tbuckley/cabot-search huggingface dataset:
Immune tolerance improves the efficacy of enzyme replacement therapy in canine mucopolysaccharidosis I
Authors: Patricia Dickson, Maryn Peinovich, Michael McEntee, Thomas Lester, Steven Le, Aimee Krieger, Hayden Manuel, Catherine Jabagat, Merry Passage, Emil D. Kakkis
Journal: Journal of Clinical Investigation (2008)

Mucopolysaccharidoses (MPSs) are lysosomal storage diseases caused by a deficit in the enzymes needed for glycosaminoglycan (GAG) degradation. Enzyme replacement therapy with recombinant human α-l-iduronidase successfully reduces lysosomal storage in canines and humans with iduronidase-deficient MPS I, but therapy usually also induces antibodies specific for the recombinant enzyme that could reduce its efficacy. To understand the potential impact of α-l-iduronidase–specific antibodies, we studied whether inducing antigen-specific immune tolerance to iduronidase could improve the effectiveness of recombinant iduronidase treatment in canines. A total of 24 canines with MPS I were either tolerized to iduronidase or left nontolerant. All canines received i.v. recombinant iduronidase at the FDA-approved human dose or a higher dose for 9–44 weeks. Nontolerized canines developed iduronidase-specific antibodies that proportionally reduced in vitro iduronidase uptake. Immune-tolerized canines achieved increased tissue enzyme levels at either dose in most nonreticular tissues and a greater reduction in tissue GAG levels, lysosomal pathology, and urinary GAG excretion. Tolerized MPS I dogs treated with the higher dose received some further benefit in the reduction of GAGs in tissues, urine, and the heart valve. Therefore, immune tolerance to iduronidase improved the efficacy of enzyme replacement therapy with recombinant iduronidase in canine MPS I and could potentially improve outcomes in patients with MPS I and other lysosomal storage diseases.
Identification of airborne dissemination of epidemic multiresistant strains of Pseudomonas aeruginosa at a CF centre during a cross infection outbreak
Authors: A M Jones
Journal: Thorax (2003)

Chronic Pseudomonas aeruginosa infection is a major cause of morbidity and mortality for individuals with cystic fibrosis (CF). P aeruginosa cross infection outbreaks have recently been reported at CF holiday camps and specialist centres. The mechanism of cross infection is unknown. A study was performed to look for the presence of epidemic strains of P aeruginosa in the environment of a CF centre during a cross infection outbreak and to examine their potential modes of spread between patients.Microbiological sampling of the environment of the CF facility was performed, including room air sampling. Individual P aeruginosa strains were identified by bacterial fingerprinting. The typing patterns were compared with those of epidemic strains responsible for cross infection among the patients.Epidemic P aeruginosa strains were isolated from room air when patients performed spirometric tests, nebulisation, and airway clearance, but were not present in other areas of the inanimate environment of the CF centre.Aerosol dissemination may be the most important factor in patient-to-patient spread of epidemic strains of P aeruginosa during recent cross infection outbreaks at adult CF centres.
Sex, susceptibility to smoking and chronic obstructive pulmonary disease: the effect of different diagnostic criteria. Analysis of the Health Survey for England
Authors: Rachel E Jordan, Martin R Miller, Kin-bong Hubert Lam, K K Cheng, Jennifer Marsh, Peymané Adab
Journal: Thorax (2012)

Some previous studies suggest there are sex differences in susceptibility to, and prevalence of, chronic obstructive pulmonary disease (COPD) but findings are inconsistent. In this study, whether different diagnostic criteria for COPD may contribute to these conflicting findings was examined.Cross sectional analysis of data from the 1995, 1996 and 2001 Health Survey for England was undertaken, including participants of white ethnicity, aged 40+ years with a valid smoking history and lung function data. COPD was defined using Global Initiative for Chronic Obstructive Lung Disease (GOLD), National Institute for Health and Clinical Excellence (NICE) and lower limit of normal (LLN) spirometric criteria, in the absence of a diagnosis of asthma.COPD was present in 3035 (16.1%), 1304 (7.0%) and 1684 (9.0%) people, according to the GOLD, NICE and LLN criteria, respectively. With both the GOLD and NICE definitions, men had significant independent increased risks of COPD compared with women (OR 1.46 (95% CI 1.34 to 1.59) and 1.30 (1.15 to 1.48), respectively). With the LLN definition, this effect was removed (OR 0.96 (0.87 to 1.07). With the use of both the GOLD and NICE criteria, women had significantly greater susceptibility to COPD (25-30% higher risk) for the same level of pack years of exposure. This was not observed with the LLN criteria.The study indicates that sex differences in risk of COPD reported in previous studies are influenced by the definition used for COPD. When using a statistically driven definition (LLN), no independent sex difference was found and there was no evidence of an increased susceptibility to COPD among female compared with male smokers.
Safety and Pharmacokinetics of Ganitumab (AMG 479) Combined with Sorafenib, Panitumumab, Erlotinib, or Gemcitabine in Patients with Advanced Solid Tumors
Authors: Lee S. Rosen, Igor Puzanov, Gregory Friberg, Emily Chan, Yuying C. Hwang, Hongjie Deng, Jill Gilbert, Devalingam Mahalingam, Ian McCaffery, Shaunita A. Michael, Alain C. Mita, Monica M. Mita, Marilyn Mulay, Poornima Shubhakar, Min Zhu, John Sarantopoulos
Journal: Clinical Cancer Research (2012)

This phase 1b dose-escalation study assessed safety, tolerability, and pharmacokinetics of ganitumab, a fully human monoclonal antibody against the insulin-like growth factor 1 (IGF1) receptor, combined with targeted agents or cytotoxic chemotherapy in patients with advanced solid tumors.Patients with treatment-refractory advanced solid tumors were sequentially enrolled at 2 ganitumab dose levels (6 or 12 mg/kg i.v. every 2 weeks) combined with either sorafenib 400 mg twice daily, panitumumab 6 mg/kg every 2 weeks, erlotinib 150 mg once daily, or gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 of each 4-week cycle. The primary end points were safety and pharmacokinetics of ganitumab.Ganitumab up to 12 mg/kg appeared well tolerated combined with sorafenib, panitumumab, erlotinib, or gemcitabine. Treatment-emergent adverse events were generally mild and included fatigue, nausea, vomiting, and chills. Three patients had dose-limiting toxicities: grade 3 hyperglycemia (ganitumab 6 mg/kg and panitumumab), grade 4 neutropenia (ganitumab 6 mg/kg and gemcitabine), and grade 4 thrombocytopenia (ganitumab 12 mg/kg and erlotinib). Ganitumab-binding and panitumumab-binding antibodies were detected in 5 and 2 patients, respectively; neutralizing antibodies were not detected. The pharmacokinetics of ganitumab and each cotherapy did not appear affected by coadministration. Circulating total IGF1 and IGF binding protein 3 increased from baseline following treatment. Four patients (9%) had partial responses.Ganitumab up to 12 mg/kg was well tolerated, without adverse effects on pharmacokinetics in combination with either sorafenib, panitumumab, erlotinib, or gemcitabine. Ganitumab is currently under investigation in combination with some of these and other agents.
Toxicity and Metabolism of the Neurotoxic Hexacarbons n-Hexane, 2-Hexanone, and 2,5-Hexanedione
Authors: D Couri, M Milks
Journal: The Annual Review of Pharmacology and Toxicology (1982)

Human exposure to hexacarbon compounds is quite pervasive, including occupational exposures to industrial solvents as well as unintentional and sometimes deliberate exposures to hexacarbon solvents contained in innumerable commercial products. The exact mechanism of hexacarbon neurotoxicity has not yet been identified, but an interference with neuronal axoplasmic flow seems most likely. Metabolism of n-hexane and 2-hexanone to 2,5-hexanedione is a prominent feature which appears to be causally related to the neuropathologic syndrome, and mixed solvent effects have been noted in regard to potentiation of hexacarbon neurotoxicity. Continued effort in investigating the chemically induced peripheral neuropathy is essential not only to define the precise molecular mechanism, but to advance our basic understanding of other polyneuropathies as well. Ultimately, progress in these areas should yield such benefits as early diagnosis of potential neuropathology, better measures for the prevention of neurotoxicities, and more effective modalities of treatment. Indeed, sustained research efforts are imperative in maintaining human health and safety throughout our current era of advancing global technology.
Hypertriglyceridemia and cholesteryl ester transfer protein interact to dramatically alter high density lipoprotein levels, particle sizes, and metabolism. Studies in transgenic mice.
Authors: T Hayek, N Azrolan, R B Verdery, A Walsh, T Chajek-Shaul, L B Agellon, A R Tall, J L Breslow
Journal: Journal of Clinical Investigation (1993)

Several types of transgenic mice were used to study the influence of hypertriglyceridemia and cholesteryl ester transfer protein (CETP) expression on high density lipoprotein (HDL) levels, particle sizes, and metabolism. The presence of the CETP transgene in hypertriglyceridemic human apo CIII transgenic mice lowered HDL-cholesterol (HDL-C) 48% and apolipoprotein (apo) A-I 40%, decreased HDL size (particle diameter from 9.8 to 8.8 nm), increased HDL cholesterol ester (CE) fractional catabolic rate (FCR) 65% with a small decrease in HDL CE transport rate (TR) and increased apo A-I FCR 15% and decreased apo A-I TR 29%. The presence of the CETP transgene in hypertriglyceridemic mice with human-like HDL, human apo A-I apo CIII transgenic mice, lowered HDL-C 61% and apo A-I 45%, caused a dramatic diminution of HDL particle size (particle diameters from 10.3 and 9.1 to 7.6 nm), increased HDL CE FCR by 107% without affecting HDL CE TR, and increased apo A-I FCR 35% and decreased apo A-I TR 48%. Moreover, unexpectedly, hypertriglyceridemia alone in the absence of CETP was also found to cause lower HDL-C and apo A-I levels primarily by decreasing TRs. Decreased apo A-I TR was confirmed by an in vivo labeling study and found to be associated with a decrease in intestinal but not hepatic apo A-I mRNA levels. In summary, the introduction of the human apo A-I, apo CIII, and CETP genes into transgenic mice produced a high-triglyceride, low-HDL-C lipoprotein phenotype. Human apo A-I gene overexpression caused a diminution of mouse apo A-I and a change from monodisperse to polydisperse HDL. Human apo CIII gene overexpression caused hypertriglyceridemia with a significant decrease in HDL-C and apo A-I levels primarily due to decreased HDL CE and apo A-I TR but without a profound change in HDL size. In the hypertriglyceridemic mice, human CETP gene expression further reduced HDL-C and apo A-I levels, primarily by increasing HDL CE and apo A-I FCR, while dramatically reducing HDL size. This study provides insights into the genes that may cause the high-triglyceride, low-HDL-C phenotype in humans and the metabolic mechanisms involved.
Impact of Combination Evidence-Based Medical Therapy on Mortality in Patients With Acute Coronary Syndromes
Authors: Debabrata Mukherjee, Jianming Fang, Stanley Chetcuti, Mauro Moscucci, Eva Kline-Rogers, Kim A. Eagle
Journal: Circulation (2004)

Several individual pharmacological agents, such as antiplatelet drugs, beta-blockers, ACE inhibitors, and lipid-lowering agents, have proven efficacy in reducing mortality in patients with acute coronary syndromes. However, the impact of the combination of these agents on clinical outcomes has not been studied before.A total of 1358 consecutive patients presenting with acute coronary syndromes between January 1999 and March 2002 were identified, and data on baseline demographics, comorbidities, and in-hospital management were collected. On the basis of discharge use of evidence-based therapies, we created a composite appropriateness score depending on the number of the drugs used divided by the number of the drugs potentially indicated for each patient. The impact of the composite score on 6-month mortality was analyzed using a risk-adjusted logistic regression model. The odds ratio for death for all indicated medications used (appropriateness level IV) versus none of the indicated medications used (appropriateness level 0) was 0.10 (95% CI, 0.03 to 0.42; P<0.0001); similarly, odds ratio for appropriateness level III versus level 0 was 0.17 (95% CI, 0.04 to 0.75; P=0.0018), odds ratio for appropriateness level II versus level 0 was 0.18 (95% CI, 0.04 to 0.77; P=0.01), and odds ratio for appropriateness level I versus level 0 was 0.36 (95% CI, 0.08 to 1.75; P=0.20).Use of combination evidence-based medical therapies was independently and strongly associated with lower 6-month mortality in patients with acute coronary syndromes. Such therapies, most of which are generic and inexpensive today, seem to offer a marked survival advantage compared with patients in whom such therapies are omitted.
Severity-of-illness assessment in community-acquired pneumonia
Authors: K. Challen, A. Bentley, D. Walter
Journal: Thorax (2010)

We believe the authors of the 2009 update of the guidelines for the management of community-acquired pneumonia1 have confused mortality predictors with severity-of-illness scores. They state ‘we have concentrated only on studies that have used mortality as the main outcome measure’. We recognise that there are difficulties in using intensive care admission as an outcome measure because of variation in admission criteria. However, 30-day survival of patients with low mortality predictor scores does not mean they were not severely ill, merely that …
Relationship between the early, late, and rechallenge reaction to nasal challenge with antigen: Observations on the role of inflammatory mediators and cells
Authors: Othon Iliopoulos, David Proud, N. Franklin Adkinson, Philip S. Norman, Anne Kagey-Sobotka, Lawrence M. Lichtenstein, Robert M. Naclerio
Journal: Journal of Allergy and Clinical Immunology (1990)
Electromagnetic Fields: Human Safety Issues
Authors: Om P. Gandhi
Journal: Annual Review of Biomedical Engineering (2002)

▪ Abstract Most of the recently revised safety standards worldwide are set in terms of internal rates of electromagnetic energy deposition (specific absorption rates or SAR) at radio frequencies (RF) and microwave frequencies, and of induced electric fields or current densities at lower frequencies up to 10 MHz. Numerical methods have been developed that use millimeter resolution anatomically based models of the human body to determine SAR or the induced electric fields and current densities for real-life EM exposure conditions. A popular method for use at RF and microwave frequencies is the finite-difference time-domain method. This method is described and illustrated for SAR distributions due to cellular telephones for head models based on human anatomy. A method often used for calculations of induced electric fields and current densities at low frequencies is the impedance method. Use of this method is illustrated by an example of an electronic article surveillance (EAS) system for anatomic models of an adult and 10- and 5-year-old children. Experimental phantoms using a fluid to simulate the dielectric properties of the brain may be used for determination of peak 1- or 10-g SAR needed for compliance with the various safety standards.
Differential regulation of acidic and basic fibroblast growth factor gene expression in fibroblast growth factor-treated rat aortic smooth muscle cells.
Authors: G F Alberts, D K Hsu, K A Peifley, J A Winkles
Journal: Circulation Research (1994)

The acidic fibroblast growth factor (aFGF) and basic fibroblast growth factor (bFGF) proteins are potent vascular smooth muscle cell (SMC) mitogens that are expressed by endothelial cells and SMCs in vivo. Overexpression of these proteins in transfected cell lines can result in autocrine transformation; therefore, the precise control of fibroblast growth factor gene expression in the vessel wall may be an important mechanism regulating vascular cell growth. In the present study, we demonstrate that bFGF can induce bFGF mRNA expression, but not aFGF mRNA expression, in serum-starved rat aortic SMCs. bFGF autoinduction is maximal at 4 hours, requires de novo RNA and protein synthesis, and is mediated predominantly by a protein kinase C-dependent signaling pathway. Furthermore, aFGF treatment of rat SMCs also increases bFGF mRNA and protein expression; however, aFGF mRNA levels are only slightly modulated. These results suggest that the local release of aFGF or bFGF within the vessel wall could promote a prolonged period of elevated bFGF synthesis. This, in turn, could be of importance in the SMC hyperplasia that occurs in response to vascular injury and during atherosclerotic plaque formation.
Determinants of Rib Motion in Flail Chest
Authors: MATTEO CAPPELLO, ALEXANDRE LEGRAND, ANDRÉ DE TROYER
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

We have previously developed a canine model of isolated flail chest to assess the effects of this condition on the mechanics of breathing, and these studies have led to the conclusion that the respiratory displacement of the fractured ribs is primarily determined by the fall in pleural pressure ( Δ Ppl) and the action of the parasternal intercostal muscles. The present studies were designed to test the validity of this conclusion. A flail was induced in six supine anesthetized animals by fracturing both dorsally and ventrally the second to fifth ribs on the right side of the chest, after which the phrenic nerve roots were bilaterally sectioned in the neck. Sectioning the phrenic nerves caused a 34% decrease in Δ Ppl, associated with a 39% increase in parasternal intercostal inspiratory EMG activity (p < 0.05), and resulted in a marked reduction in the inspiratory inward displacement of the ribs. In three animals, the inward rib displacement was even reversed into a small outward displacement. When the airway was then occluded at end-expiration to increase Δ Ppl during the subsequent inspiration, all animals again showed a clear-cut inward rib displacement. These observations therefore confirm that in dogs with flail chest, the inspiratory displacement of the fractured ribs is set by the balance between the force related to pleural pressure and that generated by the parasternal intercostals. These observations also point to the critical importance of the pattern of inspiratory muscle activation in determining the magnitude of rib cage paradox in such patients.
Cytotoxic lymphocyte maturation factor (interleukin 12) is a synergistic growth factor for hematopoietic stem cells.
Authors: S E Jacobsen, O P Veiby, E B Smeland
Journal: The Journal of Experimental Medicine (1993)

The recently cloned cytotoxic lymphocyte maturation factor (interleukin 12 [IL-12]) has been described as a growth factor for mature lymphocytes. The present study investigated whether purified recombinant murine IL-12 (rMuIL-12) also could affect the proliferation of primitive bone marrow progenitor cells. Using a population of Lin-Sca-1+ murine bone marrow stem cells, we now demonstrate that IL-12 is a potent synergistic factor for primitive hematopoietic stem cells. The synergy of IL-12 was observed in single-cell cloning assays, demonstrating that its effects are directly mediated. Specifically, IL-12 enhanced stem cell factor-induced myelopoiesis of Lin-Sca-1+ cells sevenfold, and synergized with colony-stimulating factors (CSFs) to induce proliferation of Lin-Sca-1+ stem cells. IL-12 increased the number of responding progenitor cells as well as the size of the colonies formed. IL-12 also increased colony formation of high proliferative potential colony-forming cells with multiple CSF combinations. The effects of IL-12 were concentration dependent with a 50% effective dose of 2-20 and 20-200 ng/ml, resulting in maximum stimulation. Furthermore, a neutralizing anti-IL-12 antibody blocked the synergistic effects of rMuIL-12. In addition, IL-12 was found to have synergistic effects on more committed bone marrow progenitors as well. Our results therefore suggest that in addition to being a potent lymphopoietic stimulator, IL-12 is a regulator of the growth of hematopoietic stem cells and their myeloid progeny.
SYSTEMIC LUPUS ERYTHEMATOSUS PRESENTING AS SUBARACHNOID HAEMORRHAGE AND SPACE OCCUPYING LESION
Authors: EOIN B. CASEY, LINDSAY SYMON
Journal: British Journal of Dermatology (1971)

Journal Article SYSTEMIC LUPUS ERYTHEMATOSUS PRESENTING AS SUBARACHNOID HAEMORRHAGE AND SPACE OCCUPYING LESION Get access EOIN B. CASEY, EOIN B. CASEY The National Hospital for Nervous Diseases, Queen Square, London, W.C.1 Search for other works by this author on: Oxford Academic Google Scholar LINDSAY SYMON LINDSAY SYMON The National Hospital for Nervous Diseases, Queen Square, London, W.C.1 Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 84, Issue 2, 1 February 1971, Pages 157–160, https://doi.org/10.1111/j.1365-2133.1971.tb06859.x Published: 01 February 1971 Article history Accepted: 18 September 1970 Published: 01 February 1971
Comparison of methods to assess airborne rat and mouse allergen levels. II. Factors influencing antigen detection
Authors: A Renström, S Gordon, A Hollander, J Spithoven, PH Larsson, KM Venables, D Heederik, P Malmberg
Journal: Allergy (1999)

Potential factors influencing antigen detection in immunoassays for measuring rat or mouse aeroallergen (i.e., assay setup, antigen specificities, standard extracts used, and antigen decay) were investigated in a three‐country study (the UK, The Netherlands, Sweden). An inhibition enzyme immunoassay (EIA) setup gave nominal rat urinary allergen (RUA) sample values seven times higher than a sandwich EIA setup utilizing identical antibodies and standards. In immunoblotting experiments, pooled patient serum and polyclonal rabbit antibodies partly detected different rat antigens; monoclonal antibody specificity could not be determined. Immunoblot detection of mouse urinary antigens (MUA) by the polyclonal rabbit antibodies from all laboratories was similar. In both the RUA and the MUA assays, urinary antigen standards were detected with similar potency, except purified Rat n 1, which was an inefficient inhibitor in the RUA RAST inhibition. In the sandwich EIA RUA assays, a rat room‐dust extract was detected with 700–800‐fold less sensitivity than rat urine, whereas in the RAST RUA assay, dust inhibited equally with rat urine. Simulated decay did not decrease the potency of urinary antigen in any assay. Thus, assay setup and choice of detection antibodies strongly influence the nominal allergen levels. We recommend the use of standardized and characterized antibodies and standard extracts in sandwich EIAs to measure airborne rodent urinary allergens. Abbreviations: NHLI: National Heart and Lung Institute, London, UK; WAU: Wageningen Agricultural University, Wageningen, The Netherlands; NIWL: National Institute for Working Life, Solna, Sweden; Ab: antibody; mAb: monoclonal antibody; EIA: enzyme immunoassay; RAST: radioallergosorbent test; RIA: radioimmunoassay; MUA: mouse urinary allergen; RUA: rat urinary allergen; BSA: bovine serum albumin; HSA: human serum albumin; PBS: phosphate‐buffered saline; PTFE: polytetrafluoroethylene (Teflon); TBS: Tris‐buffered saline.