tbuckley/cabot-search huggingface dataset:
The Seattle Criteria increase the specificity of preparticipation ECG screening among elite athletes
Authors: Maria Brosnan, Andre La Gerche, Jon Kalman, Wilson Lo, Kieran Fallon, Andrew MacIsaac, David Prior
Journal: British Journal of Sports Medicine (2013)

Background In 2010, the European Society of Cardiology (ESC) released recommendations for the interpretation of the 12-lead ECG in athletes, dividing changes into group 1 (training related) and group 2 (training unrelated). Recently, the ‘Seattle Criteria’, a series of revisions to these recommendations, was published, with the aim of improving the specificity of ECG screening in athletes. Objectives First, to assess the prevalence of ECG abnormalities in a cohort of elite Australian athletes using the 2010 ESC recommendations and determine how often group 2 ECG changes correlate with the evidence of significant cardiac pathology on further investigation. Second, to assess the impact of the ‘Seattle Criteria’ in reducing the number of athletes with ECG abnormalities in whom further cardiac testing is unremarkable (‘false positives’). Design 1197 elite athletes underwent cardiovascular screening between 2011 and 2012, of whom 1078 aged 16–35 years volunteered and were eligible to participate. Results 186 (17.3%) had an abnormal ECG according to ESC recommendations and a further 30 (2.8)% had unclassified changes. Three athletes (0.3%) were found to have a cardiac abnormality on further investigation. Using the Seattle Criteria, the number of athletes classified as abnormal fell to 48 (4.5%, p&lt;0.0001) and the three with an underlying cardiac abnormality were still identified. The improved specificity was due to reclassification of 71 athletes (6.6%) with an equivocal QTc interval, 42 (3.9%) with T wave inversion isolated to V1–2 and 22 (2%) with either isolated right axis deviation or right ventricular hypertrophy on voltage criteria. Conclusions The ‘Seattle Criteria’ reduced the false-positive rate of ECG screening from 17% to 4.2%, while still identifying the 0.3% of athletes with a cardiac abnormality.
Human sex hormone–binding globulin variants associated with hyperandrogenism and ovarian dysfunction
Authors: Kevin N. Hogeveen, Patrice Cousin, Michel Pugeat, Didier Dewailly, Benoît Soudan, Geoffrey L. Hammond
Journal: Journal of Clinical Investigation (2002)

The access of testosterone and estradiol to target tissues is regulated by sex hormone–binding globulin (SHBG) in human blood. Serum SHBG levels are low in patients with hyperandrogenism, especially in association with polycystic ovarian syndrome (PCOS) and in individuals at risk for diabetes and heart disease. Here, we identify SHBG coding region variations from a compound heterozygous patient who presented with severe hyperandrogenism during pregnancy. Serum SHBG levels in this patient measured 2 years after her pregnancy were exceptionally low, and her non–protein-bound testosterone concentrations greatly exceeded the normal reference range. A single-nucleotide polymorphism within the proband’s maternally derived SHBG allele encodes a missense mutation, P156L, which allows for normal steroid ligand binding but causes abnormal glycosylation and inefficient secretion of SHBG. This polymorphism was identified in four other patients with either PCOS, ioiopathic hirsutism, or ovarian failure. The proband’s paternal SHBG allele carries a single-nucleotide deletion within exon 8, producing a reading-frame shift within the codon for E326 and a premature termination codon. CHO cells transfected with a SHBG cDNA carrying this mutation fail to secrete the predicted truncated form of SHBG. To our knowledge, these are the first examples of human SHBG variants linked to hyperandrogenism and ovarian dysfunction.
Biomarker Analyses from a Placebo-Controlled Phase II Study Evaluating Erlotinib ± Onartuzumab in Advanced Non–Small Cell Lung Cancer: MET Expression Levels Are Predictive of Patient Benefit
Authors: Hartmut Koeppen, Wei Yu, Jiping Zha, Ajay Pandita, Elicia Penuel, Linda Rangell, Rajiv Raja, Sankar Mohan, Rajesh Patel, Rupal Desai, Ling Fu, An Do, Vaishali Parab, Xiaoling Xia, Tom Januario, Sharianne G. Louie, Ellen Filvaroff, David S. Shames, Ignacio Wistuba, Marina Lipkind, Jenny Huang, Mirella Lazarov, Vanitha Ramakrishnan, Lukas Amler, See-Chun Phan, Premal Patel, Amy Peterson, Robert L. Yauch
Journal: Clinical Cancer Research (2014)

Abstract Purpose: In a recent phase II study of onartuzumab (MetMAb), patients whose non–small cell lung cancer (NSCLC) tissue scored as positive for MET protein by immunohistochemistry (IHC) experienced a significant benefit with onartuzumab plus erlotinib (O+E) versus erlotinib. We describe development and validation of a standardized MET IHC assay and, retrospectively, evaluate multiple biomarkers as predictors of patient benefit. Experimental Design: Biomarkers related to MET and/or EGF receptor (EGFR) signaling were measured by IHC, FISH, quantitative reverse transcription PCR, mutation detection techniques, and ELISA. Results: A positive correlation between IHC, Western blotting, and MET mRNA expression was observed in NSCLC cell lines/tissues. An IHC scoring system of MET expression taking proportional and intensity-based thresholds into consideration was applied in an analysis of the phase II study and resulted in the best differentiation of outcomes. Further analyses revealed a nonsignificant overall survival (OS) improvement with O+E in patients with high MET copy number (mean ≥5 copies/cell by FISH); however, benefit was maintained in “MET IHC-positive”/MET FISH-negative patients (HR, 0.37; P = 0.01). MET, EGFR, amphiregulin, epiregulin, or HGF mRNA expression did not predict a significant benefit with onartuzumab; a nonsignificant OS improvement was observed in patients with high tumor MET mRNA levels (HR, 0.59; P = 0.23). Patients with low baseline plasma hepatocyte growth factor (HGF) exhibited an HR for OS of 0.519 (P = 0.09) in favor of onartuzumab treatment. Conclusions: MET IHC remains the most robust predictor of OS and progression-free survival benefit from O+E relative to all examined exploratory markers. Clin Cancer Res; 20(17); 4488–98. ©2014 AACR.
Impact of high-dose oral acyclovir prophylaxis on cytomegalovirus (CMV) disease in CMV high-risk renal transplant recipients.
Authors: J Kletzmayr, H Kotzmann, T Popow-Kraupp, J Kovarik, R Klauser
Journal: Journal of the American Society of Nephrology (1996)

Recent studies showed contradictory results concerning the efficacy of oral acyclovir in the prevention or amelioration of cytomegalovirus (CMV) disease after renal transplantation (TX). This study evaluated the incidence and severity of CMV disease within the first year after TX in high-risk renal transplant recipients (CMV-seropositive donor, seronegative recipient) treated prophylactically with oral acyclovir (800 to 3200 mg/day) over a period of 12 wk (ACY, N = 22), compared with high-risk patients randomly assigned as controls (CO, N = 10). Follow-up for CMV infection included serological determination of CMV-specific immunoglobulin G and immunoglobulin M antibodies, antigen detection in peripheral blood leukocytes (PP 65), shell vial culture (blood), and virus isolation/early antigen detection (urine). Severity of CMV disease was quantified by a scoring system for CMV-related symptoms. Nine patients (40.1%) in the acyclovir group and four patients (40%) in the control group developed CMV disease. Neither severity (ACY, 11.4 versus CO; 12.5 points score), nor duration of disease (ACY, 21 days; CO, 22 days), nor transplant function at the end of the observation period differed significantly. The onst of CMV disease was not delayed significantly in acyclovir-treated patients compared with controls (ACY, 47 +/- 34 days versus CO, 27 +/- 14 days after TX, not significant). Our results show no beneficial effect of oral acyclovir prophylaxis in CMV high-risk renal transplant recipients.
Particulate Air Pollution as a Predictor of Mortality in a Prospective Study of U.S. Adults
Authors: C. Arden Pope, Michael J. Thun, Mohan M. Namboodiri, Douglas W. Dockery, John S. Evans, Frank E. Speizer, Clark W. Heath
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

Time-series, cross-sectional, and prospective cohort studies have observed associations between mortality and particulate air pollution but have been limited by ecologic design or small number of subjects or study areas. The present study evaluates effects of particulate air pollution on mortality using data from a large cohort drawn from many study areas. We linked ambient air pollution data from 151 U.S. metropolitan areas in 1980 with individual risk factor on 552,138 adults who resided in these areas when enrolled in a prospective study in 1982. Deaths were ascertained through December, 1989. Exposure to sulfate and fine particulate air pollution, which is primarily from fossil fuel combustion, was estimated from national data bases. The relationships of air pollution to all-cause, lung cancer, and cardiopulmonary mortality was examined using multivariate analysis which controlled for smoking, education, and other risk factors. Although small compared with cigarette smoking, an association between mortality and particulate air pollution was observed. Adjusted relative risk ratios (and 95% confidence intervals) of all-cause mortality for the most polluted areas compared with the least polluted equaled 1.15 (1.09 to 1.22) and 1.17 (1.09 to 1.26) when using sulfate and fine particulate measures respectively. Particulate air pollution was associated with cardiopulmonary and lung cancer mortality but not with mortality due to other causes. Increased mortality is associated with sulfate and fine particulate air pollution at levels commonly found in U.S. cities. The increase in risk is not attributable to tobacco smoking, although other unmeasured correlates of pollution cannot be excluded with certainty.
Treating idiopathic pulmonary fibrosis with the addition of co-trimoxazole: a randomised controlled trial
Authors: Ludmila Shulgina, Anthony P Cahn, Edwin R Chilvers, Helen Parfrey, Allan B Clark, Edward C F Wilson, Orion P Twentyman, Anthony G Davison, John J Curtin, Michael B Crawford, Andrew M Wilson
Journal: Thorax (2012)

Idiopathic pulmonary fibrosis (IPF) is a fatal condition with limited treatment options. However, in a previous small study, co-trimoxazole was found to be beneficial.In a double-blind multicentre study, 181 patients with fibrotic idiopathic interstitial pneumonia (89% diagnosed as definite/probable IPF) were randomised to receive co-trimoxazole 960 mg twice daily or placebo for 12 months in addition to usual care. Measurements were made of forced vital capacity (FVC) (primary endpoint), diffusing capacity of carbon monoxide (Dlco) and EuroQol (EQ5D)-based utility, 6-minute walk test (6MWT) and Medical Research Council (MRC) dyspnoea score (secondary endpoints). All-cause mortality and adverse events were recorded (tertiary endpoints).Co-trimoxazole had no effect on FVC (mean difference 15.5 ml (95% CI -93.6 to 124.6)), Dlco (mean difference -0.12 mmol/min/kPa (95% CI 0.41 to 0.17)), 6MWT or MRC dyspnoea score (intention-to-treat analysis). The findings of the per-protocol analysis were the same except that co-trimoxazole treatment resulted in a significant improvement in EQ5D-based utility (mean difference 0.12 (95% CI 0.01 to 0.22)), a reduction in the percentage of patients requiring an increase in oxygen therapy (OR 0.05 (95% CI 0.00 to 0.61)) and a significant reduction in all-cause mortality (co-trimoxazole 3/53, placebo 14/65, HR 0.21 (95% CI 0.06 to 0.78), p=0.02)) compared with placebo. The use of co-trimoxazole reduced respiratory tract infections but increased the incidence of nausea and rash.The addition of co-trimoxazole therapy to standard treatment for fibrotic idiopathic interstitial pneumonia had no effect on lung function but resulted in improved quality of life and a reduction in mortality in those adhering to treatment. ISRCTN22201583.
Personhood and Neuroscience: Naturalizing or Nihilating?
Authors: Martha J. Farah, Andrea S. Heberlein
Journal: The American Journal of Bioethics (2007)

Personhood is a foundational concept in ethics, yet defining criteria have been elusive. In this article we summarize attempts to define personhood in psychological and neurological terms and conclude that none manage to be both specific and non-arbitrary. We propose that this is because the concept does not correspond to any real category of objects in the world. Rather, it is the product of an evolved brain system that develops innately and projects itself automatically and irrepressibly onto the world whenever triggered by stimulus features such as a human-like face, body, or contingent patterns of behavior. We review the evidence for the existence of an autonomous person network in the brain and discuss its implications for the field of ethics and for the implicit morality of everyday behavior.
S45 Functional KCa3.1 K+ channels are required for human fibrocyte migration
Authors: S. M. Duffy, G. Cruse, S. Singh, C. Doe, R. Saunders, C. E. Brightling, P. Bradding
Journal: Thorax (2010)

<h3>Background</h3> Fibrocytes are bone marrow-derived CD34<sup>+</sup> collagen I<sup>+</sup> cells present in peripheral blood that are implicated in the pathogenesis of tissue remodelling and fibrosis in both asthma and pulmonary fibrosis. Ion channels play key roles in cell function, but the ion channel repertoire of human fibrocytes is not known. The aim of this study was to assess whether human fibrocytes express the K<sub>Ca</sub>3.1 K<sup>+</sup> channel. <h3>Methods</h3> Human fibrocytes were isolated from peripheral blood taken from both normal and asthmatic subjects and maintained in cell culture. Channel expression was examined using RT-PCR, Western blot, and patch clamp electrophysiology. Migration assays were performed using the Transwell system. <h3>Results</h3> Fibrocytes expressed both K<sub>Ca</sub>3.1 mRNA and protein. At baseline unstimulated fibrocytes (n=30 healthy cells from 7 donors, n=17 asthmatic cells from 4 donors) demonstrated heterogeneity of the resting whole cell current, with a small outwardly rectifying current in 91% of cells, a steeply inwardly rectifying current in 30% of cells, and a linear current in 9% of cells. The K<sub>Ca</sub>3.1 opener 1-EBIO (100 mM) elicited typical K<sub>Ca</sub>3.1 currents in 46/47 cells tested. Whole cell current at +40 mV increased from 122±25 pA pre-1-EBIO to 795±104 pA post 1-EBIO (p&lt;0.0001). This was accompanied by a negative shift in reversal potential from −29.8±3.0 mV to −61.8±1.6 mV (p&lt;0.0001). 1-EBIO induced a greater current in asthmatic fibrocytes (1-EBIO-dependent current at +40 mV 969±216 pA; n=17 cells) compared to healthy fibrocytes (1-EBIO-induced current 506±94 pA; n=30 cells; p=0.029). K<sub>Ca</sub>3.1 currents were blocked by the selective K<sub>Ca</sub>3.1 blocker TRAM-34. The migration of differentiated fibrocytes induced by airway smooth muscle supernatant was inhibited by 71.1±6.9 % by TRAM-34 200 nM (p&lt;0.0001). The CXCL12-dependent migration of fibrocyte progenitors within a freshly isolated PBMC population was reduced by 70.9±7.9% by TRAM-34 (p=0.003). <h3>Conclusions</h3> The K<sup>+</sup> channel K<sub>Ca</sub>3.1 is expressed in human fibrocytes, and plays a key role in their migration. K<sub>Ca</sub>3.1 blockers may therefore offer a novel approach to the treatment of airway wall remodelling in asthma, and parenchymal fibrosis in idiopathic pulmonary fibrosis.
An expanded population of natural killer cells in mice with severe combined immunodeficiency (SCID) lack rearrangement and expression of T cell receptor genes.
Authors: R J Lauzon, K A Siminovitch, G M Fulop, R A Phillips, J C Roder
Journal: The Journal of Experimental Medicine (1986)

Mice with severe combined immunodeficiency syndrome (SCID) exhibit an impairment in both T and B cell maturation, whereas myelopoiesis remains unaffected. We report here that spleens from SCID mice have undergone phenotypic expansion of cells bearing the NK-2 and asialo GM1 markers (70-80%) characteristic of NK cells and this expansion is accompanied by a 3-4-fold enrichment in NK cytolytic activity over their normal C.B-17 littermates. Furthermore, the NK cells from SCID mice do not rearrange or express T cell receptor alpha or beta genes, or a third T cell rearranging gene, gamma. These findings suggest that (a) T cell receptors are not necessary for NK-mediated cytolysis, and (b) either NK cells constitute an entirely distinct lineage or NK cell function is acquired in pre-T cells prior to the expression of T cell receptor genes.
Analysis of the Normal and Abnormal Vectorcardiogram in Its Own Reference Frame
Authors: HUBERT V. PIPBERGER, THOMAS N. CARTER, Hanna A. Pipberger
Journal: Circulation (1962)

Vectorcardiograms from 296 patients with a variety of ECG abnormalities were compared with normal standards obtained from 249 subjects without evidence of heart disease. A reference frame based on the spatial orientation of QRS loops rather than on conventional plane projections was used. Burger's polar vector and Schellong's QRS plane form the main parameters of such a reference frame. Spatial QRS orientation is defined by one term, the polar vector, which is perpendicular to the QRS plane. The direction of this vector can be determined through rotation of the QRS loop into its principal plane by means of a VCG lead resolver. Further analysis of QRS in its principal plane then becomes independent of inter-individual variability in spatial QRS direction. Separation between normal and abnormal was used as an indicator for the diagnostic quality of various measurements. Two corrected orthogonal lead systems designed by Schmitt and Frank were used for the study. These systems did not differ appreciably in the extent of normal ranges nor in the discrimination between normal and abnormal. The polar vector appeared as the best indicator for abnormalities. In 65 per cent of the pathologic cases this parameter was found outside normal limits. Measurements derived from the contour and principal axes of QRS planes improved the recognition rate for abnormalities. Ratios expressing the degree of QRS planarity, however, contributed little to diagnostic accuracy. The QRS-T angle obtained in the QRS plane improved the recognition rate mainly in the series with ventricular hypertrophies. It could be demonstrated that without evaluation of time and voltage criteria between 85 and 100 per cent of all pathologic records could be recognized as abnormal when the vectorcardiograms were analyzed in their own reference frame. Thus, it appeared that this method of analysis has a considerable diagnostic potential and compares favorably with those used more commonly in clinical electrocardiography and vectorcardiography.
Effect of Mutation Order on Myeloproliferative Neoplasms
Authors: Christina A. Ortmann, David G. Kent, Jyoti Nangalia, Yvonne Silber, David C. Wedge, Jacob Grinfeld, E. Joanna Baxter, Charles E. Massie, Elli Papaemmanuil, Suraj Menon, Anna L. Godfrey, Danai Dimitropoulou, Paola Guglielmelli, Beatriz Bellosillo, Carles Besses, Konstanze Döhner, Claire N. Harrison, George S. Vassiliou, Alessandro Vannucchi, Peter J. Campbell, Anthony R. Green
Journal: New England Journal of Medicine (2015)

Cancers result from the accumulation of somatic mutations, and their properties are thought to reflect the sum of these mutations. However, little is known about the effect of the order in which mutations are acquired.We determined mutation order in patients with myeloproliferative neoplasms by genotyping hematopoietic colonies or by means of next-generation sequencing. Stem cells and progenitor cells were isolated to study the effect of mutation order on mature and immature hematopoietic cells.The age at which a patient presented with a myeloproliferative neoplasm, acquisition of JAK2 V617F homozygosity, and the balance of immature progenitors were all influenced by mutation order. As compared with patients in whom the TET2 mutation was acquired first (hereafter referred to as "TET2-first patients"), patients in whom the Janus kinase 2 (JAK2) mutation was acquired first ("JAK2-first patients") had a greater likelihood of presenting with polycythemia vera than with essential thrombocythemia, an increased risk of thrombosis, and an increased sensitivity of JAK2-mutant progenitors to ruxolitinib in vitro. Mutation order influenced the proliferative response to JAK2 V617F and the capacity of double-mutant hematopoietic cells and progenitor cells to generate colony-forming cells. Moreover, the hematopoietic stem-and-progenitor-cell compartment was dominated by TET2 single-mutant cells in TET2-first patients but by JAK2-TET2 double-mutant cells in JAK2-first patients. Prior mutation of TET2 altered the transcriptional consequences of JAK2 V617F in a cell-intrinsic manner and prevented JAK2 V617F from up-regulating genes associated with proliferation.The order in which JAK2 and TET2 mutations were acquired influenced clinical features, the response to targeted therapy, the biology of stem and progenitor cells, and clonal evolution in patients with myeloproliferative neoplasms. (Funded by Leukemia and Lymphoma Research and others.).
On Artificial Respiration as a Remedy in Diseases of the Chest
Authors: H. Dobell
Journal: BMJ (1869)

the tongue were free, and there was no difficulty of deglutition.She did not seem to have lost any of her intellectual powers; but her emo- tional sensibility was certainly increased.Her general health continued good up to the timre of the last fatal seizure, which occurred in April 1850, without any premonitory symptoms.At the post mortem exa- mination, the upper two-thirds of the anterior lobe of the left hemi- * This case of suspension of the mental faculties, of the powers of speech and special senses, with the exception of sight and touch, and continuing for many months, I published, with a Commentary on its bearings, upon the Philosophy of the Human Mind, and the Physiological Psychology of Man, in this JOURNAL inI855.
Diagnostic pitfall; interpretation of CA 19-9 concentrations in the presence of hepatic dysfunction.
Authors: S Pearce, H Thornes, D Carr, A Tanner
Journal: Gut (1994)

A 50 year old man is described with hepatic dysfunction and chronic pancreatitis in whom greatly increased concentrations of the pancreatic tumour marker CA 19-9 combined with an abnormal appearance at endoscopic retrograde cholangiopancreatography lead to the false suspicion of pancreatic carcinoma. CA 19-9 concentrations should be interpreted with caution in patients with intrinsic liver disease or biliary obstruction.