tbuckley/cabot-search huggingface dataset:
Genome-Wide Study of Percent Emphysema on Computed Tomography in the General Population. The Multi-Ethnic Study of Atherosclerosis Lung/SNP Health Association Resource Study
Authors: Ani Manichaikul, Eric A. Hoffman, Joanna Smolonska, Wei Gao, Michael H. Cho, Heather Baumhauer, Matthew Budoff, John H. M. Austin, George R. Washko, J. Jeffrey Carr, Joel D. Kaufman, Tess Pottinger, Charles A. Powell, Cisca Wijmenga, Pieter Zanen, Harry J. M. Groen, Dirkje S. Postma, Adam Wanner, Farshid N. Rouhani, Mark L. Brantly, Rhea Powell, Benjamin M. Smith, Dan Rabinowitz, Leslie J. Raffel, Karen D. Hinckley Stukovsky, James D. Crapo, Terri H. Beaty, John E. Hokanson, Edwin K. Silverman, Josée Dupuis, George T. O’Connor, H. Marike Boezen, Stephen S. Rich, R. Graham Barr
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

Rationale: Pulmonary emphysema overlaps partially with spirometrically defined chronic obstructive pulmonary disease and is heritable, with moderately high familial clustering.Objectives: To complete a genome-wide association study (GWAS) for the percentage of emphysema-like lung on computed tomography in the Multi-Ethnic Study of Atherosclerosis (MESA) Lung/SNP Health Association Resource (SHARe) Study, a large, population-based cohort in the United States.Methods: We determined percent emphysema and upper-lower lobe ratio in emphysema defined by lung regions less than −950 HU on cardiac scans. Genetic analyses were reported combined across four race/ethnic groups: non-Hispanic white (n = 2,587), African American (n = 2,510), Hispanic (n = 2,113), and Chinese (n = 704) and stratified by race and ethnicity.Measurements and Main Results: Among 7,914 participants, we identified regions at genome-wide significance for percent emphysema in or near SNRPF (rs7957346; P = 2.2 × 10−8) and PPT2 (rs10947233; P = 3.2 × 10−8), both of which replicated in an additional 6,023 individuals of European ancestry. Both single-nucleotide polymorphisms were previously implicated as genes influencing lung function, and analyses including lung function revealed independent associations for percent emphysema. Among Hispanics, we identified a genetic locus for upper-lower lobe ratio near the α-mannosidase–related gene MAN2B1 (rs10411619; P = 1.1 × 10−9; minor allele frequency [MAF], 4.4%). Among Chinese, we identified single-nucleotide polymorphisms associated with upper-lower lobe ratio near DHX15 (rs7698250; P = 1.8 × 10−10; MAF, 2.7%) and MGAT5B (rs7221059; P = 2.7 × 10−8; MAF, 2.6%), which acts on α-linked mannose. Among African Americans, a locus near a third α-mannosidase–related gene, MAN1C1 (rs12130495; P = 9.9 × 10−6; MAF, 13.3%) was associated with percent emphysema.Conclusions: Our results suggest that some genes previously identified as influencing lung function are independently associated with emphysema rather than lung function, and that genes related to α-mannosidase may influence risk of emphysema.
A means of measuring serial changes in anal sphincter tone in patients with spinal cord compression
Authors: D. M. Chaput de Saintonge
Journal: BMJ (2014)

I wish to report a simple, serial measurement of the response to radiotherapy of spinal cord compression.

The patient, a 71 year old man with a five year history of spinal deposits of metastatic prostatic carcinoma, complained of unsteadiness and paraesthesia in his feet increasing over a five day period. Tendon and anal reflexes were intact. Magnetic resonance imaging …
The basic helix-loop-helix transcription factor, dHAND, is required for vascular development
Authors: Hiroyuki Yamagishi, Eric N. Olson, Deepak Srivastava
Journal: Journal of Clinical Investigation (2000)

Reciprocal interactions between vascular endothelial cells and vascular mesenchymal cells are essential for angiogenesis. Here we show that the basic helix-loop-helix transcription factor, dHAND/Hand2, is expressed in the developing vascular mesenchyme and its derivative, vascular smooth muscle cells (VSMCs). Targeted deletion of the dHAND gene in mice revealed severe defects of embryonic and yolk sac vascular development by embryonic day 9.5. Vascular endothelial cells expressed most markers of differentiation. Vascular mesenchymal cells migrated appropriately but failed to make contact with vascular endothelial cells and did not differentiate into VSMCs. In a screen for genes whose expression was dependent upon dHAND (using subtractive hybridization comparing wild-type and dHAND-null hearts), the VEGF165 receptor, neuropilin-1, was found to be downregulated in dHAND mutants. These results suggest that dHAND is required for vascular development and regulates angiogenesis, possibly through a VEGF signaling pathway.
Direct Evidence for Cytokine Involvement in Neointimal Hyperplasia
Authors: John E. Rectenwald, Lyle L. Moldawer, Thomas S. Huber, James M. Seeger, C. Keith Ozaki
Journal: Circulation (2000)

Background —Tumor necrosis factor-α (TNF-α) and interleukin 1 (IL-1) are proximal inflammatory cytokines that stimulate expression of adhesion molecules and induce synthesis of other proinflammatory cytokines. In addition, TNF-α and IL-1 influence vascular smooth muscle cell migration and proliferation in vitro. In view of the inflammatory nature of neointimal hyperplasia (NIH), we tested the hypothesis that endogenous TNF-α and IL-1 modulate low shear stress–induced NIH. Methods and Results —Mice underwent unilateral common carotid artery (CCA) ligation. Low shear stress in the patent ligated CCA has previously been shown to result in remodeling and NIH. Reverse transcriptase–polymerase chain reaction for TNF-α and IL-1α mRNA demonstrated both TNF-α and IL-1α mRNA in ligated CCAs, whereas normal and sham-operated CCAs had none. Mice lacking functional TNF-α (TNF−/−) developed 14-fold less neointimal area than WT controls ( P &lt;0.05). p80 IL-1 type I receptor knockout (IL-1RI−/−) mice tended to develop less (7-fold, P &gt;0.05) neointimal area than WT controls. Furthermore, no IL-1α mRNA expression was detected in CCAs from TNF−/− mice; however, TNF-α mRNA expression was found in the IL-1RI−/− mice. Mice that overexpress membrane-bound TNF-α but produce no soluble TNF-α display an accentuated fibroproliferative response to low shear stress ( P &lt;0.05). Conclusions —These results directly demonstrate that TNF-α and IL-1 modulate NIH induced by low shear stress. NIH can proceed by way of soluble TNF-α–independent mechanisms. Specific anti–TNF-α and anti–IL-1 therapies may lessen NIH.
The groin triangle: a patho-anatomical approach to the diagnosis of chronic groin pain in athletes
Authors: E C Falvey, A Franklyn-Miller, P R McCrory
Journal: British Journal of Sports Medicine (2008)

Chronic groin pain is a common presentation in sports medicine. It is most often a problem in those sports that involve kicking and twisting movements while running. The morbidity of groin pain should not be underestimated, ranking behind only fracture and anterior cruciate ligament reconstruction in terms of time out of training and play. Due to the insidious onset and course of pathology in the groin region it commonly presents with well-established pathology. Without a clear clinical/pathological diagnosis, the subsequent management of chronic groin pain is difficult. The combination of complex anatomy, variability of presentation and the non-specific nature of the signs and symptoms make the diagnostic process problematical. This paper proposes a novel educational model based on patho-anatomical concepts. Anatomical reference points were selected to form a triangle, which provides the discriminative power to restrict the differential diagnosis and form the basis of ensuing investigation. This paper forms part of a series addressing the three-dimensional nature of proximal lower limb pathology. The 3G approach (groin, gluteal and greater trochanter triangles) acknowledges this, permitting the clinician to move throughout the region, considering pathologies appropriately.
A comparison between secretin alone and sequential and simultaneous secretin and cholecystokinin administration in the assessment of pancreatic function
Authors: J. Clain, S. Bank, G. O. Barbezat, B. H. Novis, I. N. Marks
Journal: Gut (1974)

Pancreatic volume, bicarbonate and enzyme secretion were studied after sequential and after simultaneous secretin and cholecystokinin (CCK) stimulation and the results compared. No statistical difference between sequential or simultaneous stimulation was noted. A comparison of secretin alone with simultaneous secretin plus cholecystokinin stimulation showed that the combination yielded a significantly higher trypsin concentration. Volume and bicarbonate were unchanged.
Quality Improvement Strategies for Children With Asthma
Authors: Dena M. Bravata, Allison L. Gienger, Jon-Erik C. Holty, Vandana Sundaram, Nayer Khazeni, Paul H. Wise, Kathryn M. McDonald, Douglas K. Owens
Journal: JAMA Pediatrics (2009)

Objective  To evaluate the evidence that quality improvement (QI) strategies can improve the processes and outcomes of outpatient pediatric asthma care.
The definition of myocardial ischaemia
Authors: G. J Gross
Journal: Cardiovascular Research (1995)

Journal Article The definition of myocardial ischaemia Get access Garret J Gross Garret J Gross Professor of Pharmacology and Toxicology Medical College of Wisconsin, Milwaukee, WI, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 29, Issue 1, January 1995, Page 141, https://doi.org/10.1016/S0008-6363(96)88559-2 Published: 01 January 1995
Breakdown of B cell tolerance in a mouse model of systemic lupus erythematosus.
Authors: J H Roark, C L Kuntz, K A Nguyen, A J Caton, J Erikson
Journal: The Journal of Experimental Medicine (1995)

Anti-DNA antibodies, specifically those that stain nuclei in a homogenous nuclear (HN) fashion, are diagnostic of systemic lupus erythematosus (SLE) and the MRL-lpr/lpr SLE murine model. We have used a heavy chain transgene that increases the frequency of anti-HN antibodies to address whether their production in SLE is the consequence of a defect in B cell tolerance. Anti-HN B cells were undetectable in nonautoimmune-prone transgenic mice, but in MRL-lpr/lpr transgenic mice their Ig was evident in the sera and they were readily retrievable as hybridomas. We conclude that nonautoimmune animals actively delete anti-HN-specific B cells, and that MRL-lpr/lpr mice are defective in this process possibly because of the lpr defect in the fas gene.
The Complexity of Natural Killer Cells
Authors: Elfriede Noessner, Julia S. Schleypen
Journal: Clinical Cancer Research (2007)

In Response: We read with interest the comment by Sconocchia et al. describing a cell population with CD56dimCD16low/negative phenotype derived from interleukin 2/stem cell factor–cultured CD34+ cells which lack cytotoxic markers and cytotoxicity. Based on CD33 expression, the authors propose that
Analysis of HER-3, insulin growth factor-1, nuclear factor-kB and epidermal growth factor receptor gene copy number in the prediction of clinical outcome for K-RAS wild-type colorectal cancer patients receiving irinotecan–cetuximab
Authors: M. Scartozzi, R. Giampieri, E. Maccaroni, A. Mandolesi, L. Giustini, R. Silva, A. Zaniboni, T. Biscotti, S. Biagetti, E. Galizia, F. Loupakis, A. Falcone, I. Bearzi, S. Cascinu
Journal: Annals of Oncology (2011)
Influence of cell interactions in a novel model of postnatal mucosal regeneration.
Authors: H R Patel, I S Tait, G S Evans, F C Campbell
Journal: Gut (1996)

Conventional models of postnatal mucosal regeneration are cumbersome and limited: a novel model is described here. In addition, the influence of cell interactions on mucosal regeneration is examined within the model.Postnatal rat small intestinal mucosa was digested by enzymes to yield heterotypic cell aggregates (CA). CA colony forming ability, growth, and limited cytodifferentiation were assessed in vitro. CA were transplanted subcutaneously and retrieved for histological examination at staggered intervals to assess neomucosal morphogenesis and cytodifferentiation in vivo. Cell interactions in CA were disrupted by enzymes, thus producing cell suspensions (CS). Regeneration by CA and CS were compared.CA produced proliferative colonies in vitro and showed a temporal sequence of neomucosal morphogenesis and differentiation in vivo. CA colonies were more numerous within 24 hours of primary culture and had greater cellularity by 96 hours than CS colonies. Alkaline phosphatase was expressed only by 258 of 696 CA colonies (37%). CA subcutaneous grafts (48 of 56 (87%)) regenerated small intestinal neomucosa while CS were unsuccessful.These methods provide a model of mucosal regeneration which includes constituent processes of colony formation, growth, neomucosal morphogenesis, and cytodifferentiation. Preservation of cell interactions within CA seems advantageous to regeneration within the model.
Paralogy and Orthology of Tyrosine Kinases that Can Extend the Life Span of Caenorhabditis elegans
Authors: Brad A. Rikke, Shin Murakami, Thomas E. Johnson
Journal: Molecular Biology and Evolution (2000)

Modification of any one of three transmembrane protein tyrosine kinase (PTK) genes, old-1, old-2 (formerly tkr-1 and tkr-2, respectively), and daf-2 can extend the mean and maximum life span of the nematode Caenorhabditis elegans. To identify paralogs and orthologs, we delineated relationships between these three PTKs and all known transmembrane PTKs and all known mammalian nontransmembrane PTKs using molecular phylogenetics. The tree includes a number of invertebrate receptor PTKs and a novel mammalian receptor PTK (inferred from the expressed-sequence tag database) that have not previously been analyzed. old-1 and old-2 were found to be members of a surprisingly large C. elegans PTK family having 16 members. Interestingly, only four members of this transmembrane family appeared to have receptor domains (immunoglobulin-like in each case). The C-terminal domain of this family was found to have a unique sequence motif that could be important for downstream signaling. Among mammalian PTKs, the old-1/old-2 family appeared to be most closely related to the Pdgfr, Fgfr, Ret, and Tie/Tek families. However, these families appeared to have split too early from the old-1/old-2 family to be orthologs, suggesting that a mammalian ortholog could yet be discovered. An extensive search of the expressed-sequence tag database suggested no additional candidate orthologs. In contrast to old-1 and old-2, daf-2 had no C. elegans paralogs. Although daf-2 was most closely related to the mammalian insulin receptor family, a hydra insulin receptor–like sequence suggested that daf-2 might not be an ortholog of the insulin receptor family. Among PTKs, the old-1/old-2 family and daf-2 were not particularly closely related, raising the possibility that other PTK families might extend life span. On a more general note, our survey of the expressed-sequence tag database suggested that few, if any, additional mammalian PTK families are likely to be discovered. The one novel family that was discovered could represent a novel oncogene family, given the prevalence of oncogenes among PTKs. Finally, the PTK tree was consistent with nematodes and fruit flies being as divergent as nematodes and mammals, suggesting that life extension mechanisms shared by nematodes and fruit flies would be reasonable candidates for extending mammalian life spans.
The Chronic Fatigue Syndrome: A Comprehensive Approach to Its Definition and Study
Authors: Keiji Fukuda
Journal: Annals of Internal Medicine (1994)

The complexities of the chronic fatigue syndrome and the methodologic problems associated with its study indicate the need for a comprehensive, systematic, and integrated approach to the evaluation, classification, and study of persons with this condition and other fatiguing illnesses. We propose a conceptual framework and a set of guidelines that provide such an approach. Our guidelines include recommendations for the clinical evaluation of fatigued persons, a revised case definition of the chronic fatigue syndrome, and a strategy for subgrouping fatigued persons in formal investigations. *For a listing of members of the Study Group, see Appendix.
Recording flow in the first second of a maximal forced expiratory manoeuvre: influence of frequency content
Authors: M.R. Miller, J. Lloyd, P. Bright
Journal: European Respiratory Journal (2002)

The frequency content of the first second of the maximum forced expiratory manoeuvre (MFEM) was measured to determine if the currently accepted frequency limit of 20 Hz for MFEM is adequate for recording peak expiratory flow (PEF). The frequency response of a Fleisch pneumotachograph (PT) was measured and used to record MFEM from 24 patients attending a lung-function laboratory and 26 normal volunteers. The first 1.024 s of the signal recorded at 1,000 Hz for that blow with maximum PEF, underwent fast Fourier transformation using a triangular window function, applied after 0.75 s to reduce flow linearly to zero. All the frequencies above a set limit were removed, followed by inverse transformation to reconstitute the blow. The limits for this frequency cut-off were progressively varied from 100 Hz down to 15 Hz, with the resulting PEF being compared with the PEF from the reconstituted blow with no frequency reduction. The average±sd age for the group was 47±18 yrs and the average PEF was 450±187 L·min −1 , which, when expressed as a standardized residual, was 0.1±2.1, with a range from −4.5–3.9 indicating a good spread around normal values. Average rise time to PEF was 83±38 ms and dwell time &gt;90% PEF was 45±25 ms. Cut-off &gt;20 Hz reduced the mean PEF of the group by 8.5 L·min −1 (95% confidence limit 5.5–11.4 L·min −1 ), whereas cut-off &gt;30 Hz reduced mean PEF by 4.4 L·min −1 (2.6–6.2). In the present study subjects, 30 Hz was on the 95th percentile of frequencies for defining the upper limit for 98% of the power spectrum for the first second of the blow. It has been shown that there are frequencies &gt;20 Hz that contribute to peak expiratory flow enough to influence readings made using conventional hand-held peak expiratory flow meters, such as the mini-Wright. Devices used for recording flow from a maximum forced expiratory manoeuvre should therefore have an adequate frequency response of up to 30 Hz.
Effect of Noninsulin Antidiabetic Drugs Added to Metformin Therapy on Glycemic Control, Weight Gain, and Hypoglycemia in Type 2 Diabetes
Authors: Olivia J. Phung
Journal: JAMA (2010)

DIABETES ASSOciation (ADA) recommends metformin and lifestyle modifications for initial pharmacological therapy of type 2 diabetes mellitus (DM). 1 However, due to the progressive nature of the disease, most patients will require the use of combination pharmacological therapy to reach therapeutic goals.The ADA recommends adding a sulfonylurea or insulin when metformin monotherapy is insufficient to reach or maintain target goals. 1The thiazolidinedione pioglitazone may be recommended when the risk of hypoglycemia is especially undesirable, and the glucagon-like peptide-1 (GLP-1) analog exenatide may be recommended if weight loss is a major goal of therapy. 1 Remaining drugs (glinides, ␣-glucosidase inhibitors [AGIs], and dipeptidyl peptidase-4 [DPP-4] inhibitors) get only cursory mention in the ADA guidelines due to limited data supporting their relative efficacy. 1uch of the available literature in type 2 DM evaluates antidiabetic drugs as monotherapy or in combination with
Variant LTC4 synthase allele modifies cysteinyl leukotriene synthesis in eosinophils and predicts clinical response to zafirlukast
Authors: A P Sampson, S Siddiqui, D Buchanan, P H Howarth, S T Holgate, J W Holloway, I Sayers
Journal: Thorax (2000)

Clinical trials with leukotriene synthesis inhibitors and cysteinyl leukotriene (cys-LT) receptor antagonists have shown that cys-LTs (LTC4, LTD4, and LTE4) are the predominant mediators of bronchoconstriction in response to diverse asthma triggers including allergen, PAF, sulphur dioxide, and non-steroidal anti-inflammatory drugs (NSAIDs).1 In addition, inhalation of a single dose of a cys-LT causes persistent eosinophilia in the bronchial mucosa and sputum of asthmatic patients,2 3 and LT modifier drugs significantly reduce airway and blood eosinophilia in clinical asthma.4 

We have shown that, in the asthmatic airway, eosinophils represent the majority of cells that express the terminal enzyme in the cys-LT pathway, LTC4 synthase, and hence have the capacity to generate cys-LT upon stimulation.5 6 Inflammation and bronchoconstriction in the asthmatic airway may be sustained by a vicious cycle of cys-LT synthesis and eosinophil recruitment (fig 1). Anomalies in the genetic and cytokine factors that regulate cys-LT pathway enzymes in eosinophils may thus be central to the pathophysiology of asthma.



Figure 1 
Schematic diagram illustrating that genetic and cytokine factors modulate the vicious cycle of cysteinyl leukotriene synthesis and eosinophil recruitment in the asthmatic airway.



Cys-LTs are synthesised from membrane derived arachidonic acid. During stimulus-specific cell activation, arachidonic acid released by phospholipases including cytosolic phospholipase A2(PLA2)is translocated to the 5-lipoxygenase activating protein (FLAP) and converted in two steps to leukotriene (LT)A4 by 5-lipoxygenase (5- LO). LTA4 is converted to LTB4 by cells expressing LTA4hydrolase, and/or to LTC4 by cells expressing LTC4 synthase, which conjugates LTA4 to reduced glutathione. After carrier mediated cellular export of LTC4, the sequential cleavage of glutamate and glycine residues provides the extracellular receptor active metabolites LTD4 and LTE4, respectively. Cys-LTs act at specific …
Platelet survival in patients with beta‐thalassemia
Authors: A. Eldor, Y. Krausz, H. Atlan, D. Snyder, A. Goldfarb, E. Hy‐Am, E. A. Rachmilewitz, H. F. Kotze, A. Du P. Heyns
Journal: American Journal of Hematology (1989)

Thromboembolic events associated with significant morbidity and mortality have been observed in patients with beta-thalassemia major (TM). These include arterial as well as venous thrombosis and the development of early arteriosclerosis. To elucidate the possibility that TM patients may develop a hypercoagulable state we carried out a study of platelet kinetics on ten patients with TM and four patients with thalassemia intermedia (TI). Autologous platelets were labeled with indium-111-oxine, and the platelet lifespan (PLS) was determined. A significant shortening of PLS was observed in 13 out of 14 patients examined. The mean PLS (+/- 1 SD) in ten patients (8 TM, 2 TI) who underwent splenectomy was 107 +/- 36 hr (control splenectomized 248 + 51 hr) (P less than .001) and in four nonsplenectomized patients (2 TM, 2 TI) was 102 +/- 64 hr (control 224 + 23 hr) (P less than .01). The short PLS in addition to reported findings of increased circulating platelet aggregates and the decreased response of TM platelets to aggregating agents suggests in vivo platelet activation in thalassemic patients.