tbuckley/cabot-search huggingface dataset:
Role for the Kunitz-3 Domain of Tissue Factor Pathway Inhibitor-α in Cell Surface Binding
Authors: Orlando Piro, George J. Broze
Journal: Circulation (2004)

Background— Tissue factor pathway inhibitor (TFPI)-α, a key regulator of tissue factor–induced coagulation, contains 3 tandem Kunitz-type inhibitory domains. Kunitz-1 binds and inhibits factor VIIa in the factor VIIa/tissue factor complex, and Kunitz-2 binds and inhibits factor Xa. The role of the Kunitz-3 domain of TFPI-α, however, has remained an enigma. Methods and Results— To determine the structures within TFPI-α involved in its binding to cell surface, altered forms of TFPI-α were expressed in C127 (mouse mammary) cells: C-terminal truncated forms TFPI-α (252), TFPI-α (242), and TFPI-α (181), which also lacks the third Kunitz domain (K3); TFPI-α (desK3), which lacks only the K3 domain; and TFPI-α (R199L), in which the putative P1 site in K3 is changed from arginine to leucine. By flow cytometry (fluorescence-activated cell sorting), the altered forms 252, 242, and R199L showed significantly reduced binding, whereas the forms 181 and desK3 completely failed to bind to the cell surface. Transient expression of WT-, desK3-, and K3/K2-TFPI-α (in which K3 is replaced with K2) in another cell line (b-end3, mouse endothelial) produced comparable results. Exogenously added C-terminal truncated and R199L forms of TFPI-α bound poorly and desK3 did not bind at all to the surface of ECV304 cells in which TFPI-α expression had been “knocked down” by RNA interference. Conclusions— Optimal cell binding of endogenously expressed TFPI-α requires its K3 and C-terminal domains, and within the K3 domain, the P1 (R199) residue plays an important role. Thus, one role of the K3 domain involves the cell surface localization of TFPI-α.
Comparison of a Clinical Model, the Oral Glucose Tolerance Test, and Fasting Glucose for Prediction of Type 2 Diabetes Risk in Japanese Americans
Authors: Marguerite J. McNeely, Edward J. Boyko, Donna L. Leonetti, Steven E. Kahn, Wilfred Y. Fujimoto
Journal: Diabetes Care (2003)

OBJECTIVE—To test the validity of a published clinical model for predicting incident diabetes in Japanese Americans. RESEARCH DESIGN AND METHODS—A total of 465 nondiabetic Japanese Americans (243 men, 222 women), aged 34–75 years, were studied at baseline and at 5–6 years. A total of 412 subjects were studied at 10 years. The clinical model included age, sex, ethnicity, BMI, systolic blood pressure, fasting plasma glucose (FPG), HDL cholesterol, and family history of diabetes at baseline. Diabetes status at 5–6 and 10 years was determined by 75-g oral glucose tolerance test. The clinical model, 2-h glucose, and FPG were compared using receiver-operating characteristic (ROC) curves. RESULTS—The diabetes risk associated with BMI, sex, and HDL cholesterol differed by age (P ≤ 0.011). At 5–6 years, the clinical model ROC curve area (0.896) was higher than that for FPG (0.776, P = 0.008), but not for 2-h glucose (0.851, P = 0.341), for subjects aged ≤55 years. For older subjects, the clinical model ROC curve area (0.599) was lower than that for 2-h glucose (0.792, P ≤ 0.001), but not for FPG (0.627, P = 0.467). At 10 years, there were no significant differences between the clinical model, FPG, and 2-h glucose ROC curve areas in either age group. CONCLUSIONS—In Japanese Americans aged ≤55 years, a clinical model was better than FPG for predicting diabetes after 5–6 years but not after 10 years. The model was not useful in older Japanese Americans, whereas 2-h glucose was useful for predicting diabetes risk regardless of age.
Lymphocyte Homing to Bronchus-associated Lymphoid Tissue (BALT) Is Mediated by L-selectin/PNAd, α4β1 Integrin/VCAM-1, and LFA-1 Adhesion Pathways
Authors: Baohui Xu, Norbert Wagner, Linh Nguyen Pham, Vincent Magno, Zhongyan Shan, Eugene C. Butcher, Sara A. Michie
Journal: The Journal of Experimental Medicine (2003)

Bronchus-associated lymphoid tissue (BALT) participates in airway immune responses. However, little is known about the lymphocyte–endothelial adhesion cascades that recruit lymphocytes from blood into BALT. We show that high endothelial venules (HEVs) in BALT express substantial levels of VCAM-1, in marked contrast to HEVs in other secondary lymphoid tissues. BALT HEVs also express the L-selectin ligand PNAd. Anti–L-selectin, anti-PNAd, and anti–LFA-1 mAbs almost completely block the homing of B and T lymphocytes into BALT, whereas anti–α4 integrin and anti–VCAM-1 mAbs inhibit homing by nearly 40%. α4β7 integrin and MAdCAM-1 are not involved. Importantly, we found that mAbs against α4 integrin and VCAM-1 significantly block the migration of total T cells (80% memory phenotype) but not naive T and B cells to BALT. These results suggest that an adhesion cascade, which includes L-selectin/PNAd, α4β1 integrin/VCAM-1, and LFA-1, targets specific lymphocyte subsets to BALT. This high level of involvement of α4β1 integrin/VCAM-1 is unique among secondary lymphoid tissues, and may help unify lymphocyte migration pathways and immune responses in BALT and other bronchopulmonary tissues.
Proposals for Salaried Service
Authors: H. L. Leaming
Journal: BMJ (1965)

JBouwing.A family history of depressive illness should increase awareness of the possibility that a particular child's behaviour, which is causing concern, may be based on a primary disturbance of mood.Suicidal threats, gestures, and, occa- sionally, successful attempts are not unknown in the young, and suicidal threats and gestures should always be taken seriously as being distress signals.The fact that emotionally disturbed children may be referred to paediarricians, physicians, surgeons, child-guidance clinics, and school medical officers, initially makes diagnosis diffi- cult.It is customary in many child-guidance clinics outside the hospital service for a psychiatric social worker to become involved in case work with one or both parents and for a psychiatrist to be responsible for the therapy of the child.Parents bringing a child to a psychiatric clinic, especially within the hospital service, should always be seen and interviewed by the psychiatrist in charge of the case.This is a medical matter and the training, skill, and experience of the psychiatrist are needed in order to elicit accurate details concerning the medical aspects of the child's problems.Application of diagnostic criteria used for adult patients suffering from depressive ill- ness, to children and adolescents, increases the difficulties.
Cortical Morphology in 6- to 10-Year Old Children With Autistic Traits: A Population-Based Neuroimaging Study
Authors: Laura M.E. Blanken, Sabine E. Mous, Akhgar Ghassabian, Ryan L. Muetzel, Nikita K. Schoemaker, Hanan El Marroun, Aad van der Lugt, Vincent W.V. Jaddoe, Albert Hofman, Frank C. Verhulst, Henning Tiemeier, Tonya White
Journal: American Journal of Psychiatry (2015)

Objective: Recent evidence suggests that symptoms of social impairment in autism spectrum disorder (ASD) form a spectrum that extends into the general population. However, it is unclear whether the neuroanatomy of ASD also shows a similar continuum in the general population. Therefore, the goal of the present study was to investigate the relationship between cortical morphology and autistic traits along a continuum in a large population-based sample of young children. Method: The study included 717 children, aged 6–10 years, who are participants in the Generation R Study, a large population-based cohort. Autistic traits were measured using the Social Responsiveness Scale when the children were approximately 6 years old. High-resolution MRI was obtained, and morphological measures of the cortex, including cortical thickness and gyrification, were quantified brain-wide. Results: Children with more autistic traits showed widespread areas of decreased gyrification. After excluding children with the highest autistic traits and confirmed ASD, the association remained present in a large cluster involving the left hemisphere temporal and precuneus regions. Comparable, but nonsignificant, effects when comparing a small sample of confirmed ASD case subjects with age- and gender-matched control subjects were observed. Conclusions: Differences in cortical morphology related to autistic traits along a continuum in a large population-based sample of school-aged children were found. Part of these differences remained after excluding the most severely affected children. These findings lend support to an extension of the neurobiology of autistic traits to the general population.
Thiol Isomerases in Thrombus Formation
Authors: Bruce Furie, Robert Flaumenhaft
Journal: Circulation Research (2014)

Protein disulfide isomerase (PDI), ERp5, and ERp57, among perhaps other thiol isomerases, are important for the initiation of thrombus formation. Using the laser injury thrombosis model in mice to induce in vivo arterial thrombus formation, it was shown that thrombus formation is associated with PDI secretion by platelets, that inhibition of PDI blocked platelet thrombus formation and fibrin generation, and that endothelial cell activation leads to PDI secretion. Similar results using this and other thrombosis models in mice have demonstrated the importance of ERp5 and ERp57 in the initiation of thrombus formation. The integrins, α IIb β 3 and α V β 3 , play a key role in this process and interact directly with PDI, ERp5, and ERp57. The mechanism by which thiol isomerases participate in thrombus generation is being evaluated using trapping mutant forms to identify substrates of thiol isomerases that participate in the network pathways linking thiol isomerases, platelet receptor activation, and fibrin generation. PDI as an antithrombotic target is being explored using isoquercetin and quercetin 3-rutinoside, inhibitors of PDI identified by high throughput screening. Regulation of thiol isomerase expression, analysis of the storage, and secretion of thiol isomerases and determination of the electron transfer pathway are key issues to understanding this newly discovered mechanism of regulation of the initiation of thrombus formation.
Contrast-enhanced dynamic magnetic resonance imaging of the rat kidney.
Authors: R Fransen, H J Muller, W H Boer, K Nicolay, H A Koomans
Journal: Journal of the American Society of Nephrology (1996)

This study was designed to assess whether contrast-enhanced dynamic 1H magnetic resonance imaging (DMRI) can be used to detect the effects of the loop diuretic furosemide and the vasoactive peptide angiotensin II on tubular water reabsorption in the rat kidney. A bolus of gadolinium-DTPA-dimeglumine (Gd-DTPA) (0.025 or 0.1 mmol/kg) was used as a contrast agent. The signal intensity in the magnetic resonance images relative to the precontrast signal intensity (RSI) was assessed as a function of time in the cortex and medulla. In the cortex, no differences were observed between high and low bolus injection, and between different treatment groups and controls. In the medulla, RSI patterns were different between high and low bolus, with the high bolus showing lower RSI values, because of T2 shortening at high Gd-DTPA concentrations. No difference was observed between controls and angiotensin II-infused animals. This is in line with the finding that angiotensin II did not alter medullary water reabsorption, as evidenced by unchanged urine flow and osmolality compared with controls. Medullary RSI patterns during furosemide infusion differed markedly from controls, in a manner suggesting that a lower concentration of Gd-DTPA was present compared with controls. This agrees with the well-known inhibiting effect of furosemide on medullary water reabsorption. It was concluded that, with the method used, small concentration differences of Gd-DTPA in the cortex resulting from small changes of plus or minus 20% in tubular water reabsorption, previously found to be present by direct micropuncture measurements, cannot be detected in rats. However, large changes in renal concentrating ability do result in different RSI patterns in the medulla.
Paralysis of ventilated newborn babies does not influence resistance of the total respiratory system
Authors: R. Burger, S. Fanconi, B. Simma
Journal: European Respiratory Journal (1999)

Paralysis with pancuronium bromide is used in newborn infants to facilitate ventilatory support during respiratory failure. Changes in lung mechanics have been attributed to paralysis. The aim of this study was to examine whether or not paralysis per se has an influence on the passive respiratory mechanics, resistance (Rrs) and compliance (Crs) of the respiratory system in newborn infants. In 30 infants with acute respiratory failure, Rrs was measured during paralysis with pancuronium bromide and after stopping pancuronium bromide (group A). Rrs was also measured in an additional 10 ventilated infants in a reversed fashion (group B): Rrs was measured first in nonparalysed infants and then they were paralysed, mainly for diagnostic procedures, and the Rrs measurement repeated. As Rrs is highly dependent on lung volume, several parameters, that depend directly on lung volume were recorded: inspiratory oxygen fraction (FI,O2), arterial oxygen tension/alveolar oxygen tension (a/A) ratio and volume above functional residual capacity (FRC). In group A, the Rrs was not different during (0.236+/-0.09 cmH2O x s x mL(-1)) and after (0.237+/-0.07 cmH2O x s x mL(-1)) paralysis. Also, in group B, Rrs did not change (0.207+/-0.046 versus 0.221+/-0.046 cm x s x mL(-1) without versus with pancuronium bromide). FI,O2, a/A ratio and volume above FRC remained constant during paralysis. These data demonstrate that paralysis does not influence the resistance of the total respiratory system in ventilated term and preterm infants when measured at comparable lung volumes.
Modified cell cycle status in a mouse model of altered neuronal vulnerability (slow Wallerian degeneration; Wlds)
Authors: Thomas M Wishart, Helen N Pemberton, Sally R James, Chris J McCabe, Thomas H Gillingwater
Journal: Genome biology (2008)

Altered neuronal vulnerability underlies many diseases of the human nervous system, resulting in degeneration and loss of neurons. The neuroprotective slow Wallerian degeneration (Wld s ) mutation delays degeneration in axonal and synaptic compartments of neurons following a wide range of traumatic and disease-inducing stimuli, providing a powerful experimental tool with which to investigate modulation of neuronal vulnerability. Although the mechanisms through which Wld s confers neuroprotection remain unclear, a diverse range of downstream modifications, incorporating several genes/pathways, have been implicated. These include the following: elevated nicotinamide adenine dinucleotide (NAD) levels associated with nicotinamide mononucleotide adenylyltransferase 1 (Nmnat1; a part of the chimeric Wld s gene); altered mRNA expression levels of genes such as pituitary tumor transforming gene 1 (Pttg1); changes in the location/activity of the ubiquitin-proteasome machinery via binding to valosin-containing protein (VCP/p97); and modified synaptic expression of proteins such as ubiquitin-activating enzyme E1 (Ube1). Wld s expression in mouse cerebellum and HEK293 cells induced robust increases in a broad spectrum of cell cycle-related genes. Both NAD-dependent and Pttg1-dependent pathways were responsible for mediating different subsets of these alterations, also incorporating changes in VCP/p97 localization and Ube1 expression. Cell proliferation rates were not modified by Wld s , suggesting that later mitotic phases of the cell cycle remained unaltered. We also demonstrate that Wld s concurrently altered endogenous cell stress pathways. We report a novel cellular phenotype in cells with altered neuronal vulnerability. We show that previous reports of diverse changes occurring downstream from Wld s expression converge upon modifications in cell cycle status. These data suggest a strong correlation between modified cell cycle pathways and altered vulnerability of axonal and synaptic compartments in postmitotic, terminally differentiated neurons.
On Auscultation of the OEsophagus
Authors: T. C. Allbutt
Journal: BMJ (1875)

DiSEASES of the oEsophagus often prov:e somewhat difficult of investi- gation, and it is not likely that we shall ever succeed in bringing this tube within the range of vision, as we have brought the larynx, the inner eye, and even the cavity of the bladder.Diseases of the aesopha.gus, moreover, even when benignant in character, have a peculiar terror in the peril of starvation wvhich th'eatens the sufferer.Any help, then, which we can obtain either ikm our diagnosis or our treat.ment of disease in this part, should be carefully cherished; and for this reason I venture to bring berore you a means of diagnosis which, in my opinion, has been unduly neglected.The only means used in cases of alleged disease of the amsophagus are the catechising of.the
Simvastatin selectively inhibits TSLP-production in primary bronchial epithelial cells from COPD donors
Authors: Angelica Brandelius, Jenny Calvén, Leif Bjermer, Irma Mahmutovic Persson, Carl Persson, Morgan Andersson, Lena Uller
Journal: European Respiratory Journal (2011)

Background:  Possibly reflecting anti-inflammatory properties, statin treatment may ameliorate COPD exacerbations. Viral infections apparently cause TH2 type COPD exacerbations. We have shown previously that thymic stromal lymphopoietin (TSLP), a cytokine linking innate and adaptive immunity and switching on TH2 type inflammation, is overproduced in viral stimulated epithelial cells from GOLD stage IV COPD donors.   Objective:  Explore effects of simvastatin on viral-induced TSLP in epithelial cells from patients with GOLD stage II COPD.   Methods:  Primary bronchial epithelial cells, obtained by fibre optic bronchoscopy from COPD (n=4) and healthy individual (n=3) donors, were grown in 12-well plates and stimulated with a synthetic viral surrogate, double-stranded RNA (dsRNA, 10μg/ml) to induce cytokine expression (3h, RT-qPCR) and production (24 h, ELISA). Simvastatin (0,2-5μg) with or without mevalonate (13μg/ml) was added 18 h prior to dsRNA. Alternatively, dexamethasone (1μM) was added 1 h prior to dsRNA.   Results:  dsRNA induced TSLP, TNF-alpha and IL-8 mRNA and protein expression (p 0.05).   Conclusion:  Independent of the mevalonic pathway, simvastatin selectively inhibited dsRNA-induced TSLP-production in COPD cells. These data support exploration of statin treatment in viral-induced COPD exacerbations. The pharmacology of simvastatin may unravel paths of selective inhibition of TSLP-production in COPD epithelium.
BRCA1 Interacts with and Is Required for Paclitaxel-Induced Activation of Mitogen-Activated Protein Kinase Kinase Kinase 3
Authors: Paula M. Gilmore, Nuala McCabe, Jennifer E. Quinn, Richard D. Kennedy, Julia J. Gorski, Heather N. Andrews, Stewart McWilliams, Michael Carty, Paul B. Mullan, W. Paul Duprex, Edison T. Liu, Patrick G. Johnston, D. Paul Harkin
Journal: Cancer Research (2004)

BRCA1 has been implicated in a number of cellular processes, including transcriptional regulation, DNA damage repair, cell cycle arrest, and apoptosis. We identified mitogen-activated protein kinase (MAPK) kinase kinase 3 (MEKK3), an upstream regulator of the c-Jun NH(2)-terminal kinase/stress-activated protein kinase and p38/MAPK pathways, as a novel BRCA1-interacting protein in a yeast two-hybrid screen and confirmed the interaction by coimmunoprecipitation in mammalian cells. Deletion mapping demonstrated that amino acids 1611-1863 are required to mediate the interaction with MEKK3 in yeast. BRCA1 disease-associated mutations abrogated the interaction in yeast, and BRCA1 failed to interact with MEKK3 in BRCA1 mutant HCC1937 breast cancer cells. We demonstrate that small interfering RNA-based inhibition of endogenous BRCA1 reduces MEKK3 kinase activity and conversely that inducible expression of BRCA1 activates MEKK3 and p38/MAPK. Finally, we demonstrate using complementary approaches that BRCA1 is required for paclitaxel-induced activation of MEKK3. These data indicate that BRCA1 is a key regulator of the paclitaxel-induced stress response pathway and suggest that the ability of BRCA1 to associate with, and mediate the activation of, MEKK3 represents a potential mechanism through which this pathway is regulated.
Serial antinuclear antibodies titre in pleural and pericardial fluid
Authors: D-Y. Wang, P-C. Yang, W-L. Yu, S-H Kuo, N-Y Hsu
Journal: European Respiratory Journal (2000)

The antinuclear antibodies (ANA) test has been a cornerstone of the evaluation of connective tissue disease. The aim of this study was to investigate the diagnostic value of the ANA test in pleural or pericardial effusions of unknown causes. Over a 3-yr period, a total of 126 pleural fluid and 30 pericardial fluid samples were analysed. ANA tests were performed using a commercially available kit. The ANA kit used an indirect immunofluorescent antibody method with a human epithelial (HEP-2) cell line as substrate. Patients with high fluid ANA titre (&gt;1:160) received a second aspiration 2 weeks after the initial aspiration if diagnosis was not confirmed. ANA results were positive in 39 pleural and 10 pericardial fluid samples. All but one of the effusions with positive ANA testing were exudative. Eleven pleural or pericardial effusions due to active systematic lupus erythematosus were identified and all had high ANA titres (1:160) with various staining patterns. Thirty-eight of 145 patients (26%) with effusions of nonlupus aetiologies had positive ANA testing in pleural or pericardial fluid. Thirteen of these 38 patients had high ANA titre. Malignant or paramalignant effusions constituted 11 of the 13 samples. In conclusion, although a negative antinuclear antibodies test makes a diagnosis of lupus serositis unlikely, high antinuclear antibodies titres in pleural or pericardial fluid are not diagnostic of lupus serositis even when as high as 1:5,120. An unexplained high antinuclear antibodies titre in pleural or pericardial effusion warrants search for malignancy.
Interobserver Agreement of the Echocardiographic Diagnosis of LV Hypertrabeculation/Noncompaction
Authors: Claudia Stöllberger, Birgit Gerecke, Rolf Engberding, Bernhard Grabner, Cosima Wandaller, Josef Finsterer, Matthias Gietzelt, Andreas Balzereit
Journal: JACC. Cardiovascular imaging (2015)