tbuckley/cabot-search huggingface dataset:
The value of multiple tests of respiratory muscle strength
Authors: J. Steier, S. Kaul, J. Seymour, C. Jolley, G. Rafferty, W. Man, Y. M Luo, M. Roughton, M. I Polkey, J. Moxham
Journal: Thorax (2007)

<h3>Background:</h3> Respiratory muscle weakness is an important clinical problem. Tests of varying complexity and invasiveness are available to assess respiratory muscle strength. The relative precision of different tests in the detection of weakness is less clear, as is the value of multiple tests. <h3>Methods:</h3> The respiratory muscle function tests of clinical referrals who had multiple tests assessed in our laboratories over a 6-year period were analysed. Thresholds for weakness for each test were determined from published and in-house laboratory data. The patients were divided into three groups: those who had all relevant measurements of global inspiratory muscle strength (group A, n = 182), those with full assessment of diaphragm strength (group B, n = 264) and those for whom expiratory muscle strength was fully evaluated (group C, n = 60). The diagnostic outcome of each inspiratory, diaphragm and expiratory muscle test, both singly and in combination, was studied and the impact of using more than one test to detect weakness was calculated. <h3>Results:</h3> The clinical referrals were primarily for the evaluation of neuromuscular diseases and dyspnoea of unknown cause. A low maximal inspiratory mouth pressure (Pimax) was recorded in 40.1% of referrals in group A, while a low sniff nasal pressure (Sniff Pnasal) was recorded in 41.8% and a low sniff oesophageal pressure (Sniff Poes) in 37.9%. When assessing inspiratory strength with the combination of all three tests, 29.6% of patients had weakness. Using the two non-invasive tests (Pimax and Sniff Pnasal) in combination, a similar result was obtained (low in 32.4%). Combining Sniff Pdi (low in 68.2%) and Twitch Pdi (low in 67.4%) reduced the diagnoses of patients with diaphragm weakness to 55.3% in group B. 38.3% of the patients in group C had expiratory muscle weakness as measured by maximum expiratory pressure (Pemax) compared with 36.7% when weakness was diagnosed by cough gastric pressure (Pgas), and 28.3% when assessed by Twitch T10. Combining all three expiratory muscle tests reduced the number of patients diagnosed as having expiratory muscle weakness to 16.7%. <h3>Conclusion:</h3> The use of single tests such as Pimax, Pemax and other available individual tests of inspiratory, diaphragm and expiratory muscle strength tends to overdiagnose weakness. Combinations of tests increase diagnostic precision and, in the population studied, they reduced the diagnosis of inspiratory, specific diaphragm and expiratory muscle weakness by 19–56%. Measuring both Pimax and Sniff Pnasal resulted in a relative reduction of 19.2% of patients falsely diagnosed with inspiratory muscle weakness. The addition of Twitch Pdi to Sniff Pdi increased diagnostic precision by a smaller amount (18.9%). Having multiple tests of respiratory muscle function available both increases diagnostic precision and makes assessment possible in a range of clinical circumstances.
The molecular pathogenesis of head and neck squamous cell carcinoma
Authors: S. Michael Rothenberg, Leif W. Ellisen
Journal: Journal of Clinical Investigation (2012)

Squamous cell carcinoma of the head and neck (HNSCC) is a relatively common human cancer characterized by high morbidity, high mortality, and few therapeutic options outside of surgery, standard cytotoxic chemotherapy, and radiation. Although the most important risk factors are tobacco use and alcohol consumption, the disease is also linked to infection with high-risk types of human papilloma viruses (HPVs). Recent genetic analyses have yielded new insights into the molecular pathogenesis of this disease. Overall, while somatic activating mutations within classical oncogenes including PIK3CA and RAS occur in HNSCC, they are relatively uncommon. Instead genetic data point to a contribution of multiple tumor suppressor pathways, including p53, Rb/INK4/ARF, and Notch, in tumor initiation, progression, and maintenance. The increasingly refined knowledge of HNSCC genetics, combined with ever-more-sophisticated animal models and newer drug targeting strategies, should promote novel therapeutic approaches and improved disease outcomes.
Relative Contributions of Connexins 40 and 43 to Atrial Impulse Propagation in Synthetic Strands of Neonatal and Fetal Murine Cardiomyocytes
Authors: Philippe Beauchamp, Kathryn A. Yamada, Alex J. Baertschi, Karen Green, Evelyn M. Kanter, Jeffrey E. Saffitz, André G. Kléber
Journal: Circulation Research (2006)

Atrial tissue expresses both connexin 40 (Cx40) and 43 (Cx43) proteins. To assess the relative roles of Cx40 and Cx43 in atrial electrical propagation, we synthesized cultured strands of atrial myocytes derived from mice with genetic deficiency in Cx40 or Cx43 expression and measured propagation velocity (PV) by high-resolution optical mapping of voltage-sensitive dye fluorescence. The amount of Cx40 and/or Cx43 in gap junctions was measured by immunohistochemistry and total or sarcolemmal Cx43 or Cx40 protein by immunoblotting. Progressive genetic reduction in Cx43 expression decreased PV from 34±6 cm/sec in Cx43 +/+ to 30±8 cm/sec in Cx43 +/− and 19±11 cm/sec in Cx43 −/− cultures. Concomitantly, the cell area occupied by Cx40 immunosignal in gap junctions decreased from 2.0±1.6% in Cx43 +/+ to 1.7±0.5% in Cx43 +/− and 1.0±0.2% in Cx43 −/− strands. In contrast, progressive genetic reduction in Cx40 expression increased PV from 30±2 cm/sec in Cx40 +/+ to 40±7 cm/sec in Cx40 +/− and 45±10 cm/sec in Cx40 −/− cultures. Concomitantly, the cell area occupied by Cx43 immunosignal in gap junctions increased from 1.2±0.9% in Cx40 +/+ to 2.8±1.4% in Cx40 +/− and 3.1±0.6% in Cx40 −/− cultures. In accordance with the immunostaining results, immunoblots of the Triton X-100–insoluble fraction revealed an increase of Cx43 in gap junctions in extracts from Cx40-ablated atria, whereas total cellular Cx43 remained unchanged. Our results suggest that the relative abundance of Cx43 and Cx40 is an important determinant of atrial impulse propagation in neonatal hearts, whereby dominance of Cx40 decreases and dominance of Cx43 increases local propagation velocity.
High sensitivity cardiac troponin and the under-diagnosis of myocardial infarction in women: prospective cohort study
Authors: Anoop S V Shah, Megan Griffiths, Kuan Ken Lee, David A McAllister, Amanda L Hunter, Amy V Ferry, Anne Cruikshank, Alan Reid, Mary Stoddart, Fiona Strachan, Simon Walker, Paul O Collinson, Fred S Apple, Alasdair J Gray, Keith A A Fox, David E Newby, Nicholas L Mills
Journal: BMJ (2015)

<b>Objective</b> To evaluate the diagnosis of myocardial infarction using a high sensitivity troponin I assay and sex specific diagnostic thresholds in men and women with suspected acute coronary syndrome. <b>Design</b> Prospective cohort study. <b>Setting</b> Regional cardiac centre, United Kingdom. <b>Participants</b> Consecutive patients with suspected acute coronary syndrome (n=1126, 46% women). Two cardiologists independently adjudicated the diagnosis of myocardial infarction by using a high sensitivity troponin I assay with sex specific diagnostic thresholds (men 34 ng/L, women 16 ng/L) and compared with current practice where a contemporary assay (50 ng/L, single threshold) was used to guide care. <b>Main outcome measure</b> Diagnosis of myocardial infarction. <b>Results</b> The high sensitivity troponin I assay noticeably increased the diagnosis of myocardial infarction in women (from 11% to 22%; P&lt;0.001) but had a minimal effect in men (from 19% to 21%, P=0.002). Women were less likely than men to be referred to a cardiologist or undergo coronary revascularisation (P&lt;0.05 for both). At 12 months, women with undisclosed increases in troponin concentration (17-49 ng/L) and those with myocardial infarction (≥50 ng/L) had the highest rate of death or reinfarction compared with women without (≤16 ng/L) myocardial infarction (25%, 24%, and 4%, respectively; P&lt;0.001). <b>Conclusions</b> Although having little effect in men, a high sensitivity troponin assay with sex specific diagnostic thresholds may double the diagnosis of myocardial infarction in women and identify those at high risk of reinfarction and death. Whether use of sex specific diagnostic thresholds will improve outcomes and tackle inequalities in the treatment of women with suspected acute coronary syndrome requires urgent attention.
cAbl Tyrosine Kinase Mediates Reactive Oxygen Species– and Caveolin-Dependent AT <sub>1</sub> Receptor Signaling in Vascular Smooth Muscle
Authors: Masuko Ushio-Fukai, Lian Zuo, Satoshi Ikeda, Taiki Tojo, Nikolay A. Patrushev, R. Wayne Alexander
Journal: Circulation Research (2005)

Important output signals of the angiotensin subtype 1 receptor (AT 1 R) in vascular smooth muscle cells (VSMCs) are mediated by angiotensin II (Ang II)-stimulated transactivation of the epidermal growth factor receptor (EGF-R), which is critical for vascular hypertrophy.Ang II-induced EGF-R transactivation is mediated through cSrc, a proximal target of reactive oxygen species (ROS) derived from NAD(P)H oxidase (NOX) and is dependent on AT 1 R trafficking through caveolin1 (Cav1)-enriched lipid rafts.Underlying molecular mechanisms are incompletely understood.The nonreceptor tyrosine kinase, proto-oncogene cAbl is a substrate of Src and is a major mediator for ROS-dependent tyrosine phosphorylation of Cav1.We thus hypothesized that cAbl is important for ROS-, cSrc-, and Cav1-dependent growth-related AT 1 R signal transduction.Here we show that Ang II induces tyrosine phosphorylation of cAbl in rat VSMCs and mouse aorta, and that Ang II promotes association of cAbl with AT 1 R, both of which are Src-dependent.Pretreatment of rat VSMCs with the NOX inhibitor diphenylene iodonium or the antioxidants N-acetylcysteine or ebselen significantly inhibited Ang II-induced cAbl phosphorylation.Cell fractionation shows that both EGF-Rs and cAbl are found basally in Cav1-enriched membrane fractions.Knockdown of cAbl protein using small interference RNA inhibits Ang II-stimulated: (1) trafficking of AT 1 R into, and EGF-R out of, Cav1-enriched lipid rafts; (2) EGF-R transactivation;(3) appearance of the transactivated EGF-R and phospho-Cav1 at focal adhesions; and (4) vascular hypertrophy.These studies provide a novel role of cAbl in the spatial and temporal organization of growth-related AT 1 R signaling in VSMCs and suggest that cAbl may be generally important in signaling of G-protein coupled receptors.(Circ
Evidence for an adenosine receptor on the surface of dog coronary myocytes.
Authors: R A Olsson, C J Davis, E M Khouri, R E Patterson
Journal: Circulation Research (1976)

Adenosine and theophylline were linked covalently to oxidized stachyose to produce compounds too large to penetrate cell membranes. These compounds were used in two conscious and six open-chest anesthetized dogs to test the hypothesis that there is an adenosine receptor on the surface of the coronary myocyte. Intracoronary infusions of the adenosine derivative produced dose-dependent coronary vasodilation which was antagonized by theophylline; two types of theophylline derivative antagonized the coronary vasodilatory action of adenosine. Although these results show that both adenosine and theophylline exert their coronary effects at the surface of the smooth muscle cells, this evidence does not establish that they are competing for a common receptor.
Propagation of Impulses across the Purkinje Fiber-Muscle Junctions in the Dog Heart
Authors: CARLOS MENDEZ, WILLIAM J. MUELLER, XAVIER URGUIAGA
Journal: Circulation Research (1970)

In canine Purkinje fiber-papillary muscle preparations it was shown directly that electrotonic spread can take place across the junctions between Purkinje fibers and ordinary muscle fibers (P-M junctions). The P-M delay recorded during orthodromic propagation varied considerably within any given preparation. Moderate increases in the external concentration of K + (up to 6 m M ) consistently decreased the P-M delay; when the concentration of external K + was increased to 8 m M the P-M delay increased. With larger concentrations of K + (10 to 11 m M ), total conduction block from the terminal Purkinje fibers to the muscle occurred; under the same conditions antidromic propagation from muscle to Purkinje fiber was still possible. The results can be explained satisfactorily by assuming that propagation across the P-M junction is electrical and that the geometry of the functional syncytium changes progressively from a cable-like system at the level of the terminal Purkinje fibers to a two- or three-dimensional irregular syncytium at the bulk of the myocardial mass.
Polymerase ε1 mutation in a human syndrome with facial dysmorphism, immunodeficiency, livedo, and short stature (“FILS syndrome”)
Authors: Jana Pachlopnik Schmid, Roxane Lemoine, Nadine Nehme, Valéry Cormier-Daire, Patrick Revy, Franck Debeurme, Marianne Debré, Patrick Nitschke, Christine Bole-Feysot, Laurence Legeai-Mallet, Annick Lim, Jean-Pierre de Villartay, Capucine Picard, Anne Durandy, Alain Fischer, Geneviève de Saint Basile
Journal: The Journal of Experimental Medicine (2012)

DNA polymerase ε (Polε) is a large, four-subunit polymerase that is conserved throughout the eukaryotes. Its primary function is to synthesize DNA at the leading strand during replication. It is also involved in a wide variety of fundamental cellular processes, including cell cycle progression and DNA repair/recombination. Here, we report that a homozygous single base pair substitution in POLE1 (polymerase ε 1), encoding the catalytic subunit of Polε, caused facial dysmorphism, immunodeficiency, livedo, and short stature (“FILS syndrome”) in a large, consanguineous family. The mutation resulted in alternative splicing in the conserved region of intron 34, which strongly decreased protein expression of Polε1 and also to a lesser extent the Polε2 subunit. We observed impairment in proliferation and G1- to S-phase progression in patients’ T lymphocytes. Polε1 depletion also impaired G1- to S-phase progression in B lymphocytes, chondrocytes, and osteoblasts. Our results evidence the developmental impact of a Polε catalytic subunit deficiency in humans and its causal relationship with a newly recognized, inherited disorder.
Clinical significance of ZAP-70 protein expression in B-cell chronic lymphocytic leukemia
Authors: Maria Ilaria Del Principe, Giovanni Del Poeta, Francesco Buccisano, Luca Maurillo, Adriano Venditti, Antonella Zucchetto, Rita Marini, Pasquale Niscola, Maria Antonietta Irno Consalvo, Carla Mazzone, Licia Ottaviani, Paola Panetta, Antonio Bruno, Riccardo Bomben, Giovanna Suppo, Massimo Degan, Valter Gattei, Paolo de Fabritiis, Maria Cantonetti, Francesco Lo Coco, Domenico Del Principe, Sergio Amadori
Journal: Blood (2006)
Relationship of Maternal Smoking During Pregnancy With Criminal Arrest and Hospitalization for Substance Abuse in Male and Female Adult Offspring
Authors: Patricia A. Brennan, Emily R. Grekin, Erik Lykke Mortensen, Sarnoff A. Mednick
Journal: American Journal of Psychiatry (2002)

OBJECTIVE: Maternal prenatal smoking has been found to be related to externalizing behavior problems in male offspring, but this relationship has rarely been examined in female offspring. Preliminary evidence suggests that maternal prenatal smoking may be particularly related to antisocial behavior outcomes in male offspring and substance abuse problems in female offspring. This study attempted to replicate these findings in a large-scale, longitudinal community cohort study. METHOD: Subjects were a birth cohort of 4,169 male and 3,943 female offspring born between 1959 and 1961 in Copenhagen, Denmark. During the third trimester of pregnancy, the subjects' mothers self-reported the number of cigarettes smoked on a daily basis. When the offspring were adults, their criminal arrest histories and psychiatric hospitalizations for substance abuse were checked in national registers. Additional data were collected concerning maternal rejection of the infant, socioeconomic status, maternal age, pregnancy and delivery complications, use of drugs in pregnancy, paternal criminal history, and parental psychiatric hospitalization. RESULTS: Results indicate a dose-response relationship between the amount of maternal prenatal smoking and both criminal arrest and psychiatric hospitalization for substance abuse in male and female offspring. These relationships remained significant after potential demographic, parental, and perinatal risk confounds were controlled. Hospitalization of offspring for substance abuse mediated the relationship between maternal prenatal smoking and criminal arrest for female but not for male offspring. CONCLUSIONS: Maternal prenatal smoking is related to criminal and substance abuse outcomes in male and female offspring. Higher rates of index arrests for female offspring may be related to their substance abuse problems.
Increased detection of interleukin-;5 in sputum by addition of protease inhibitors
Authors: M.M. Kelly, R. Leigh, S. Carruthers, P. Horsewood, G.J. Gleich, F.E. Hargreave, G. Cox
Journal: European Respiratory Journal (2001)

The measurement of interleukin (IL)-;5 in sputum is problematic, with interfering factors affecting immunoassay. The authors investigated whether sputum proteases could be acting as interfering factors by studying the effect of protease inhibitors (PI) on sputum IL-;5 measurement. Induced sputa from 20 subjects with asthma were divided into aliquots, processed with and without protease inhibitors (in low and high concentrations) and the levels of IL-;5 (spiked and endogenous) measured by enzyme immunoassay were compared. The concentration of sputum IL-;5 was significantly increased by PI, with median (interquartile range) levels processed with no, low and high PI concentrations being 0 (0), 41.8 (75.6) and 66.1 (124.4) pg·mL −1 , respectively. There was also a significant increase in percentage recovery of spiked IL-;5. Although high concentrations of PI reduced cell viability, there was no effect on total or differential cell counts and low concentrations of PI had no effect on cell counts or viability. Levels of endogenous interleukin-;5 in sputum of asthmatic subjects can be significantly increased by the addition of protease inhibitors, and samples which would be regarded as negative for interleukin-;5 without protease inhibitors may instead have considerable amounts of interleukin-;5 detected.
Comparing long-term toxicity and efficacy of combined modality treatment including extended- or involved-field radiotherapy in early-stage Hodgkin's lymphoma
Authors: S. Sasse, B. Klimm, H. Görgen, M. Fuchs, A. Heyden-Honerkamp, A. Lohri, O. Koch, M. Wilhelm, G. Trenn, J. Finke, R.P. Müller, V. Diehl, H.T. Eich, P. Borchmann, A. Engert
Journal: Annals of Oncology (2012)
Nitrite-Mediated <i>S</i> -Nitrosylation of Caspase-3 Prevents Hypoxia-Induced Endothelial Barrier Dysfunction
Authors: Yen-Chun Lai, Kuan-Ting Pan, Gao-Fong Chang, Chia-Hao Hsu, Kay-Hooi Khoo, Chen-Hsiung Hung, Yun-Jin Jiang, Feng-Ming Ho, Tzu-Ching Meng
Journal: Circulation Research (2011)

Hypoxia is a significant perturbation that exacerbates endothelial barrier dysfunction, contributing to the disruption of vascular homeostasis and the development of various diseases such as atherosclerosis and metastasis of tumors. To date, it is not known what strategy might be used to counter the effect of hypoxia on endothelial permeability.This study investigated the role of nitrite in regulating vascular integrity under hypoxic conditions.We found denitrosylation and the resulting activation of caspase-3 to be critical for hypoxia-induced endothelial permeability. Nitrite treatment led to S-nitrosylation and the inactivation of caspase-3, suppressing the barrier dysfunction of endothelia caused by hypoxia. This process required the conversion of nitrite to bioactive nitric oxide in a nitrite reductase-dependent manner. Using primary human umbilical vein endothelial cells as a model, we showed that in the presence of nitrite, the S-nitrosylated and inactivated form of caspase-3 was unable to cleave β-catenin, a key component in the VE-cadherin complex. Therefore, nitrite treatment led to the maintenance of VE-cadherin-mediated adherens junctions under hypoxic conditions. In in vivo experiments using a zebrafish model, nitrite was found to protect blood vessels from hypoxia-induced vascular leakage.These results are the first to demonstrate that nitrite plays a critical role in the protection of endothelial barrier function against hypoxic insult. Our findings show that nitrite holds great potential for the treatment of diseases associated with hypoxia-induced disorder of vascular homeostasis.
Medical students' characteristics as predictors of career practice location: retrospective cohort study tracking graduates of Nepal's first medical college
Authors: M. Zimmerman, R. Shakya, B. M. Pokhrel, N. Eyal, B. P. Rijal, R. N. Shrestha, A. Sayami
Journal: BMJ (2012)

<b>Objective</b> To determine, in one low income country (Nepal), which characteristics of medical students are associated with graduate doctors staying to practise in the country or in its rural areas. <b>Design</b> Observational cohort study. <b>Setting</b> Medical college registry, with internet, phone, and personal follow-up of graduates. <b>Participants</b> 710 graduate doctors from the first 22 classes (1983-2004) of Nepal's first medical college, the Institute of Medicine. <b>Main outcome measures</b> Career practice location (foreign or in Nepal; in or outside of the capital city Kathmandu) compared with certain pre-graduation characteristics of medical student. <b>Results</b> 710 (97.7%) of the 727 graduates were located: 193 (27.2%) were working in Nepal in districts outside the capital city Kathmandu, 261 (36.8%) were working in Kathmandu, and 256 (36.1%) were working in foreign countries. Of 256 working abroad, 188 (73%) were in the United States. Students from later graduating classes were more likely to be working in foreign countries. Those with pre-medical education as paramedics were twice as likely to be working in Nepal and 3.5 times as likely to be in rural Nepal, compared with students with a college science background. Students who were academically in the lower third of their medical school class were twice as likely to be working in rural Nepal as those from the upper third. In a regression analysis adjusting for all variables, paramedical background (odds ratio 4.4, 95% confidence interval 1.7 to 11.6) was independently associated with a doctor remaining in Nepal. Rural birthplace (odds ratio 3.8, 1.3 to 11.5) and older age at matriculation (1.1, 1.0 to 1.2) were each independently associated with a doctor working in rural Nepal. <b>Conclusions</b> A cluster of medical students' characteristics, including paramedical background, rural birthplace, and lower academic rank, was associated with a doctor remaining in Nepal and with working outside the capital city of Kathmandu. Policy makers in medical education who are committed to producing doctors for underserved areas of their country could use this evidence to revise their entrance criteria for medical school.