phenotype of E-Selectin–Deficient Mice
Authors: Eric J. Kunkel, Klaus Ley
Journal: Circulation Research (1996)

Leukocyte capture and rolling are mediated by calcium-dependent lectins expressed on most leukocytes (L-selectin) and the vascular endothelium (P- and E-selectin). To study the role of the selectins during inflammation, we have investigated leukocyte rolling in venules of tumor necrosis factor-α (TNF-α)–treated mouse cremaster muscles in wild-type mice and gene-targeted mice with homozygous deficiency for L-, P-, or E-selectin (L−/−, P−/−, or E−/−, respectively). TNF-α treatment induces expression of E-selectin and increases expression of P-selectin on endothelial cells. Consistent with previous reports of redundant P- and E-selectin function, a combination of monoclonal antibodies (mAbs) against P- and E-selectin (RB40.34 and 9A9, respectively) was necessary to block rolling in wild-type mice. The rolling leukocyte flux fraction (percent rolling cells) in L−/− mice was similar to that in wild-type mice, but rolling in these mice was blocked by a P-selectin mAb. The velocity of rolling leukocytes in TNF-α–treated wild-type, P−/−, or L−/− mice was 5 to 10 times slower (3 to 7 μm/s) than during trauma-induced rolling (20 to 50 μm/s). In contrast, leukocytes in venules of TNF-α–treated E−/− mice rolled significantly faster (12 to 20 μm/s); the rolling leukocyte flux fraction was more than doubled compared with wild-type, L−/−, or P−/− mice; and the number of adherent leukocytes was reduced. Addition of an E-selectin mAb, but not a P-selectin mAb, increased rolling flux fraction and rolling velocity in wild-type mice. Histological analysis revealed that 90% to 95% of all leukocytes interacting (rolling and adherent) with the venular endothelium in TNF-α–treated wild-type, L−/−, P−/−, and E−/− mice were granulocytes. These results identify a previously unrecognized phenotype of E−/− mice by establishing that at the site densities prevailing in vivo, E-selectin is responsible for slow (≈5 μm/s) granulocyte rolling. E-selectin–dependent slow rolling drastically increases the transit time of leukocytes rolling through an inflamed tissue and thus aids in targeting leukocytes activated by chemoattractants to the inflammatory microenvironment.
Targeting Protein Phosphatase 1 in Heart Failure
Authors: Hunter C. Champion
Journal: Circulation Research (2005)

ver the past three decades the treatment of heart failure has shifted from a palliative care approach to a more successful focus on neurohormonal modulation through drugs that inhibit ␤-adrenergic, angiotensin, and aldosterone signaling.Despite these relatively recent advances, the clinical syndrome of heart failure remains progressive in nature.This observation begs the question as to a unifying aberrancy in cardiomyocyte phenotype that occurs in heart failure.2][3][4] This slower decline has been attributed to a decrease in the Ca 2ϩ uptake into the sarcoplasmic reticulum (SR); and particularly with the relative role of phospholamban (PLB) and the SR Ca 2ϩ -ATPase (SERCA). 4,5][4][5][6] In this issue, Pathak and del Monte et al show that targeted inhibition of protein phosphatase 1 (PP1) by increased activity of its inhibitor, inhibitor-1 in the heart, results in enhanced contractility and is protective against the development of cardiac hypertrophy and heart failure stimulated by hemodynamic load. 7In failing hearts, the downregulation of adrenergic receptor and cAMP-dependent protein kinase signaling leads to the inactivation of inhibitor-1 which, in turn, results in increased activity of PP1. 7,8This activation of PP1 leads to the dephosphorylation of phospholamban thus reducing calcium uptake by SERCA-2a.In an important series of experiments in transgenic mice and using gene transfer in rats, Kranias, Hajjar, and colleagues now show that the targeted inhibition of protein phosphatase 1 by overexpression of inhibitor-1 enhances cardiac contractility under normal hemodynamic conditions as well as in response to adrenergic stimulation with isoproterenol.Moreover, the authors show that targeted gene transfer of active inhibitor-1 in rats results in marked attenuation of the functional and morphometric changes associated with chronic pressure overload.
Abstract IA10: Pathology of lung neuroendocrine tumors: In search of evidence for classification
Authors: Ilona Linnoila
Journal: Clinical Cancer Research (2012)

Abstract Neuroendocrine (NE) tumors comprise approximately 25% of all tumors in human lung. As a group they continue to provide challenges at biological, molecular and pathological level for uniform classification. The prototype of NE tumors is the highly aggressive small cell lung cancer (SCLC) that accounts 15% of human lung cancers. For years lung cancers were clinically classified mainly into SCLCs and non-SCLCs (NSCLCs) while it has become evident that lung NE tumors actually form a complex spectrum from SCLC to carcinoid with shifting boundaries. The current WHO classification recognizes SCLC, its variant form combined SCLC, typical and atypical carcinoids as well as large cell NE carcinoma (LCNEC) and its variant form combined large cell carcinoma, the last two cancers under the main NSCLC category of large cell carcinoma. With the exception of the LCNEC, it is expected that the diagnoses will be rendered by routine hematoxylin-eosin stain according the established criteria. Benign entities include diffuse idiopathic pulmonary NE cell hyperplasia which is described in the chapter of preinvasive lesions. Over time there have been several efforts to place lung NE tumors into two to four-tier categories according to their malignant potential (high versus low grade) or degree of differentiation often leaving behind confusing terminology that is later misused. Unlike surgically resected NSCLCs, most NE tumors are frequently diagnosed from biopsies which remains a seldom recognized fact that may create its own biases. The diagnosis that experts most often agree with is SCLC, while distinctions between atypical carcinoid and LCNEC that are in the middle of the spectrum are often disputed. Many molecular studies have also “correctly” classified the endpoints of the NE spectrum while grouping in the middle of it has produced varied results. Moreover, several studies have suggested that NSCLCs with NE features (NSCLC-NEs) is a distinct carcinoma type with worse prognosis than ordinary non-NE NSCLC, while others disagree. Biologically this category is very interesting as NSCLCs and SCLCs are ultimately thought to be derived from the same cell. The regulation of NE differentiation is poorly understood. The proneural achaete-scute homolog 1 (ASCL1), a lineage-dependent oncogene may be a key factor for NE differentiation. On the other hand, it was recently shown that the deletion of the tumor suppressor genes Rb1 and p53 specifically in NE cells, a subpopulation of cells in normal airways, or in alveolar non-NE type2 pneumocytes of mice resulted in SCLCs closely mimicking human disease. These results provide experimental evidence for the close relationship of NE and non-NE epithelial cells in carcinogenesis.
Changes to alveolar macrophage phenotype in HIV infected individuals with normal CD4 counts and no respiratory disease.
Authors: M C Lipman, M A Johnson, D H Bray, L H Poulter
Journal: Thorax (1995)

BACKGROUND--It has previously been shown that HIV infected individuals with pneumonitis have identifiable abnormalities in alveolar macrophages obtained by bronchoalveolar lavage (BAL). In particular, alterations in the expression of alveolar macrophage surface antigens associated with macrophage function have been reported. To determine whether these changes reflect HIV infection or the respiratory episode itself, a population of HIV infected patients with no respiratory disease was studied. METHODS--Twenty two HIV antibody positive individuals with a peripheral blood CD4 count of &gt; 400/microliters and 10 healthy volunteer controls underwent bronchoscopy and BAL. Cytospin preparations from the recovered cells were stained using immunoperoxidase and double immunofluorescence techniques with monoclonal antibodies RFD1, RFD7, EBM11/CD68 (mature macrophages), UCHM1/CD14 (monocyte marker), and HLA-DR (RFDR1). Differential cell counts were also performed. RESULTS--There was an increase in overall alveolar macrophage HLA-DR expression in the HIV population. This was not reflected in a change in the percentage of cells staining CD14 (monocytes) or CD68 (mature macrophages) positive. The relative proportions of cells staining RFD1 + RFD7- (inducer cells), RFD1 - RFD7+ (effector cells), and RFD1 + RFD7+ (suppressive cells) were unchanged between HIV and control groups. CONCLUSIONS--In a population of HIV infected individuals with normal CD4 counts and no respiratory disease there was an increase in overall alveolar macrophage HLA-DR expression which occurred independently of any alteration in the relative proportions of alveolar macrophage subpopulations.
Genome-wide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2
Authors: Fred A Wright, Lisa J Strug, Vishal K Doshi, Clayton W Commander, Scott M Blackman, Lei Sun, Yves Berthiaume, David Cutler, Andreea Cojocaru, J Michael Collaco, Mary Corey, Ruslan Dorfman, Katrina Goddard, Deanna Green, Jack W Kent, Ethan M Lange, Seunggeun Lee, Weili Li, Jingchun Luo, Gregory M Mayhew, Kathleen M Naughton, Rhonda G Pace, Peter Paré, Johanna M Rommens, Andrew Sandford, Jaclyn R Stonebraker, Wei Sun, Chelsea Taylor, Lori L Vanscoy, Fei Zou, John Blangero, Julian Zielenski, Wanda K O'Neal, Mitchell L Drumm, Peter R Durie, Michael R Knowles, Garry R Cutting
Journal: Nature Genetics (2011)
Antiviral protection by virus-immune cytotoxic T cells: infected target cells are lysed before infectious virus progeny is assembled.
Authors: R M Zinkernagel, A Althage
Journal: The Journal of Experimental Medicine (1977)

Virus-immune cytotoxic T cells can inhibit effectively growth of vaccinia virus in acutely infected target cells in vitro by destroying infected target cells before infectious virus progeny is assembled. Together with the fact that virus-specific T cells are demonstrable after 3 days, very early during infection, and with strong circumstantial evidence from adoptive transfer models in vivo, these data suggest that in some virus infections T cells may in fact act cytolytically in vivo to prevent virus growth and spread and be an important early antiviral effector mechanism.
Caveolae Localize Protein Kinase A Signaling to Arterial ATP-Sensitive Potassium Channels
Authors: Laura J. Sampson, Yasunobu Hayabuchi, Nick B. Standen, Caroline Dart
Journal: Circulation Research (2004)

Arterial ATP-sensitive K + (K ATP ) channels are critical regulators of vascular tone, forming a focal point for signaling by many vasoactive transmitters that alter smooth muscle contractility and so blood flow. Clinically, these channels form the target of antianginal and antihypertensive drugs, and their genetic disruption leads to hypertension and sudden cardiac death through coronary vasospasm. However, whereas the biochemical basis of K ATP channel modulation is well-studied, little is known about the structural or spatial organization of the signaling pathways that converge on these channels. In this study, we use discontinuous sucrose density gradients and Western blot analysis to show that K ATP channels localize with an upstream signaling partner, adenylyl cyclase, to smooth muscle membrane fractions containing caveolin, a protein found exclusively in cholesterol and sphingolipid-enriched membrane invaginations known as caveolae. Furthermore, we show that an antibody against the K ATP pore-forming subunit, Kir6.1 co-immunoprecipitates caveolin from arterial homogenates, suggesting that Kir6.1 and caveolin exist together in a complex. To assess whether the colocalization of K ATP channels and adenylyl cyclase to smooth muscle caveolae has functional significance, we disrupt caveolae with the cholesterol-depleting agent, methyl-β-cyclodextrin. This reduces the cAMP-dependent protein kinase A–sensitive component of whole-cell K ATP current, indicating that the integrity of caveolae is important for adenylyl cyclase–mediated channel modulation. These results suggest that to be susceptible to protein kinase A–dependent activation, arterial K ATP channels need to be localized in the same lipid compartment as adenylyl cyclase; the results also provide the first indication of the spatial organization of signaling pathways that regulate K ATP channel activity.
Renin, A Physiologic Regulator of Renal Hemodynamics?
Authors: Herman E. Schmid
Journal: Circulation Research (1962)

1. Injections of hog renin and formation of antirenin in the dog will prevent or reduce the elevation of blood pressure associated with constriction of the renal arteries, but will not affect the systemic blood pressure in the normal animal. 2. The kidneys of both the normal and renal artery constricted animal respond with an increase in renin content during hog-renin injections which correlates closely with the serum antirenin titer. 3. The juxtaglomerular cell appears to be the site of renin formation and in this location may affect postglomerular vascular resistance. 4. Dogs with high titers of antirenin apparently have a reduced capacity to respond to an alteration in postglomerular resistance. 5. It is proposed that renin formation is controlled normally by a pressure-sensitive feedback mechanism operating across the glomerulus between the juxtaglomerular cell and postglomerular resistance.
Laser ablation of upper gastrointestinal vascular ectasias: long term results.
Authors: I R Sargeant, L A Loizou, D Rampton, M Tulloch, S G Bown
Journal: Gut (1993)

Forty one patients with bleeding vascular ectasias of the upper gastrointestinal tract who required blood transfusion were treated with endoscopic Nd:YAG laser photocoagulation and followed for 34 months (median). Four distinct groups of patients were identified. There was a sustained reduction in transfusion requirements after laser treatment in all those with single (nine patients) and multiple (seven patients) angiodysplasia, in 12 of 16 (75%) patients with watermelon stomachs, and in six of nine (66%) patients with hereditary haemorrhagic telangiectasia. Overall, 25 patients (61%) required minimal or no transfusion after treatment and nine (22%) whose bleeding was controlled initially, later developed recurrent bleeding which was controlled with further laser (total 34 of 41, 83%). Surgery succeeded in a further three patients (7%) in whom laser had failed (in one case possibly because of laser induced haemorrhage). Five more cases of possible laser induced haemorrhage resolved with conservative treatment. One patient sustained a treatment related perforation and died: one patient with cirrhosis died of encephalopathy within one month of starting laser treatment. In two patients transfusion requirements were unchanged despite laser. Nd:YAG laser is a safe and effective treatment for most patients with upper gastrointestinal angiodysplasia.
RELATION BETWEEN HISTORY, PERSONALITY AND FAMILY PATTERN AND BEHAVIORAL RESPONSE AFTER FRONTAL LOBE SURGERY
Authors: MILTON GREENBLATT
Journal: American Journal of Psychiatry (1959)

Studies of many patients before and after lobotomy indicate complex relationships between history, personality and behavioral response after frontal lobe surgery. It has been shown, for example, that postoperative changes may move in either direction along a given parameter–sometimes favorable and sometimes unfavorable. For example, worry and fear were greatly allayed after operation, yet not produced at all by operation. On the other hand, outspokenness existing before operation was removed as a symptom in one-third of the cases after operation, yet in a half of the cases in which it was of no significance preoperatively, outspokenness was produced as a postoperative, undesired characteristic. It is possible to illustrate poignantly how a given change, such as an increase in aggressiveness or dominance, in some instances pleased the family, and in others caused constraints. Conversely, a decrease in aggressiveness or dominance could either please or displease the important persons in the patient's family circle. Social interaction studies showed that there was considerable dependence of postoperative change on preoperative level or type of socialization. In general, the tendency was towards a normalization of behavior: patients who showed excessive activity became more moderate, and patients with deficient activity tended to have a release of this activity after operation. Concerning the problem of prediction of mental status after operation, it was noted that the primary predictors of good outcome were rapid onset, high tension, insight present, hallucinations absent, verbalness and friendliness, and, finally, a diagnosis of psychoneurosis rather than schizophrenia. The experience suggests that the reactions to severe brain cutting are not to be predicted alone on the basis of the type and amount of brain cut or destroyed, but in relation to many factors from the background and personality of the patient.
Pioglitazone for Diabetes Prevention in Impaired Glucose Tolerance
Authors: Ralph A. DeFronzo, Devjit Tripathy, Dawn C. Schwenke, MaryAnn Banerji, George A. Bray, Thomas A. Buchanan, Stephen C. Clement, Robert R. Henry, Howard N. Hodis, Abbas E. Kitabchi, Wendy J. Mack, Sunder Mudaliar, Robert E. Ratner, Ken Williams, Frankie B. Stentz, Nicolas Musi, Peter D. Reaven
Journal: New England Journal of Medicine (2011)

Impaired glucose tolerance is associated with increased rates of cardiovascular disease and conversion to type 2 diabetes mellitus. Interventions that may prevent or delay such occurrences are of great clinical importance.We conducted a randomized, double-blind, placebo-controlled study to examine whether pioglitazone can reduce the risk of type 2 diabetes mellitus in adults with impaired glucose tolerance. A total of 602 patients were randomly assigned to receive pioglitazone or placebo. The median follow-up period was 2.4 years. Fasting glucose was measured quarterly, and oral glucose tolerance tests were performed annually. Conversion to diabetes was confirmed on the basis of the results of repeat testing.Annual incidence rates for type 2 diabetes mellitus were 2.1% in the pioglitazone group and 7.6% in the placebo group, and the hazard ratio for conversion to diabetes in the pioglitazone group was 0.28 (95% confidence interval, 0.16 to 0.49; P<0.001). Conversion to normal glucose tolerance occurred in 48% of the patients in the pioglitazone group and 28% of those in the placebo group (P<0.001). Treatment with pioglitazone as compared with placebo was associated with significantly reduced levels of fasting glucose (a decrease of 11.7 mg per deciliter vs. 8.1 mg per deciliter [0.7 mmol per liter vs. 0.5 mmol per liter], P<0.001), 2-hour glucose (a decrease of 30.5 mg per deciliter vs. 15.6 mg per deciliter [1.6 mmol per liter vs. 0.9 mmol per liter], P<0.001), and HbA(1c) (a decrease of 0.04 percentage points vs. an increase of 0.20 percentage points, P<0.001). Pioglitazone therapy was also associated with a decrease in diastolic blood pressure (by 2.0 mm Hg vs. 0.0 mm Hg, P=0.03), a reduced rate of carotid intima-media thickening (31.5%, P=0.047), and a greater increase in the level of high-density lipoprotein cholesterol (by 7.35 mg per deciliter vs. 4.5 mg per deciliter [0.4 mmol per liter vs. 0.3 mmol per liter], P=0.008). Weight gain was greater with pioglitazone than with placebo (3.9 kg vs. 0.77 kg, P<0.001), and edema was more frequent (12.9% vs. 6.4%, P=0.007).As compared with placebo, pioglitazone reduced the risk of conversion of impaired glucose tolerance to type 2 diabetes mellitus by 72% but was associated with significant weight gain and edema. (Funded by Takeda Pharmaceuticals and others; ClinicalTrials.gov number, NCT00220961.).
Proportional classifications of COPD phenotypes
Authors: S E Marsh, J Travers, M Weatherall, M V Williams, S Aldington, P M Shirtcliffe, A L Hansell, M R Nowitz, A A McNaughton, J B Soriano, R W Beasley
Journal: Thorax (2008)

Chronic obstructive pulmonary disease (COPD) encompasses a group of disorders characterised by the presence of incompletely reversible airflow obstruction with overlapping subsets of different phenotypes including chronic bronchitis, emphysema or asthma. The aim of this study was to determine the proportion of adult subjects aged >50 years within each phenotypic subgroup of COPD, defined as a post-bronchodilator ratio of forced expiratory volume in 1 s/forced vital capacity (FEV(1)/FVC) <0.7, in accordance with current international guidelines.Adults aged >50 years derived from a random population-based survey undertook detailed questionnaires, pulmonary function tests and chest CT scans. The proportion of subjects in each of 16 distinct phenotypes was determined based on combinations of chronic bronchitis, emphysema and asthma, with and without incompletely reversible airflow obstruction defined by a post-bronchodilator FEV(1)/FVC ratio of 0.7.A total of 469 subjects completed the investigative modules, 96 of whom (20.5%) had COPD. Diagrams were constructed to demonstrate the relative proportions of the phenotypic subgroups in subjects with and without COPD. 18/96 subjects with COPD (19%) had the classical phenotypes of chronic bronchitis and/or emphysema but no asthma; asthma was the predominant COPD phenotype, being present in 53/96 (55%). When COPD was defined as a post-bronchodilator FEV(1)/FVC less than the lower limit of normal, there were one-third fewer subjects with COPD and a smaller proportion without a defined emphysema, chronic bronchitis or asthma phenotype.This study provides proportional classifications of the phenotypic subgroups of COPD which can be used as the basis for further research into the pathogenesis and treatment of this heterogeneous disorder.