tbuckley/cabot-search huggingface dataset:
Long-term multicentre trial in chronic nonspecific lung disease: methodology and baseline assessment in adult patients. Dutch CNSLD Study Group
Authors: PL Brand, HA Kerstjens, DS Postma, PJ Sterk, PH Quanjer, HJ Sluiter, JH Dijkman, CL van Herwaarden, C Hilvering, HM Jansen, al. et
Journal: European Respiratory Journal (1992)

Airways obstruction and airways hyperresponsiveness are two dominant features in patients with chronic nonspecific lung disease (asthma and chronic obstructive pulmonary disease (COPD)). We set up a study to determine whether long-term (3 yrs) therapeutic intervention directed at airways obstruction and hyperresponsiveness is superior to one directed at airways obstruction alone. Patients were selected on functional criteria (age, baseline forced expiratory volume in one second (FEV1), and airways hyperresponsiveness) and, furthermore, extensively characterized by history, smoking habits, allergy, reversibility of airways obstruction and quality of life. The methodology and practical problems of setting up this large multicentre study are outlined, together with an analysis of baseline data. Standardization of methods and techniques and recruitment of patients required much effort, recruitment taking about twice as long as expected. A 3 month feasibility study allowed us to eliminate minor problems in the protocol. Over a 16 month period, 274 adult patients (18-60 yrs) from the out-patient clinics of six university centres entered the study; 99 met the diagnostic criteria for asthma, 51 for COPD, 88 for asthmatic bronchitis, and 36 could not be classified. Their mean (SD) FEV1% pred was 65.1 (15.2)%. Their geometric mean provoking concentration of histamine producing a 20% fall in FEV1 (PC20 histamine) was 0.28 mg.ml-1. In a multiple regression analysis, more severe airways hyperresponsiveness was associated with lower prechallenge FEV1% pred (p less than 0.0001), higher pack-years of smoking (p = 0.0099), blood eosinophil count (p = 0.0004), skin test reactivity (p = 0.0047) and with female sex (p = 0.0302). We conclude that setting up long-term multicentre trials in chronic nonspecific lung disease (CNSLD) is feasible and that these may offer valuable information on treatment and outcome of the disease.
Perceptions of Cancer Risks and Predictors of Colon and Endometrial Cancer Screening in Women Undergoing Genetic Testing for Lynch Syndrome
Authors: Donald W. Hadley, Jean F. Jenkins, Seth M. Steinberg, David Liewehr, Stephanie Moller, Jean C. Martin, Kathleen A. Calzone, Peter W. Soballe, Ilan R. Kirsch
Journal: Journal of Clinical Oncology (2008)

Lynch syndrome poses multiple cancer risks, yet attention has focused on screening for colorectal cancer. Estimated risks for endometrial cancer equal risks for colorectal cancer. This study (1) evaluated women's perceived risks for cancers, (2) compared endometrial cancer screening and colonoscopy, and (3) identified predictors of screening before and after genetic testing.Sixty-five adult women at 50% risk for carrying a cancer-predisposing mutation, without a history of endometrial cancer or hysterectomy, participated in genetic counseling and received unequivocal genetic test results for Lynch syndrome. Participants completed questionnaires before and after receipt of genetic results.Pretest, perceived risks for colon cancer were significantly higher than for extracolonic cancers (P < .0001). Use of colonoscopy was significantly higher (P = .006) than endometrial cancer screening. Post-test, carriers demonstrated a significant (P < .0001) increase in their perceived risk for extracolonic cancers and increased both colonoscopy (P = .79) and endometrial cancer screening (P = .11). Mutation status, age, perceived likelihood of carrying a mutation, and communication of test results to their physician independently predicted cancer screening at follow-up.Women in families with Lynch syndrome are less aware of their risks for extracolonic cancers and undergo endometrial cancer screening significantly less often than colonoscopy before genetic counseling. Given the significantly increased risks for endometrial and ovarian cancers and the mortality associated with ovarian cancer, additional efforts to inform families of cancer risks and screening recommendations seem prudent. Physicians play a critical role in ensuring appropriate cancer screening in women with Lynch syndrome.
Limbic Circuitry in Patients With Autism Spectrum Disorders Studied With Positron Emission Tomography and Magnetic Resonance Imaging
Authors: M. Mehmet Haznedar, Monte S. Buchsbaum, Tse-Chung Wei, Patrick R. Hof, Charles Cartwright, Carol A. Bienstock, Eric Hollander
Journal: American Journal of Psychiatry (2000)

Cytoarchitectonic changes in the anterior cingulate cortex, hippocampus, subiculum, entorhinal cortex, amygdala, mammillary bodies, and septum were reported in a postmortem study of autism. Previously, the authors found smaller cingulate volume and decreased metabolism of the cingulate in seven autistic patients. In this study, they measured the volume and glucose metabolism of the amygdala, hippocampus, and cingulate gyrus in an expanded group of 17 patients with autism spectrum disorders (autism [N=10] or Asperger's disorder [N=7]) and 17 age- and sex-matched healthy volunteers.Subjects performed a serial verbal learning test during (18)F-deoxyglucose uptake. The amygdala, hippocampus, and cingulate gyrus were outlined on magnetic resonance imaging scans, volumes of the structures were applied to matching coregistered positron emission tomography scans, and three-dimensional significance probability mapping was performed.Significant metabolic reductions in both the anterior and posterior cingulate gyri were visualized in the patients with autism spectrum disorders. Both Asperger's and autism patients had relative glucose hypometabolism in the anterior and posterior cingulate as confirmed by analysis of variance; regional differences were also found with three-dimensional significance probability mapping. No group differences were found in either the metabolism or the volume of the amygdala or the hippocampus. However, patients with autism spectrum disorders showed reduced volume of the right anterior cingulate gyrus, specifically in Brodmann's area 24'.Compared with age- and sex-matched healthy volunteers, patients with autism spectrum disorders showed significantly decreased metabolism in both the anterior and posterior cingulate gyri.
New Pansomatostatin Ligands and Their Chelated Versions: Affinity Profile, Agonist Activity, Internalization, and Tumor Targeting
Authors: Mihaela Ginj, Hanwen Zhang, Klaus-Peter Eisenwiener, Damian Wild, Stefan Schulz, Hans Rink, Renzo Cescato, Jean Claude Reubi, Helmut R. Maecke
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Somatostatin receptor (sst) targeting is an established method to image and treat sst-positive tumors. Particularly, neuroendocrine tumors express the receptor subtype 2 in high density, but sst1, sst3, sst4, and sst5 are also expressed to some extent in different human tumors. Currently used targeting peptides mainly have sst2 affinity. We aimed at developing (radio)peptides that bind with high affinity to all receptor subtypes. Experimental Design: Carbocyclic octapeptides were coupled with macrocyclic chelators for radiometal labeling. Affinity, internalization, and agonist potencies were determined on sst1- to sst5-expressing cell lines. Biodistribution was determined on nude mice bearing HEK-sst2 or AR4-2J and HEK-sst3 tumors. Results: High affinity to all receptor subtypes was found. YIII-KE88 showed agonistic properties at all five sst receptor subtypes as it inhibits forskolin-stimulated cyclic AMP production. Surprisingly, very low or even absent sst2 receptor internalization was found compared with currently clinically established octapeptides, whereas the sst3 internalization was very efficient. Biodistribution studies of [111In]KE88 and [67Ga]KE88/[68Ga]KE88 reflected the in vitro data. In nude mice with s.c. implanted sst2 (HEK-sst2, AR4-2J)-expressing and sst3 (HEK-sst3)-expressing tumors, high and persistent uptake was found in sst3-expressing tumors, whereas the uptake in the sst2-expressing tumors was lower and showed fast washout. The kidney uptake was high but blockable by coinjection of lysine. Conclusion: This peptide family shows pansomatostatin potency. As radiopeptides, they are the first to show a full pansomatostatin profile. Despite some drawback, they should be useful for imaging sst2-expressing tumors with short-lived radiometals, such as 68Ga, at early time points and for sst3-expressing tumors at later time points with longer-lived radiometals, such as 64Cu or 86Y.
Activating alleles of JAK3 in acute megakaryoblastic leukemia
Authors: Denise K. Walters, Thomas Mercher, Ting-Lei Gu, Thomas O'Hare, Jeffrey W. Tyner, Marc Loriaux, Valerie L. Goss, Kimberly A. Lee, Christopher A. Eide, Matthew J. Wong, Eric P. Stoffregen, Laura McGreevey, Julie Nardone, Sandra A. Moore, John Crispino, Titus J. Boggon, Michael C. Heinrich, Michael W. Deininger, Roberto D. Polakiewicz, D. Gary Gilliland, Brian J. Druker
Journal: Cancer Cell (2006)
Percutaneous Mitral Valve Repair for Mitral Regurgitation in High-Risk Patients
Authors: Donald D. Glower, Saibal Kar, Alfredo Trento, D. Scott Lim, Tanvir Bajwa, Ramon Quesada, Patrick L. Whitlow, Michael J. Rinaldi, Paul Grayburn, Michael J. Mack, Laura Mauri, Patrick M. McCarthy, Ted Feldman
Journal: Journal of the American College of Cardiology (2014)
GENETIC DISORDERS OF CARNITINE METABOLISM AND THEIR NUTRITIONAL MANAGEMENT
Authors: Janos Kerner, Charles Hoppel
Journal: Annual Review of Nutrition (1998)

▪ Abstract Carnitine functions as a substrate for a family of enzymes, carnitine acyltransferases, involved in acyl-coenzyme A metabolism and as a carrier for long-chain fatty acids into mitochondria. Carnitine biosynthesis and/or dietary carnitine fulfill the body's requirement for carnitine. To date, a genetic disorder of carnitine biosynthesis has not been described. A genetic defect in the high-affinity plasma membrane carnitine-carrier in leads to renal carnitine wasting and primary carnitine deficiency. Myopathic carnitine deficiency could be due to an increase in efflux moderated by the carnitine-carrier out . Defects in the carnitine transport system for fatty acids in mitochondria have been described and are being examined at the molecular and pathophysiological levels. The nutritional management of these disorders includes a high-carbohydrate, low-fat diet and avoidance of those events that promote fatty acid oxidation, such as fasting, prolonged exercise, and cold. Large-dose carnitine treatment is effective in systemic carnitine deficiency.
CYTOTOXICITY MEDIATED BY SOLUBLE ANTIGEN AND LYMPHOCYTES IN DELAYED HYPERSENSITIVITY
Authors: Nancy H. Ruddle, Byron H. Waksman
Journal: The Journal of Experimental Medicine (1968)

In the presence of specific antigen, lymph node cells from inbred rats with delayed hypersensitivity to tuberculoprotein, bovine gammaglobulin, and egg albumin produced progressive destruction of monolayers of rat embryo fibroblasts in tissue culture, first apparent at 48 hr and maximal at 72 hr. The effect was specific and did not depend on a genetic difference between the lymph node cells and target cells. It required antigen concentrations equal to or greater than 1.25 µg/ml and lymphocyte: target cell ratios of approximately 10 or 20:1. It could be evaluated both by a plaquing technique and by cell enumeration with an electronic particle counter.
Treatment of phenylketonuria using minicircle-based naked-DNA gene transfer to murine liver
Authors: Hiu Man Viecelli, Richard P. Harbottle, Suet Ping Wong, Andrea Schlegel, Marinee K. Chuah, Thierry VandenDriessche, Cary O. Harding, Beat Thöny
Journal: Hepatology (2014)

Host immune response to viral vectors, persistence of nonintegrating vectors, and sustained transgene expression are among the major challenges in gene therapy. To overcome these hurdles, we successfully used minicircle (MC) naked-DNA vectors devoid of any viral or bacterial sequences for the long-term treatment of murine phenylketonuria, a model for a genetic liver defect. MC-DNA vectors expressed the murine phenylalanine hydroxylase ( Pah ) complementary DNA (cDNA) from a liver-specific promoter coupled to a de novo designed hepatocyte-specific regulatory element, designated P3, which is a cluster of evolutionary conserved transcription factor binding sites. MC-DNA vectors were subsequently delivered to the liver by a single hydrodynamic tail vein (HTV) injection. The MC-DNA vector normalized blood phenylalanine concomitant with reversion of hypopigmentation in a dose-dependent manner for more than 1 year, whereas the corresponding parental plasmid did not result in any phenylalanine clearance. MC vectors persisted in an episomal state in the liver consistent with sustained transgene expression and hepatic PAH enzyme activity without any apparent adverse effects. Moreover, 14-20% of all hepatocytes expressed transgenic PAH, and the expression was observed exclusively in the liver and predominately around pericentral areas of the hepatic lobule, while there was no transgene expression in periportal areas. Conclusion : This study demonstrates that MC technology offers an improved safety profile and has the potential for the genetic treatment of liver diseases. (Hepatology 2014;60:1035–1043)
Dissecting Aneurysm Produced by Diet
Authors: WILLIAM B. BEAN, IGNACIO V. PONSETI
Journal: Circulation (1955)

Spontaneous dissecting aneurysm of the aorta in man is most commonly a sequel of hypertension but sometimes occurs in association with degenerative liquefaction of the media of the aorta. New light has been thrown upon dissecting aneurysm by its production in growing rats by a diet high in sweet peas. The offending agent has been isolated and a number of simpler related compounds have been synthesized and found effective. The relationship of this syndrome to a spontaneous dissecting aneurysm of the aorta in man is reviewed and some suggestions are made for investigation which may lead to newer methods of therapy.
Inhibitory Effect of Interferon on the Growth of Spontaneous Mammary Tumors in Mice&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="fn3"&gt;3&lt;/xref&gt;&lt;xref ref-type="fn" rid="fn4"&gt;4&lt;/xref&gt;
Authors: E De Clercq, Z X Zhang, K Huygen, R Leyten
Journal: JNCI Journal of the National Cancer Institute (1982)

Partially purified mouse interferon type I (Mu IFN-beta), crude mouse interferon type II (Mu IFN-gamma) serum, and the interferon inducer polyinosinic acid-polycytidylic acid (poly I:C) were evaluated for their effects on the growth of spontaneously occurring mammary carcinomas in BALB/c mice. As soon as their tumors had reached a palpable size (diameter: 3-5 mm), the mice received three ip injections of Mu IFN-beta, Mu IFN-gamma, or poly I:C per week for 6 weeks. A significant (fourfold to fivefold) reduction in tumor size was achieved with Mu IFN-beta (at 10(6) U/mouse), Mu IFN-gamma (at 10(3) U/mouse), and poly I:C (at 1 mg/mouse). A similar reduction in tumor size was noted when the mice were treated with cyclophosphamide (2.5 mg/mouse, three ip injections per wk for 6 wk). Treatment with Mu IFN-beta combined with Mu IFN-gamma resulted in a greater tumor growth-inhibitory effect than treatment with either Mu IFN-beta or Mu IFN-gamma alone. In addition to inhibiting the growth of primary tumors, interferon also reduced the incidence of lung metastases. However, complete tumor regression was not observed in any mouse while under interferon therapy.
Cathepsin B inactivation attenuates hepatic injury and fibrosis during cholestasis
Authors: Ali Canbay, Maria Eugenia Guicciardi, Hajime Higuchi, Ariel Feldstein, Steven F. Bronk, Robert Rydzewski, Makiko Taniai, Gregory J. Gores
Journal: Journal of Clinical Investigation (2003)

Although a lysosomal, cathepsin B–dependent (Ctsb-dependent) pathway of apoptosis has been described, the contribution of this pathway to tissue damage remains unclear. Our aim was to ascertain if Ctsb inactivation attenuates liver injury, inflammation, and fibrogenesis after bile duct ligation (BDL). In 3-day BDL mice, hepatocyte apoptosis, mitochondrial cytochrome c release, and serum alanine aminotransferase (ALT) values were reduced in Ctsb–/– versus Ctsb+/+ animals. Likewise, R-3032 (a Ctsb inhibitor) also reduced these parameters in BDL WT mice. Both genetic and pharmacologic inhibition of Ctsb in the BDL mouse reduced (a) hepatic inflammation, as assessed by transcripts for CXC chemokines and neutrophil infiltration, and (b) fibrogenesis, as assessed by transcripts for stellate cell activation and sirius red staining for hepatic collagen deposition. These differences could not be ascribed to alterations in cholestasis. These findings support a prominent role for the lysosomal pathway of apoptosis in tissue injury and link apoptosis to inflammation and fibrogenesis. Ctsb inhibition may be therapeutic in liver diseases.
Growing Pains for the Environmental Genetics of Breast Cancer: Observations on a Study of the Glutathione S-Transferases
Authors: Karl T. Kelsey, John K. Wiencke
Journal: JNCI Journal of the National Cancer Institute (1998)

Researchers now pursue two distinct avenues of investigation in the search to understand breast cancer susceptibility; one is aimed at highly penetrant genes that confer large absolute cancer risks, while the other focuses on common gene polymorphisms associated with modest individual risk. Among the second group are genes that govern a woman’s defense against environmental exposures. In this context, environment is broadly defined and includes exogenous as well as endogenous agents. The first approach has received the greatest attention and has yielded dramatic results (e.g., BRCA1 and BRCA2), while the second avenue is less traveled and has yet to produce markers with definite clinical or public health utility. Illustrating this situation is a report appearing in this issue of the Journal by Helzlsouer et al. (1), who describe an association between genetic deficiency in isoforms of the detoxification enzyme glutathione S-transferase (GST), principally GST class mu (GSTM1), and breast cancer. In this rather small prospective study, the significant association of the GSTM1 null genotype with breast cancer is driven by women who were postmenopausal at diagnosis. These investigators also observed a nonsignificant elevated risk for breast cancer in GSTT1 (GST class theta) null individuals and women who had the variant genotype for the GSTP1 (GST class pi) enzyme. When the variant genotypes were combined, a statistically significant, almost fourfold increase in risk was observed for individuals with two or three putative high-risk genotypes. The reported risk estimates are moderate compared with familial cancer genes, but because of the high prevalence of GST deficiency, Helzlsouer et al. point to the substantial attributable risks for breast cancer that could be linked to these loci. They caution, however, that application of these markers in breast cancer prevention is premature and must await replication in other populations. We agree and note that this report seems to add to a growing list of common genetic variations impugned as potential modifiers of environmental breast cancer risk factors— e.g., N-acetyltransferase (2), CYP1A1 (3), CYP17 (4), and catechol-O-methyltransferase (5).
Cytoadherence by Plasmodium falciparum-infected erythrocytes is correlated with the expression of a family of variable proteins on infected erythrocytes.
Authors: C Magowan, W Wollish, L Anderson, J Leech
Journal: The Journal of Experimental Medicine (1988)

Plasmodium falciparum-infected erythrocytes (IRBCs) adhere specifically to venular endothelium and thereby evade spleen-dependent immune mechanisms. We have investigated the molecular basis of cytoadherence. We report here that the capacity for cytoadherence of IRBCs is correlated with the expression of a family of variable proteins on the surface of IRBCs. Essential to these studies was the use of in vitro techniques for modulating the cytoadherence phenotype of cloned parasites. In initial studies, we found culture-adapted parasites to be poorly cytoadherent or noncytoadherent. To select for cytoadherent parasites, we incubated knobbed IRBCs with C32 melanoma cells and cultured the adherent cells. Repeated rounds of selection produced parasites with increased cytoadherence. To select for noncytoadherent parasites, we cultured the cells that did not adhere to C32 melanoma cells. Cytoadherent IRBCs from two different cloned isolates had large (Mr greater than 2.4 x 10(5) radioiodinatable proteins that differed in size between the isolates but had in common the biochemical properties of trypsin sensitivity and insolubility with Triton X-100. The proteins were not detected with uninfected erythrocytes, indicating that they were parasite determined, nor were they detected with IRBCs containing parasites cultured for many months without selection. With continued selection for the cytoadherent phenotype, additional IRBC surface proteins with larger molecular sizes (Mr 2.9 x 10(5) and 3.2 x 10(5] appeared. A sequence of reversible changes in the cytoadherence phenotype of cloned parasites was accompanied by variation in the molecular size of the IRBC surface protein. Increased cytoadherence was correlated with expression of larger proteins and decreased cytoadherence was correlated with expression of smaller proteins; there was no change in the molecular size of two other parasite proteins associated with the IRBC membrane. The results indicate that the expression of this family of proteins is closely linked to the cytoadherence phenotype of the parasites, suggesting that the members of the protein family have a role in mediating cytoadherence between IRBCs and endothelial cells.
Needle aspiration techniques in the diagnosis of pneumonia.
Authors: F Manresa, J Dorca
Journal: Thorax (1991)

The findings of a survey on the use of immunohistochemistry in district general hospitals in England and Wales are reported. Immunohistochemistry is used in most district hospitals, contributes to the accuracy and objectivity of some histopathological diagnoses, and is considered to be generally useful though not without drawbacks. Its expansion is being hindered by lack of funds for reagents and staff. In a few regions attempts are being made to rationalise expenditure and coordinate development of the service. We believe that if this can be done at a regional or national level then the relatively small cost entailed will be justified by a resulting improvement in the quality of patient care.
Squamous cell carcinoma of the pleura following bronchopleural fistula.
Authors: G Prabhakar, I M Mitchell, T Guha, R Norton
Journal: Thorax (1989)

Squamous metaplasia of the pleura with malignant transformation was observed five months after the development of an empyema and bronchopleural fistula in a 58 year old woman with lingular bronchiectasis.
Clinicopathologic Correlations
Authors: JOHN B. CARTER, SURENDRA SETHI, GERALD B. LEE, JESSE E. EDWARDS
Journal: Circulation (1971)

Among the various anatomic classes of aortic valvular insufficiency is that associated with prolapse of one or several cusps of the valve. A number of etiologic factors come into play, including intrinsic weakness or excessive cuspid tissue, trauma, infection, inadequate support of the aorta as in certain ventricular septal defects, and loss of commissural support from laceration of the ascending aorta. The latter condition may result from trauma, cystic medial necrosis, inflammation, or hypertension. The lacerated aorta may either be associated with typical dissecting aneurysm or there may be little intramural dissection of blood. In some instances wherein prolapse of one or more cusps causes aortic insufficiency, the functional disturbance may be overcome by correcting the basic problem while preserving the natural aortic valve.