tbuckley/cabot-search huggingface dataset:
Increased gastro-oesophageal reflux disease in patients with severe COPD
Authors: C. Casanova, J.S. Baudet, M. del Valle Velasco, J.M. Martin, A. Aguirre-Jaime, J. Pablo de Torres, B.R. Celli
Journal: European Respiratory Journal (2004)

The prevalence and clinical consequences of gastro-oesophageal reflux disease (GERD) in chronic obstructive pulmonary disease (COPD) are not well characterised. The present study prospectively studied 42 males with COPD (forced expiratory volume in one second % predicted: 35%, range 20–49) and 16 healthy volunteers of similar age without respiratory or gastro-oesophageal symptoms. The diagnosis of GERD was confirmed using oesophageal 24 h pH monitoring. In the current study group, reflux symptoms were measured using the Vigneri score, cough and dyspnoea with the modified Medical Research Council questionnaire, and pulmonary function with bronchodilator response and health status using St George's Respiratory Questionnaire. Pathological reflux was documented in 26 out of 42 patients (62%) and in three volunteers (19%). In patients with GERD, 15 patients (58%) did not report any reflux symptoms. There were no differences in symptoms, health status, bronchodilator treatment and pulmonary function test between patients with and without GERD. Oxygen desaturation coincided with episodes of increased oesophageal acidity in 40% of patients with GERD. Patients with severe chronic obstructive pulmonary disease have a high prevalence of asymptomatic gastro-oesophageal reflux. The association between this reflux and oxygen desaturation deserves further attention.
Tumor Necrosis Factor and Interleukin-1 Inhibitors as Markers of Disease Activity of Tuberculosis
Authors: NICOLE P. JUFFERMANS, ANNELIES VERBON, SANDER J. H. van DEVENTER, HENK van DEUTEKOM, PETER SPEELMAN, TOM van der POLL
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

Serum concentrations of tumor necrosis factor- α (TNF), interleukin (IL)-1 β , and their circulating inhibitors soluble TNF receptor type I (sTNFRI), type II (sTNFRII), IL-1 receptor antagonist (IL-1ra), and soluble IL-1 receptor type II (sIL-1RII) were measured for 123 patients with tuberculosis (TB) in various stages of disease, in persons who had been in close contact with patients with contagious pulmonary TB, and in healthy controls. Levels of sTNFRI, sTNFRII, and IL-1ra, but not of sIL-1RII, were elevated in patients with active TB compared with contacts and controls and declined during treatment. The concentrations of these mediators did not differ between patients with pulmonary and extrapulmonary TB. The levels of sTNFRI and IL-1ra were higher in patients with fever and anorexia. Neither TNF nor IL-1 β was detectable. We conclude that serum concentrations of sTNFRs I and II and IL-1ra may serve as markers of disease activity of TB. Sequential measurements of these cytokine inhibitors may be useful in the monitoring of antituberculous therapy.
Preconditioning of the Tumor Vasculature and Tumor Cells by Intermittent Hypoxia: Implications for Anticancer Therapies
Authors: Philippe Martinive, Florence Defresne, Caroline Bouzin, Julie Saliez, Florence Lair, Vincent Grégoire, Carine Michiels, Chantal Dessy, Olivier Feron
Journal: Cancer Research (2006)

Abstract Hypoxia is a common feature in tumors associated with an increased resistance of tumor cells to therapies. In addition to O2 diffusion–limited hypoxia, another form of tumor hypoxia characterized by fluctuating changes in pO2 within the disorganized tumor vascular network is described. Here, we postulated that this form of intermittent hypoxia promotes endothelial cell survival, thereby extending the concept of hypoxia-driven resistance to the tumor vasculature. We found that endothelial cell exposure to cycles of hypoxia reoxygenation not only rendered them resistant to proapoptotic stresses, including serum deprivation and radiotherapy, but also increased their capacity to migrate and organize in tubes. By contrast, prolonged hypoxia failed to exert protective effects and even seemed deleterious when combined with radiotherapy. The use of hypoxia-inducible factor-1α (HIF-1α)–targeting small interfering RNA led us to document that the accumulation of HIF-1α during intermittent hypoxia accounted for the higher resistance of endothelial cells. We also used an in vivo approach to enforce intermittent hypoxia in tumor-bearing mice and found that it was associated with less radiation-induced apoptosis within both the vascular and the tumor cell compartments (versus normoxia or prolonged hypoxia). Radioresistance was further ascertained by an increased rate of tumor regrowth in irradiated mice preexposed to intermittent hypoxia and confirmed in vitro using distinctly radiosensitive tumor cell lines. In conclusion, we have documented that intermittent hypoxia may condition endothelial cells and tumor cells in such a way that they are more resistant to apoptosis and more prone to participate in tumor progression. Our observations also underscore the potential of drugs targeting HIF-1α to resensitize the tumor vasculature to anticancer treatments. (Cancer Res 2006; 66(24): 11736-44)
POINTS FROM LETTERS: Proposed Coat of Arms for B.M.A
Authors: A. E. Stevens
Journal: BMJ (1954)

Excitatory synapses can be potentiated by chemical neuromodulators, including 17β-estradiol (E2), or patterns of synaptic activation, as in long-term potentiation (LTP). Here, we investigated kinases and calcium sources required for acute E2-induced synaptic potentiation in the hippocampus of each sex and tested whether sex differences in kinase signaling extend to LTP. We recorded excitatory postsynaptic currents from CA1 pyramidal cells in hippocampal slices from adult rats and used specific inhibitors of kinases and calcium sources. This revealed that although E2 potentiates synapses to the same degree in each sex, cAMP-activated protein kinase (PKA) is required to initiate potentiation only in females. In contrast, mitogen-activated protein kinase, Src tyrosine kinase, and rho-associated kinase are required for initiation in both sexes; similarly, Ca<sup>2+</sup>/Calmodulin-activated kinase II is required for expression/maintenance of E2-induced potentiation in both sexes. Calcium source experiments showed that L-type calcium channels and calcium release from internal stores are both required for E2-induced potentiation in females, whereas in males, either L-type calcium channel activation or calcium release from stores is sufficient to permit potentiation. To investigate the generalizability of a sex difference in the requirement for PKA in synaptic potentiation, we tested how PKA inhibition affects LTP. This showed that although the magnitude of both high frequency stimulation-induced and pairing-induced LTP is the same between sexes, PKA is required for LTP in females but not males. These results demonstrate latent sex differences in mechanisms of synaptic potentiation in which distinct molecular signaling converges to common functional endpoints in males and females. <b>SIGNIFICANCE STATEMENT</b> Chemical and activity-dependent neuromodulation alters synaptic strength in both male and female brains, yet few studies have compared mechanisms of neuromodulation between the sexes. Here, we studied molecular signaling that underlies estrogen-induced and activity-dependent potentiation of excitatory synapses in the hippocampus. We found that despite similar magnitude increases in synaptic strength in males and females, the roles of cAMP-regulated protein kinase, internal calcium stores, and L-type calcium channels differ between the sexes. Thus latent sex differences in which the same outcome is achieved through distinct underlying mechanisms in males and females include kinase and calcium signaling involved in synaptic potentiation, demonstrating that sex is an important factor in identification of molecular targets for therapeutic development based on mechanisms of neuromodulation.
Tumor-Associated Macrophages Mediate Immunosuppression in the Renal Cancer Microenvironment by Activating the 15-Lipoxygenase-2 Pathway
Authors: Irina Daurkin, Evgeniy Eruslanov, Taryn Stoffs, George Q. Perrin, Chester Algood, Scott M. Gilbert, Charles J. Rosser, Li-Ming Su, Johannes Vieweg, Sergei Kusmartsev
Journal: Cancer Research (2011)

Renal cell carcinoma (RCC), the most common human kidney cancer, is frequently infiltrated with tumor-associated macrophages (TAM) that can promote malignant progression. Here, we show that TAMs isolated from human RCC produce substantial amounts of the proinflammatory chemokine CCL2 and immunosuppressive cytokine IL-10, in addition to enhanced eicosanoid production via an activated 15-lipoxygenase-2 (15-LOX2) pathway. TAMs isolated from RCC tumors had a high 15-LOX2 expression and secreted substantial amounts of 15(S)-hydroxyeicosatetraenoic acid, its major bioactive lipid product. Inhibition of lipoxygenase activity significantly reduced production of CCL2 and IL-10 by RCC TAMs. In addition, TAMs isolated from RCC were capable of inducing in T lymphocytes, the pivotal T regulatory cell transcription factor forkhead box P3 (FOXP3), and the inhibitory cytotoxic T-lymphocyte antigen 4 (CTLA-4) coreceptor. However, this TAM-mediated induction of FOXP3 and CTLA-4 in T cells was independent of lipoxygenase and could not be reversed by inhibiting lipoxygenase activity. Collectively, our results show that TAMs, often present in RCCs, display enhanced 15-LOX2 activity that contributes to RCC-related inflammation, immunosuppression, and malignant progression. Furthermore, we show that TAMs mediate the development of immune tolerance through both 15-LOX2-dependent and 15-LOX2-independent pathways. We propose that manipulating LOX-dependent arachidonic acid metabolism in the tumor microenvironment could offer new strategies to block cancer-related inflammation and immune escape in patients with RCC.
Blocking Hypoxia-Induced Autophagy in Tumors Restores Cytotoxic T-Cell Activity and Promotes Regression
Authors: Muhammad Zaeem Noman, Bassam Janji, Bozena Kaminska, Kris Van Moer, Sandrine Pierson, Piotr Przanowski, Stéphanie Buart, Guy Berchem, Pedro Romero, Fathia Mami-Chouaib, Salem Chouaib
Journal: Cancer Research (2011)

Abstract The relationship between hypoxic stress, autophagy, and specific cell-mediated cytotoxicity remains unknown. This study shows that hypoxia-induced resistance of lung tumor to cytolytic T lymphocyte (CTL)–mediated lysis is associated with autophagy induction in target cells. In turn, this correlates with STAT3 phosphorylation on tyrosine 705 residue (pSTAT3) and HIF-1α accumulation. Inhibition of autophagy by siRNA targeting of either beclin1 or Atg5 resulted in impairment of pSTAT3 and restoration of hypoxic tumor cell susceptibility to CTL-mediated lysis. Furthermore, inhibition of pSTAT3 in hypoxic Atg5 or beclin1-targeted tumor cells was found to be associated with the inhibition Src kinase (pSrc). Autophagy-induced pSTAT3 and pSrc regulation seemed to involve the ubiquitin proteasome system and p62/SQSTM1. In vivo experiments using B16-F10 melanoma tumor cells indicated that depletion of beclin1 resulted in an inhibition of B16-F10 tumor growth and increased tumor apoptosis. Moreover, in vivo inhibition of autophagy by hydroxychloroquine in B16-F10 tumor-bearing mice and mice vaccinated with tyrosinase-related protein-2 peptide dramatically increased tumor growth inhibition. Collectively, this study establishes a novel functional link between hypoxia-induced autophagy and the regulation of antigen-specific T-cell lysis and points to a major role of autophagy in the control of in vivo tumor growth. Cancer Res; 71(18); 5976–86. ©2011 AACR.
NOD-Like Receptors: Role in Innate Immunity and Inflammatory Disease
Authors: Grace Chen, Michael H. Shaw, Yun-Gi Kim, Gabriel Nuñez
Journal: Annual Review of Pathology Mechanisms of Disease (2008)

The NOD-like receptors (NLRs) are a specialized group of intracellular receptors that represent a key component of the host innate immune system. Since the discovery of the first NLR almost 10 years ago, the study of this special class of microbial sensors has burgeoned; consequently, a better understanding of the mechanism by which these receptors recognize microbes and other danger signals and of how they activate inflammatory signaling pathways has emerged. Moreover, in addition to their primary role in host defense against invading pathogens, their ability to regulate nuclear factor-kappa B (NF-kappaB) signaling, interleukin-1-beta (IL-1beta) production, and cell death indicates that they are crucial to the pathogenesis of a variety of inflammatory human diseases.
Immune-Related and Inflammatory Conditions and Risk of Lymphoplasmacytic Lymphoma or Waldenstrom Macroglobulinemia
Authors: S. Y. Kristinsson, J. Koshiol, M. Bjorkholm, L. R. Goldin, M. L. McMaster, I. Turesson, O. Landgren
Journal: JNCI Journal of the National Cancer Institute (2010)

Chronic immune stimulation appears to be associated with lymphoplasmacytic lymphoma (LPL)-Waldenström macroglobulinemia (WM); however, available information is sparse. We conducted, to our knowledge, the most comprehensive study to date to evaluate associations between a personal or family history of many immune-related and/or inflammatory disorders and the subsequent risk of LPL-WM. We used Swedish population-based registries to identify 2470 case patients with LPL-WM, 9698 matched control subjects, and almost 30 000 first-degree relatives of either case patients or control subjects. We evaluated a wide range of autoimmune, infectious, allergic, and inflammatory conditions. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) for each condition by use of logistic regression. An increased risk of LPL-WM was associated with a personal history of the following autoimmune diseases: systemic sclerosis (OR = 4.7, 95% CI = 1.4 to 15.3), Sjögren syndrome (OR = 12.1, 95% CI = 3.3 to 45.0), autoimmune hemolytic anemia (OR = 24.2, 95% CI = 5.4 to 108.2), polymyalgia rheumatica (OR = 2.9, 95% CI = 1.6 to 5.2), and giant cell arteritis (OR = 8.3, 95% CI = 2.1 to 33.1). An increased risk of LPL-WM was associated with a personal history of the following infectious diseases: pneumonia (OR = 1.4, 95% CI = 1.1 to 1.7), septicemia (OR = 2.4, 95% CI = 1.2 to 4.3), pyelonephritis (OR = 1.7, 95% CI = 1.1 to 2.5), sinusitis (OR = 2.7, 95% CI = 1.4 to 4.9), herpes zoster (OR = 3.4, 95% CI = 2.0 to 5.6), and influenza (OR = 2.9, 95% CI = 1.7 to 5.0). An increased risk of LPL-WM was associated with a family history of the following autoimmune or infectious diseases: Sjögren syndrome (OR = 5.0, 95% CI = 2.1 to 12.0), autoimmune hemolytic anemia (OR = 3.8, 95% CI = 1.1 to 13.2), Guillain–Barré syndrome (OR = 4.1, 95% CI = 1.8 to 9.4), cytomegalovirus (OR = 2.7, 95% CI = 1.4 to 5.3), gingivitis and periodontitis (OR = 1.9, 95% CI = 1.3 to 2.7), and chronic prostatitis (OR = 4.3, 95% CI = 1.7 to 11.1). Personal history of certain immune-related and/or infectious conditions was strongly associated with increased risk of LPL-WM. The association of both personal and family history of Sjögren syndrome and autoimmune hemolytic anemia with risk of LPL-WM indicates the potential for shared susceptibility for these conditions.
Modern Drug Therapy: A Hindrance to Early Cancer Diagnosis?
Authors: J. C. Moir
Journal: BMJ (1964)

ICARK"a Court of Law and might even involve the psychiatrist who repeats them in a libel action.Freud himself had later to admit that the accusations his female patients made against their fathers which he at first believed were the product of their imagination and dis- torted memory.Every policeman knows how readily people under some emotional strain may accuse themselves of murder or serious crimes they have never committed.However, such subterfuges and treating the legal profession with their own medicine should not be necessary, nor need we wait, as Dr. Spencer suggests, till some psychiatrist is prepared to go to prison.I am sure, Sir, that the whole profession and the common man in the street would wholeheartedly stand behind the B.M.A. or any medical M.P. who would propose to bring the law for the physi- cian (and incidentally the priest) in line with the solicitor, whose communications with his client are legally recognized as privileged.-I am, etc., Leicester.
Epidemic Catarrhal Jaundice in School Children
Authors: G. D. Pirrie
Journal: BMJ (1937)

SIR,-It was interesting to read the account in the Journial of October 9 (p. 703) by Dr. B. Sergeant of the epidemic in Gateshead. In the part of Surrey where I live, though we have had no epidemic for some years, there are two village schools where there are nearly always one or two families affected. Unlike Dr. Sergeant, we find it usual for more than one member of the family to be affected, and it is the rule of the local education authority, the Surrey County Council, to exclude home contacts for three weeks; it would appear that this period is too short, but in practice there seems to be little tendency for further cases to occur in the school. Local feeling would blame the grey squirrels for the infections, but this may be merely  little England  bias. This spring, in one of the villages, a boy aged 12, who attended a central school four miles away, developed jaundice ; a sister (8) and a brother (6) caught it after intervals of four and three weeks respectively; a baby of 7 months and the parents were not affected. There was no history of contact in or out of school with another case, but a Great Dane, a frequent companion of the children, had been treated for jaundice three or four weeks before the elder boy became ill. If there is to be any advance in our knowledge of this disease it will be from the observations of general practitioners and school medical officers, as only very rarely do these patients enter a hospital ; they usually are treated at home, recovering after one visit from the family doctor, or even without it.-I am, etc., Chaldon, Surrey, Oct. 10. G. D. PIRRIE.
Thrombolysis and clinical outcome in patients with stroke after implementation of the Tyrol Stroke Pathway: a retrospective observational study
Authors: Johann Willeit, Theresa Geley, Johannes Schöch, Heinrich Rinner, Andreas Tür, Hans Kreuzer, Norbert Thiemann, Michael Knoflach, Thomas Toell, Raimund Pechlaner, Karin Willeit, Natalie Klingler, Silvia Praxmarer, Michael Baubin, Gertrud Beck, Klaus Berek, Christian Dengg, Klaus Engelhardt, Thomas Erlacher, Thomas Fluckinger, Wilhelm Grander, Josef Grossmann, Hermann Kathrein, Norbert Kaiser, Benjamin Matosevic, Heinrich Matzak, Markus Mayr, Robert Perfler, Werner Poewe, Alexandra Rauter, Gudrun Schoenherr, Hans-Robert Schoenherr, Adolf Schinnerl, Heinrich Spiss, Theresa Thurner, Gernot Vergeiner, Philipp Werner, Ewald Wöll, Peter Willeit, Stefan Kiechl
Journal: The Lancet Neurology (2014)
Diagnostic Performance of Whole Body Dual Modality <sup>18</sup>F-FDG PET/CT Imaging for N- and M-Staging of Malignant Melanoma: Experience With 250 Consecutive Patients
Authors: Michael J. Reinhardt, Alexius Y. Joe, Ursula Jaeger, Andrea Huber, Alexander Matthies, Jan Bucerius, Roland Roedel, Holger Strunk, Thomas Bieber, Hans-Juergen Biersack, Thomas Tüting
Journal: Journal of Clinical Oncology (2006)

To assess the diagnostic performance of positron emission tomography/computed tomography (PET/CT) using (18)F-fluorodeoxyglucose (FDG) for N- and M-staging of cutaneous melanoma.This is a retrospective and blinded study of 250 consecutive patients (105 women, 145 men; age 58 +/- 16 years) who underwent FDG-PET/CT for staging of cutaneous melanoma at different time points in the course of disease. Whole-body FDG-PET/CT was performed 101 +/- 21 minutes postinjection of 371 +/- 41 MBq FDG. Diagnostic accuracy for N- and M-staging was determined for CT alone, PET alone, and PET/CT.PET/CT detected significantly more visceral and nonvisceral metastases than PET alone and CT alone (98.7%, 88.8%, and 69.7%, respectively). PET/CT imaging thus provided significantly more accurate interpretations regarding overall N- and M-staging than PET alone and CT alone. Overall N- and M-stage was correctly determined by PET/CT in 243 of 250 patients (97.2%; 95% CI, 95.2% to 99.4%) compared with 232 patients (92.8%; 95% CI, 89.6% to 96.0%) by PET, and 197 patients (78.8%; 95% CI, 73.7% to 83.9%) by CT. All differences were significant. Accuracy of PET/CT was significantly higher than that of PET and CT for M-staging (0.98 v 0.93 and 0.84) and significantly higher than that of CT for N-Staging (0.98 v 0.86). Change of treatment according to PET/CT findings occurred in 121 patients (48.4%).The diagnostic performance of FDG-PET/CT for N- and M-staging of melanoma patients suggests its use for whole-body tumor staging, especially for detection or exclusion of distant metastases.
A Mechanism for "False" Inhibition of Demand Pacemakers
Authors: KENNETH C. LASSETER, JACK W. BUCHANAN, KARL F. YOSHONIS
Journal: Circulation (1970)

Certain variations in discharge rate of demand pacemakers may be associated with intermittent fractures and resulting resistance changes in the electrode-lead system. These variations in rate are related to inhibition of the demand circuit of the pacemaker. Most pacemakers produce a biphasic output pulse which results in a low amplitude current during the interval between stimuli. Therefore, sudden changes of resistance in the electrode-lead system will produce a potential change at the pacemaker terminals which is of sufficient magnitude to be interpreted as spontaneous ventricular depolarization and inhibit the demand pacemaker. Such inhibition may occur in the absence of other signs of lead fracture and present a difficult differential diagnostic problem of pacemaker malfunction.
Diabetogenic action of streptozotocin: relationship of dose to metabolic response
Authors: Alain Junod, André E. Lambert, Werner Stauffacher, Albert E. Renold
Journal: Journal of Clinical Investigation (1969)

The relationship between the dose of intravenously administered streptozotocin (a N-nitroso derivative of glucosamine) and the diabetogenic response has been explored by use of the following indices of diabetogenic action: serum glucose, urine volume, and glycosuria, ketonuria, serum immunoreactive insulin (IRI), and pancreatic IRI content. Diabetogenic activity could be demonstrated between the doses of 25 and 100 mg/kg, all indices used showing some degree of correlation with the dose administered. Ketonuria was only seen with the largest dose, 100 mg/kg. The most striking and precise correlation was that between the dose and the pancreatic IRI content 24 hr after administration of the drug, and it is suggested that this represents a convenient test system either for both related and unrelated beta cytotoxic compounds or for screening for modifying agents or antidiabetic substances of a novel type. Ability to produce graded depletion of pancreatic IRI storage capacity led to an analysis of the relationship between pancreatic IRI content and deranged carbohydrate metabolism. Abnormal glucose tolerance and insulin response were seen when pancreatic IRI was depleted by about one-third, while fasting hyperglycemia and gross glycosuria occurred when the depletion had reached two-thirds and three-quarters, respectively. The mild yet persistent anomaly produced by the lowest effective streptozotocin dose, 25 mg/kg, exhibits characteristics resembling the state of chemical diabetes in humans and might thus warrant further study as a possible model. Finally, the loss of the diabetogenic action of streptozotocin by pretreatment with nicotinamide was confirmed and was shown to be a function of the relative doses of nicotinamide and streptozotocin and of the interval between injections.