tbuckley/cabot-search huggingface dataset:
Effect of High- and Low-Molecular-Weight Heparins on Thrombin-Thrombomodulin Interaction and Protein C Activation
Authors: Raimondo De Cristofaro, Erica De Candia, Raffaele Landolfi
Journal: Circulation (1998)

Background —Thrombin-thrombomodulin (TM) interaction, which is critical for accelerating the protein C anticoagulant pathway, involves the heparin-like domain of TM. This study was aimed at investigating the possible effect of heparin on thrombin-TM binding and protein C activation. Methods and Results —The affinity of thrombin-TM interaction was studied by a functional method, based on the ability of thrombin-TM adduct to activate protein C, and by evaluation of the binding of thrombin to immobilized TM. Both experimental approaches showed that the affinity of thrombin-TM interaction was decreased by micromolar heparin concentrations. Heparin had no significant effect when a recombinant TM form, lacking the chondroitin sulfate moiety, was used. Furthermore, it was also shown that the inhibitory effect of heparin was directly proportional to the heparin molecular mass (molecular weight range, 3 to 16 kDa), which suggests that the effect was mediated by formation of electrostatic bonds between heparin and thrombin. Conclusions —These results indicate that heparin at therapeutic concentrations reduces the affinity of thrombin for TM and the rate of protein C activation. The magnitude of this effect is proportionally linked to the molecular mass of heparin.
Paradoxical rise in blood pressure during propranolol treatment.
Authors: I Blum, A Atsmon, M Steiner, H Wysenbeek
Journal: BMJ (1975)

The frequency of HLA antigens was studied in 25 patients with primary sclerosing cholangitis and compared with a control group of 562 kidney donors. Fourteen patients also had ulcerative colitis. A significant increase in the frequency of HLA-B8 (60%) was found in the primary sclerosing cholangitis patients compared with controls (25%) (p less than 0.001). HLA-B8 was found in eight patients with ulcerative colitis. The frequency of HLA-B12 was significantly decreased (8%) compared with controls (30%) (p less than 0.02). Piecemeal necrosis was observed on liver histology in 66% of HLA-B8 positive and 50% of HLA-B8 negative patients. Low titres of serum autoantibodies were frequently found in the primary sclerosing cholangitis group but did not correspond to the presence of HLA-B8. Raised serum concentrations of IgM and IgG were not related to HLA-B8. This study has shown that in patients with primary sclerosing cholangitis there exists a disease susceptibility gene closely associated with the B locus of the major histocompatibility complex which may be modified by other factors such as ulcerative colitis. Patients with ulcerative colitis and HLA-B8 may be particularly liable to develop primary sclerosing cholangitis.
Cancer in patients receiving dialysis.
Authors: L J Kinlen, J B Eastwood, D N Kerr, J F Moorhead, D O Oliver, B H Robinson, H E de Wardener, A J Wing
Journal: BMJ (1980)

The incidence of cancer and related mortality was studied in 1651 patients from six dialysis centres in England over 10 years. The only type of cancer for which there was a significant excess was non-Hodgkin's lymphoma (four cases observed against an expected incidence of 0.15 (p < 0.001); three deaths against an expected 0.1 (p < 0.001)). This excess could not be attributed to either subsequent transplantation or treatment with immunosuppressive drugs. Since immunodepression is a feature of chronic renal failure, these observations together with those on patints treated with immunosuppressive drugs suggest that immunosuppression favours the development of non-Hodgkin's lymphoma. Studies in which it is concluded that patients receiving dialysis show an excess of other types of cancer have certain shortcomings; the unusual opportunities for detecting cancer in such patients may account for some of the reported excess.
Restoration of aspartoacylase activity in CNS neurons does not ameliorate motor deficits and demyelination in a model of Canavan disease
Authors: Matthias Klugmann, Claudia B. Leichtlein, C. Wymond Symes, Tadao Serikawa, Deborah Young, Matthew J. During
Journal: Molecular Therapy (2005)

Canavan disease is an early onset leukodystrophy associated with psychomotor retardation, seizures, and premature death. This disorder is caused by mutations in the gene encoding the enzyme aspartoacylase (ASPA). Normally, ASPA is enriched in oligodendrocytes and ASPA deficiency results in elevated levels of its substrate molecule, N-acetylaspartate (NAA), brain edema, and dysmyelination. Using adeno-associated virus, we permanently expressed ASPA in CNS neurons of the tremor rat, a genetic model of Canavan disease, and examined the efficacy of the treatment by monitoring NAA metabolism, myelination, motor behavior, and seizures. Assessment of ASPA protein and enzyme activity in whole brain hemispheres showed restoration to normal levels as long as 6 months after treatment. This finding correlated with a reduction of NAA levels, along with a rescue of the seizure phenotype. However, gross brain pathology, such as dilated ventricles and spongiform vacuolization, was unchanged. Moreover, hypomyelination and motor deficits were not resolved by ASPA gene transfer. Our data suggest that NAA-mediated neuronal hyperexcitation but not oligodendrocyte dysfunction can be compensated for by neuronal ASPA expression.
Are modern British children too inactive?
Authors: B Diaham, A Prentice
Journal: BMJ (1993)

<h3>BACKGROUND</h3> Inflammation, oxidative stress, and recurrent pulmonary infections are major aggravating factors in cystic fibrosis. Nitric oxide (NO), a marker of inflammation, is not increased, however, probably because it is metabolised to peroxynitrite. Exhaled carbon monoxide (CO), a product of heme degradation by heme oxygenase 1 (HO-1) which is induced by inflammatory cytokines and oxidants, was therefore tested as a non-invasive marker of airway inflammation and oxidative stress. <h3>METHODS</h3> Exhaled CO and NO concentrations were measured in 29 patients (15 men) with cystic fibrosis of mean (SD) age 25 (1) years, forced expiratory volume in one second (FEV<sub>1</sub>) 43 (6)%, 14 of whom were receiving steroid treatment. <h3>RESULTS</h3> The concentration of exhaled CO was higher in patients with cystic fibrosis (6.7 (0.6) ppm) than in 15 healthy subjects (eight men) aged 31 (3) years (2.4 (0.4) ppm, mean difference 4.3 (95% CI 2.3 to 6.1), p&lt;0.001). Patients not receiving steroid treatment had higher CO levels (8.4 (1.0) ppm) than treated patients (5.1 (0.5) ppm, mean difference 3.3 (95% CI –5.7 to -0.9), p&lt;0.01). Normal subjects had higher NO levels (6.8 (0.4) ppb) than patients with cystic fibrosis (3.2 (0.2) ppb, mean difference 3.8 (95% CI 2.6 to 4.9), p&lt;0.05) and were not influenced by steroid treatment (3.8 (0.4) ppb and 2.7 (0.3) ppb for treated and untreated patients, respectively, mean difference 0.8 (95% CI –0.6 to 2.3), p&gt;0.05). Patients homozygous for the ΔF508 CFTR mutation had higher CO and NO concentrations than heterozygous patients (CO: 7.7 (1.8) ppm and 4.0 (0.6) ppm, respectively, mean difference 3.7 (95% CI –7.1 to –0.3), p&lt;0.05; NO: 4.1 (0.5) ppb and 1.9 (0.7) ppb, respectively, mean difference 2.2 (95% CI –3.7 to –0.6), p&lt;0.05). <h3>CONCLUSIONS</h3> High exhaled CO concentrations in patients with cystic fibrosis may reflect induction of HO-1. Measurement of exhaled CO concentrations may be clinically useful in the management and monitoring of oxidation and inflammatory mediated lung injury.
THE FUNCTIONAL CAPACITY OF THE KIDNEY DENERVATED BY AUTOTRANSPLANTATION IN THE DOG1
Authors: Neal S. Bricker, Ralph A. Straffon, Edward P. Mahoney, John P. Merrill
Journal: Journal of Clinical Investigation (1958)

The influence of renal nerves on the renal tu- bular transport of sodium chloride has been a source of controversy for many years.Both con- ceptual and methodologic differences have con- tributed to the continuing conflict.The conceptual disagreements concern the primacy of glomerular filtration rate changes (as opposed to intrinsic al- teration in tubular transport) in explaining differ- ing rates of sodium excretion between denervated and innervated kidneys in the same animals.The methodologic problems relate to the validity of the procedures conventionally employed for denerva- tion.The first of these, interruption of all visible nerves entering at the hilus, has been criticized because of the possibility that some nerve fibers may be left intact.The second, section of the splanchnic nerves, has been criticized because splanchnic structures other than the kidneys lose their nerve supply.The contention of Quinby (1) that complete denervation depends upon section and resuture of renal artery, vein and ureter has been frequently cited (2).Studies have recently been reported on a human kidney which fulfilled Quinby's criteria for dener- vation (3).This organ, which had been trans- planted from one identical twin to another, was totally denervated at the time of transplantation, and the denervation was restricted to the involved organ.The objections to conventionally dener- vated kidneys were thereby obviated.The data demonstrated that the transplanted kidney could accomplish the majority of functions examined
Influence of naloxone on the total capacitance vasculature of the dog.
Authors: L Bell, E Maratea, D L Rutlen
Journal: Journal of Clinical Investigation (1985)

The opiate antagonist, naloxone, which is associated with prolonged survival in animal models of shock, has been demonstrated to increase arterial pressure and cardiac output. It is possible that the increase in cardiac output is due to a decrease in volume in the total capacitance vasculature and a subsequent increase in venous return. Because the influence of naloxone on the capacitance vasculature is unknown, the present study was undertaken to determine the influence of naloxone on intravascular volume in the total capacitance circulation. In 31 anesthetized dogs, blood from the vena cavae was drained into an extracorporeal reservoir and returned to the right atrium at a constant rate so that changes in total intravascular volume could be measured as reciprocal changes in reservoir volume. In five animals, naloxone infusion (2 mg/ml X min for 20 min) was associated with a decrease in total capacitance volume of 121 +/- 30 ml (P less than 0.05). To determine regional volume effects, naloxone was infused in 11 animals in which the splanchnic and extrasplanchnic vasculatures were separately perfused and drained: total and splanchnic volume decreased 64 +/- 13 ml (P less than 0.05) and 126 +/- 17 ml (P less than 0.0001), respectively, and extrasplanchnic volume increased 62 +/- 13 ml (P less than 0.001). After ganglionic blockade with mecamylamine (n = 3), total volume decreased 89 +/- 16 ml (P less than 0.05), splanchnic volume did not change, and extrasplanchnic volume decreased 91 +/- 32 ml (P less than 0.05). In another five animals, naloxone was infused during diversion of the splanchnic venous outflow to a nonrecirculating extracorporeal reservoir: total volume decreased 122 +/- 33 ml (P less than 0.05), splanchnic volume did not change, and extrasplanchnic volume decreased 101 +/- 16 ml (P less than 0.01). When the splanchnic venous effluent was reinfused without naloxone administration (n = 4), total volume decreased 43 +/- 5 ml (P less than 0.05), splanchnic volume decreased 113 +/- 14 ml (P less than 0.05), and extrasplanchnic volume increased 68 +/- 10 ml (P less than 0.05). Thus, naloxone is associated with a decrease in total capacitance volume, which is due entirely to a decrease in splanchnic volume. The splanchnic volume decrement would appear to be mediated through neurogenic and hormonal influences. In an animal not on bypass, it would be expected that naloxone would be associated with a decrease in total capacitance volume and subsequent increases in venous return and cardiac output.
Intact PIP implants do not need to be removed, European report confirms
Authors: I. Torjesen
Journal: BMJ (2013)

A European report has backed the findings of an expert group set up by the UK government that concluded that intact silicone breast implants manufactured by the French firm Poly Implant Prothese (PIP) do not need to be removed as a precautionary measure.

PIP went into administration in 2011, and its implants were banned amid concerns that they contained non-medical grade silicone, which articles in the French media linked to a small number of cases of cancer.1

The European Commission’s Scientific Committee on Emerging and Newly Identified Health Risks report on the safety of PIP breast implants, published this week, confirms that there are currently no convincing medical, toxicological, or other data to justify …
The Novel Tuberculosis Vaccine, AERAS-402, Induces Robust and Polyfunctional CD4<sup>+</sup>and CD8<sup>+</sup>T Cells in Adults
Authors: Brian Abel, Michele Tameris, Nazma Mansoor, Sebastian Gelderbloem, Jane Hughes, Deborah Abrahams, Lebohang Makhethe, Mzwandile Erasmus, Marwou de Kock, Linda van der Merwe, Anthony Hawkridge, Ashley Veldsman, Mark Hatherill, Giulia Schirru, Maria Grazia Pau, Jenny Hendriks, Gerrit Jan Weverling, Jaap Goudsmit, Donata Sizemore, J. Bruce McClain, Margaret Goetz, Jacqueline Gearhart, Hassan Mahomed, Gregory D. Hussey, Jerald C. Sadoff, Willem A. Hanekom
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

AERAS-402 is a novel tuberculosis vaccine designed to boost immunity primed by bacillus Calmette-Guérin (BCG), the only licensed vaccine.We investigated the safety and immunogenicity of AERAS-402 in healthy Mycobacterium tuberculosis-uninfected BCG-vaccinated adults from a tuberculosis-endemic region of South Africa.Escalating doses of AERAS-402 vaccine were administered intramuscularly to each of three groups of healthy South African BCG-vaccinated adults, and a fourth group received two injections of the maximal dose. Participants were monitored for 6 months, with all adverse effects documented. Vaccine-induced CD4(+) and CD8(+) T-cell immunity was characterized by an intracellular cytokine staining assay of whole blood and peripheral blood mononuclear cells.AERAS-402 was well tolerated, and no vaccine-related serious adverse events were recorded. The vaccine induced a robust CD4(+) T-cell response dominated by cells coexpressing IFN-gamma, tumor necrosis factor-alpha, and IL-2 ("polyfunctional" cells). AERAS-402 also induced a potent CD8(+) T-cell response, characterized by cells expressing IFN-gamma and/or tumor necrosis factor-alpha, which persisted for the duration of the study.Vaccination with AERAS-402 is safe and immunogenic in healthy adults. The immunity induced by the vaccine appears promising: polyfunctional T cells are thought to be important for protection against intracellular pathogens such as Mycobacterium tuberculosis, and evidence is accumulating that CD8(+) T cells are also important. AERAS-402 induced a robust and durable CD8(+) T-cell response, which appears extremely promising. Clinical trial registered with www.sanctr.gov.za (NHREC no. 1381).
Medical Malpractice and the Tort System
Authors: Jeffrey W. Kalenak
Journal: JAMA (1990)

To the Editor.—  Mr Jacobson's article entitled Medical 1 Malpractice and the Tort System1 was a thoughtful treatment of this controversial topic. But I am reminded of reports in the popular press that in Japan there are substantially fewer attorneys per capita than in the United States, as well as substantially fewer malpractice claims.  I encourage Mr Jacobson to publish a graph that plots the number of US attorneys per capita annually for the last two decades and frequency of malpractice claims per year during the same two decades. In addition, I would like to see a regression analysis of the two variables. The results might be illuminating. Although such data could in no way imply a cause-and-effect relationship, they might offer us a fresh perspective on the tort system.
Enhancement of efficiencies of the cellular uptake and gene silencing of chitosan/siRNA complexes via the inclusion of a negatively charged poly(γ-glutamic acid)
Authors: Zi-Xian Liao, Yi-Cheng Ho, Hsin-Lung Chen, Shu-Fen Peng, Chun-Wen Hsiao, Hsing-Wen Sung
Journal: Biomaterials (2010)
Extravascular coagulation and fibrinolysis in murine lung inflammation induced by the mycobacterial cord factor trehalose-6,6'-dimycolate.
Authors: R L Perez, J Roman, G W Staton, R L Hunter
Journal: American Journal of Respiratory and Critical Care Medicine (1994)

Diffuse pulmonary inflammation in interstitial lung diseases is associated with increased coagulation in the extravascular spaces of the lung. We hypothesized that conditions favoring coagulation over fibrinolysis in the lung are related to inflammation. Pulmonary coagulation and fibrinolysis were studied in two strains of mice susceptible or resistant to the development of lung inflammation in response to the mycobacterial cell wall glycolipid trehalose-6,6'-dimycolate (TDM). Susceptible animals treated with TDM intravenously develop well-organized collections of mononuclear cells in the lung parenchyma referred to as granulomas in this report. More granulomas were found in the susceptible ICR mice than in the resistant A/J mice after intravenous administration of TDM (7 +/- 1 granulomas/mm2 versus 1 +/- 0.3 granulomas/mm2, p = 0.005). Granuloma formation was associated with increased lung procoagulant activity (PCA) measured in bronchoalveolar lavage (BAL) cell lysates from susceptible mice. In contrast, TDM-resistant A/J mice challenged with TDM did not have a significant BAL cell PCA response, but expressed several-fold greater levels of lung BAL fluid plasminogen activator activity (PAA) than ICR mice. To examine the role of coagulation in the TDM pulmonary inflammatory response, susceptible C57Bl/10SnJ mice were anticoagulated by oral administration of warfarin prior to challenge of TDM; these mice developed fewer pulmonary granulomas than TDM-treated mice without warfarin treatment (2.6 +/- 0.5 granulomas/mm2 versus 6.5 +/- 0.8 granulomas/mm2, p < 0.001) but had similar BAL cell PCA and lung inflammatory changes as measured by lung weights and BAL cellularity.(ABSTRACT TRUNCATED AT 250 WORDS)
Current Clinical Topics in Infectious Diseases 3
Authors: John M. Leedom
Journal: JAMA (1983)

This is the third annual appearance of a multiauthored review of topics of interest in infectious diseases, edited by two distinguished professors. The subjects chosen for discussion are topical because of current clinical importance and changes in methods of diagnosis and treatment or represent in-depth reviews of somewhat neglected topics. The authors of the individual articles are recognized experts. The chapter by Owen, "Sexually Transmitted Enteric Disease," reviews a topic that is of increasing current importance and interest. The broadening concept of sexually transmitted diseases, which includes enteric protozoa, metazoal viruses, and bacteria, is reviewed in a thorough and scholarly manner. The developing field of viral chemotherapy as typified by nucleoside derivatives and interferons as antiviral agents is ably reviewed by Hirsch and Hammer. The important relevant studies are cited and analyzed. There is a short discussion of the outlook for nucleoside derivatives and a look to the future, when
Abstract 3066: Effect of stable knockdown of NOX1 gene expression with siRNA in human colon cancer cells
Authors: Agnes Juhasz, Smitha Antony, Yongzhong Wu, Jiamo Lu, Guojian Jiang, Han Liu, Krishnendu Roy, James H. Doroshow
Journal: Cancer Research (2012)

Abstract NADPH oxidase (Nox)-dependent reactive oxygen species (ROS) play a critical role in cell signaling, cell proliferation, and mitogenesis. We have previously shown that silencing NOX1 gene expression with siRNA decreases cell growth and angiogenesis in human HT-29 colon cancer xenografts. To investigate the mechanism of growth inhibition, we studied cell cycle and signaling pathways. We found using RT-PCR and Western analysis that the expression of the INK4 inhibitors (p15, p18, p19), as well as CDK6, phospho-Cyclin E, Cyclin E, and Cyclin D1 were all decreased when NOX1 was decreased by &amp;gt;80%. We detected important changes in the Raf-MEK-ERK pathway that were associated with NOX1 knockdown. Our stable knock-out cells (clone 6A) showed lower phosphorylation of Rac1, c-Raf, MEK1/2, ERK1/2, p90RSK and CREB. To understand this observation, we studied the activity of Tyr and Ser/Threonine protein phosphatases (PP) in our stable siRNA containing cells (6A) compared to stable scrambled siRNA containing cells (SA) and parental HT-29 cells. PTP1B activity was elevated (100.4+4.4 pmol of phosphate/min/µg) in 6A cells compared to both SA (69.2+3.8) and parental (47.8+2.1) cell controls, P&amp;lt;0.05. Serine/Threonine protein phosphatases demonstrated a similar pattern; elevated in 6A cells (127.3+3.8 pmol of phosphate/min/µg) versus both SA cells (91.7+2.1) and the parental line (88.9+1.9), P&amp;lt;0.05. To demonstrate that protein phosphatases play a key role in the regulation of ERK-CREB signaling, we used a c-Raf antibody to immunoprecipitate the c-Raf-PPs complex, and detected PTP1B and PP2C proteins by Western analysis. These data indicate that siRNA-mediated gene silencing of Nox1 deactivated ERK-CREB signaling, and that increased activity of protein phosphatases, that occur as a consequence of decreased Nox-mediated ROS formation, might play role in modifying the growth enhancing effects of the MAP kinase pathway in HT-29 colon cancer cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3066. doi:1538-7445.AM2012-3066
A comprehensive immunohistochemical approach of AKT/mTOR pathway and p-STAT3 in mycosis fungoides
Authors: Georgia Levidou, Marina Siakantaris, Theodora Papadaki, Evangelia Papadavid, Theodoros P. Vassilakopoulos, Maria K. Angelopoulou, Leonidas Marinos, Vassiliki Nikolaou, Aphroditi Economidi, Christina Antoniou, Efstratios Patsouris, Penelope Korkolopoulou
Journal: Journal of the American Academy of Dermatology (2013)