tbuckley/cabot-search huggingface dataset:
Immunotherapy in asthma
Authors: J. A. Douglass, F. C. Thien, R. E. O'Hehir
Journal: Thorax (1997)

Background. Although allergen immunotherapy is effective for allergic rhinitis, its role in treating asthma is unclear. Methods. We examined the efficacy of immunotherapy for asthma exacerbated by seasonal ragweed exposure. During an observation phase, adults with asthma who were sensitive to ragweed kept daily diaries and recorded peak expiratory flow rates between July and October. Those who reported seasonal asthma symptoms and medication use as well as decreased peak expiratory flow were randomly assigned to receive placebo or ragweed-extract immunotherapy in doses that increased weekly for an additional two years. Results. During the observation phase, the mean (SE) peak expiratory flow rate measured in the morning during the three weeks representing the height of the pollination season was 454 (20) litres per minute in the immunotherapy group and 444 (16) litres per minute in the placebo group. Of the 77 patients who began the treatment phase, 64 completed one year of the study treatment and 53 completed two years. During the two treatment years, the mean peak expiratory flow rate was higher in the immunotherapy group (489 (16) litres per minute vs. 453 (17) in the placebo group (p= 0.06) during the first year, and 480 (12) litres per minute vs. 461 (13) in the placebo group (p = 0.03) during the second). Medication use was higher in the immunotherapy group than in the placebo group during observation and lower during the first treatment year (p = 0.01) but did not differ in the two groups during the second year (p=0.7). Asthma symptom scores were similar in the two groups (p = 0.08 in year 1 and p = 0.3 in year 2). The immunotherapy group had reduced hayfever symptoms, skin test sensitivity to ragweed, and sensitivity to bronchial challenges and increased IgG antibodies to ragweed as compared with the placebo group; there was no longer a seasonal increase in IgE antibodies to ragweed allergen in the immunotherapy group after two years of treatment. Reduced medication costs were counterbalanced by the costs of immunotherapy. Conclusions. Although immunotherapy for adults with asthma exacerbated by seasonal ragweed exposure had positive effects on objective measures of asthma and allergy, the clinical effects were limited and many were not sustained for two years.
New concepts of sofosbuvir-based treatment regimens in patients with hepatitis C
Authors: Zoe Mariño, Florian van Bömmel, Xavier Forns, Thomas Berg
Journal: Gut (2013)

<h3>ABSTRACT</h3> Adhesion-type G protein-coupled receptors (aGPCRs) participate in a vast range of physiological processes. Correspondingly, these receptors are associated with diverse human diseases, such as developmental disorders, defects of the nervous system, allergies and cancer. Several aGPCRs have recently been linked to mechanosensitive functions suggesting that processing of mechanical stimuli may be a common feature of this receptor family. CIRL (ADGRL/Latrophilin, LPHN), one of the oldest members of the aGPCR family, sensitizes sensory responses of larval <i>Drosophila</i> to gentle touch and sound by amplifying mechanosensory signal transduction in low-threshold mechanoreceptors (Scholz et al., 2015; 2017). In the present study, we show that <i>Cirl</i> is also expressed in high-threshold mechanical nociceptors where it adjusts nocifensive behaviour under physiological and pathophysiological conditions. Optogenetic <i>in vivo</i> experiments indicate that CIRL quenches cAMP levels in both mechanosensory submodalities. However, contrasting its effect in touch sensitive neurons, CIRL dampens the response of nociceptors to mechanical stimulation. Consistent with this finding, rat nociceptors display a drop in <i>Cirl1</i> expression during allodynia. Taken together, these results demonstrate that CIRL exerts opposing modulatory functions in low-threshold mechanosensors and high-threshold nociceptors. This intriguing bipolar action likely facilitates the separation of mechanosensory signals carrying different physiological information.
Quantitative evaluation of parenchymal liver cell volume and total hepatocyte number in cirrhotic patients
Authors: Hiroshi Imamura, Seiji Kawasaki, Junji Shiga, Yasutsugu Bandai, Kensho Sanjo, Yasuo Idezuki
Journal: Hepatology (1991)

A simple morphometrical method was developed using a color image analyzing system, which allowed quantitative evaluation of parenchymal liver cell volume and total hepatocyte number in cirrhotic patients. With this method, we estimated these values in 29 cirrhotic patients who underwent hepatic resection (nine cases) or nonshunting operation (20 cases). Liver volume, calculated from computed tomographic images, was 976 +/- 196 cm3 (range = 602 to 1,376 cm3); the parenchymal cell volume ratio, obtained based on liver histological appearance with silver stain, was 0.665 +/- 0.092 (range = 0.510 to 0.881); and the parenchymal cell volume, calculated by multiplying the liver volume with the parenchymal cell volume ratio, was 645 +/- 140 cm3 (range = 403 to 936 cm3). The total hepatocyte number obtained in a similar manner using hematoxylin-stained specimens was 1.72 +/- 0.56 x 10(11) (range = 0.74 to 2.94 x 10(11)). The validity and applicability of the method is discussed, and the data are compared with those reported in other studies.
Cyclooxygenase-2 Inhibitors in Tumorigenesis (Part I)
Authors: M. M. Taketo
Journal: JNCI Journal of the National Cancer Institute (1998)

The rate-limiting enzyme in arachidonate metabolism is mediated by enzymes known as cyclooxygenases (COXs). These enzymes catalyze the biosynthesis of prostaglandin H 2 , the precursor of molecules, such as prostaglandins, prostacyclin, and thromboxanes. The COX enzyme family consists of the classical COX-1 enzyme, which is constitutively expressed in many tissues, and a second enzyme, i.e., COX-2, which is induced by various stimuli, such as mitogens and cytokines, and is involved in many inflammatory reactions. Because nonsteroidal anti-inflammatory drugs inhibit both COX-1 and COX-2, these drugs also cause unwanted side effects, exemplified by gastrointestinal bleeding. Accumulating evidence indicates that nonsteroidal anti-inflammatory drugs can reduce the incidence of colorectal cancers in human and experimental animals and can reduce the polyp number and size in patients with familial adenomatous polyposis. This Part I (of a two-part review) focuses on the discovery of the COXs; their biochemical, molecular, and structural properties; and on the discovery of isozyme-specific inhibitors of COX activity. [J Natl Cancer Inst 1998;90:1529-36]
ELIMINATION OF GRAFT-VERSUS-HOST DISEASE BY IN-VITRO DEPLETION OF ALLOREACTIVE LYMPHOCYTES WITH A MONOCLONAL RAT ANTI-HUMAN LYMPHOCYTE ANTIBODY (CAMPATH-1)
Authors: H. Waldmann, G. Hale, G. Cividalli, Z. Weshler, D. Manor, E.A. Rachmilewitz, A. Polliak, R. Or, L. Weiss, S. Samuel, C. Brautbar, S. Slavin
Journal: The Lancet (1984)
Can peak expiratory flow measurements reliably identify the presence of airway obstruction and bronchodilator response as assessed by FEV1 in primary care patients presenting with a persistent cough?
Authors: H A Thiadens, G H De Bock, J C Van Houwelingen, F W Dekker, M W M De Waal, M P Springer, D S Postma
Journal: Thorax (1999)

In general practice airway obstruction and the bronchodilator response are usually assessed using peak expiratory flow (PEF) measurements. A study was carried out in patients presenting with persistent cough to investigate to what extent PEF measurements are reliable when compared with tests using forced expiratory volume in one second (FEV(1)) as the measure of response.Data (questionnaire, physical examination, spirometry, PEF) were collected from 240 patients aged 18-75 years, not previously diagnosed with asthma or chronic obstructive pulmonary disease (COPD), who consulted their general practitioner with cough of at least two weeks duration. The relationship between low PEF (PEF < PEFpred - 1.64RSD) and low FEV(1) (FEV(1) < FEV(1)pred - 1.64RSD) was tested. A positive bronchodilator response after inhaling 400 microg salbutamol was defined as an increase in FEV(1) of > or = 9% predicted and was compared with an absolute increase in PEF with cut off values of 40, 60, and 80 l/min and DeltaPEF % baseline with cut off values of 10%, 15%, and 20%.Forty eight patients (20%) had low FEV(1), 86 (35.8%) had low PEF, and 32 (13.3%) had a positive bronchodilator response. Low PEF had a positive predictive value (PPV) for low FEV(1) of 46.5% and a negative predictive value (NPV) of 95%. DeltaPEF of > or = 10%, > or = 15%, or > or = 20% baseline had PPVs of 36%, 52%, and 67%, respectively, and DeltaPEF of > or = 40, > or = 60, and > or = 80 l/min in absolute terms had PPVs of 39%, 45%, and 57%, respectively, for DeltaFEV(1) > or = 9% predicted; NPVs were high (88-93%).Although PEF measurements can reliably exclude airway obstruction and bronchodilator response, they are not suitable for use in the assessment of the bronchodilator response in the diagnostic work up of primary care patients with persistent cough. The clinical value of PEF measurements in the diagnosis of reversible obstructive airway disease should therefore be re-evaluated.
Expression of the endoplasmic reticulum molecular chaperone (ORP150) rescues hippocampal neurons from glutamate toxicity
Authors: Yasuko Kitao, Kentaro Ozawa, Mayuki Miyazaki, Michio Tamatani, Tomohiro Kobayashi, Hideki Yanagi, Masaru Okabe, Masahito Ikawa, Tetsumori Yamashima, David M. Stern, Osamu Hori, Satoshi Ogawa
Journal: Journal of Clinical Investigation (2001)

A series of events initiated by glutamate-receptor interaction perturbs cellular homeostasis resulting in elevation of intracellular free calcium and cell death. Cells subject to such environmental change express stress proteins, which contribute importantly to maintenance of metabolic homeostasis and viability. We show that an inducible chaperone present in endoplasmic reticulum (ER), the 150-kDa oxygen-regulated protein (ORP150), is expressed both in the human brain after seizure attack and in mouse hippocampus after kainate administration. Using mice heterozygous for ORP150 deficiency, exposure to excitatory stimuli caused hippocampal neurons to display exaggerated elevation of cytosolic calcium accompanied by activation of mu-calpain and cathepsin B, as well as increased vulnerability to glutamate-induced cell death in vitro and decreased survival to kainate in vivo. In contrast, targeted neuronal overexpression of ORP150 suppressed each of these events and enhanced neuronal and animal survival in parallel with diminished seizure intensity. Studies using cultured hippocampal neurons showed that ORP150 regulates cytosolic free calcium and activation of proteolytic pathways causing cell death in neurons subject to excitatory stress. Our data underscore a possible role for ER stress in glutamate toxicity and pinpoint a key ER chaperone, ORP150, which contributes to the stress response critical for neuronal survival.
Correlation between CD8 dependency and determinant density using peptide-induced, Ld-restricted cytotoxic T lymphocytes.
Authors: M A Alexander, C A Damico, K M Wieties, T H Hansen, J M Connolly
Journal: The Journal of Experimental Medicine (1991)

We have taken advantage of some unique properties of H-2Ld to investigate the determinant density requirements for cytotoxic T lymphocyte (CTL) priming versus effector function and to correlate the determinant density requirements with CD8 dependency. In a previous study (Lie, W.-R., N. B. Myers, J. Gorka, R. J. Rubocki, J. M. Connolly, and T. H. Hansen. 1990. Nature [Lond.]. 344:439), we demonstrated that culturing normal cells with peptides known to be restricted by H-2Ld led to a two- to fourfold increase in surface Ld expression. In the present study, we demonstrate the generation of Ld-restricted, peptide-specific in vitro primary CTL by culturing spleen cells with murine cytomegalovirus or tum- peptide at concentrations previously shown to result in maximum induction of Ld expression. Target cells can be sensitized for recognition by these CTL with lower dose of peptide than are required for the primary sensitization. This demonstrates differences in the determinant density requirements for priming versus effector function. The in vitro primary CTL generated with peptide can weakly lyse target cells that express the determinant endogenously, and CTL lines and clones capable of strong lysis of endogenous expressors are easily obtained. In both cases, target cells treated with exogenous peptide are lysed better than target cells expressing antigen endogenously. This suggested that there are differences in the determinant density of peptide-fed versus endogenous targets. This interpretation was substantiated when it was observed that the level of lysis of target cells expressing endogenous determinants correlated inversely with the amount of peptide required to sensitize targets for recognition by various tum- -specific CTL clones. Furthermore, simultaneous titration of both the peptide used to treat target cells and the antibody to CD8 revealed that the various CTL clones analyzed displayed widely disparate CD8 dependencies. In each case, the CD8 dependency correlated inversely with the determinant density requirement. Therefore, CD8 dependency of CTL is relative, but shows an absolute and quantitative correlation with their dependency on determinant density. These findings suggest that under physiologic conditions, where only low determinant densities are likely to be encountered, all CTL clones will show at least partial CD8 dependency.
Oligoclonal expansion of major histocompatibility complex class I-restricted cytolytic T lymphocytes during a primary immune response in vivo: direct monitoring by flow cytometry and polymerase chain reaction.
Authors: H R MacDonald, J L Casanova, J L Maryanski, J C Cerottini
Journal: The Journal of Experimental Medicine (1993)

Previous T cell receptor (TCR) sequence analysis of a panel of 23 H-2Kd restricted cytotoxic T lymphocyte (CTL) clones recognizing the decapeptide HLA-CW3 170-179 revealed a striking conservation of TCR structure, in that all clones examined used V beta 10 and J alpha pHDS58 segments. We show here that the primary response in vivo after intraperitoneal injection of DBA/2 mice with HLA-CW3 expressing transfectants of syngeneic P815 (H-2d) tumor cells is characterized by a dramatic expansion of CD8+ V beta 10+ CTL in the peritoneal cavity and draining (mesenteric) lymph node, as well as in peripheral blood. Additional analysis of TCR on HLA-CW3 immune populations by flow cytometry and polymerase chain reaction further indicates that the vast majority of responding CD8+ cells express restricted V alpha domains, a dominant J alpha segment (pHDS58), and a conserved CDR3 length for both alpha and beta chains. This novel system provides a unique opportunity to directly monitor an oligoclonal primary antigen specific immune response in vivo at the single cell level independently of functional assays.
Costs and Effectiveness of Ximelagatran for Stroke Prophylaxis in Chronic Atrial Fibrillation
Authors: Cara L. O’Brien
Journal: JAMA (2005)

ContextRecent trials have found that ximelagatran and warfarin are equally effective in stroke prevention for patients with atrial fibrillation. Because ximelagatran can be taken in a fixed, oral dose without international normalized ratio monitoring and may have a lower risk of hemorrhage, it might improve quality-adjusted survival compared with dose-adjusted warfarin.ObjectiveTo compare quality-adjusted survival and cost among 3 alternative therapies for patients with chronic atrial fibrillation: ximelagatran, warfarin, and aspirin.DesignSemi-Markov decision model.PatientsHypothetical cohort of 70-year-old patients with chronic atrial fibrillation, varying risk of stroke, and no contraindications to anticoagulation therapy.Main Outcome MeasuresQuality-adjusted life-years (QALYs) and costs in US dollars.ResultsFor patients with atrial fibrillation but no additional risk factors for stroke, both ximelagatran and warfarin cost more than $50 000 per QALY compared with aspirin. For patients with additional stroke risk factors and low hemorrhage risk, ximelagatran modestly increased quality-adjusted survival (0.12 QALY) at a substantial cost ($116 000 per QALY) compared with warfarin. For ximelagatran to cost less than $50 000 per QALY it would have to cost less than $1100 per year or be prescribed to patients who have an elevated risk of intracranial hemorrhage (&gt;1.0% per year of warfarin) or a low quality of life with warfarin therapy.ConclusionAssuming equal effectiveness in stroke prevention and decreased hemorrhage risk, ximelagatran is not likely to be cost-effective in patients with atrial fibrillation unless they have a high risk of intracranial hemorrhage or a low quality of life with warfarin.
Elevated Pregnancy Losses at High and Low Extremes of Maternal Glucose in Early Normal and Diabetic Pregnancy
Authors: Lois Jovanovic, Robert H. Knopp, Haesook Kim, William T. Cefalu, Xiao-Dong Zhu, Young Jack Lee, Joe Leigh Simpson, James L. Mills
Journal: Diabetes Care (2005)

OBJECTIVE—Early pregnancy losses increase with marked hyperglycemia in diabetic pregnancy. However, mean loss rates do not differ from those of nondiabetic pregnancy. This observation might be explained by increased fetal losses at the extremes of glycemia in diabetic and nondiabetic pregnancy. To test this hypothesis, we examined relationships of proximate measures of prior glycemia, glycated protein and fructosamine, to pregnancy loss. RESEARCH DESIGN AND METHODS—A total of 389 diabetic and 429 nondiabetic pregnant subjects participated in the Diabetes In Early Pregnancy study. Glycated protein and fructosamine measurements were standardized as multiples of control values for each center (Z score). The logarithm of odds of pregnancy loss were plotted against Z scores and tested by logistic models. RESULTS—Mean pregnancy loss rates were 12% in diabetic and 13% in normal pregnancies. However, over six intervals of glycated protein in diabetic pregnancy, fetal loss rates at the upper and lower extremes (24 and 33%, respectively) were approximately threefold higher than the four intervening rates (8–14%). The odds ratio of pregnancy loss for these extreme intervals to the intervening intervals is 3.0 (P = 0.01). Nondiabetic losses showed a similar pattern. In confirmation, logit pregnancy losses were increased in a J-shaped curve at the glycemic extremes in normal (P &amp;lt; 0.019) and diabetic (P &amp;lt; 0.015) pregnancy. The upper glycemic extreme in diabetic pregnancy was two- to fivefold higher than in control pregnancy. CONCLUSIONS—Pregnancy losses are increased at the extremes of glycemia in both normal and diabetic pregnancy but at higher levels in diabetic pregnancy. The data suggest defensive adaptations against hyperglycemia in diabetic pregnancy.
Cd47-Signal Regulatory Protein α (Sirpα) Regulates Fcγ and Complement Receptor–Mediated Phagocytosis
Authors: Per-Arne Oldenborg, Hattie D. Gresham, Frederik P. Lindberg
Journal: The Journal of Experimental Medicine (2001)

In autoimmune hemolytic anemia (AIHA), circulating red blood cells (RBCs) opsonized with autoantibody are recognized by macrophage Fcgamma and complement receptors. This triggers phagocytosis and elimination of RBCs from the circulation by splenic macrophages. We recently found that CD47 on unopsonized RBCs binds macrophage signal regulatory protein alpha (SIRPalpha), generating a negative signal that prevents phagocytosis of the unopsonized RBCs. We show here that clearance and phagocytosis of opsonized RBCs is also regulated by CD47-SIRPalpha. The inhibition generated by CD47-SIRPalpha interaction is strongly attenuated but not absent in mice with only residual activity of the phosphatase Src homology 2 domain-containing protein tyrosine phosphatase (SHP)-1, suggesting that most SIRPalpha signaling in this system is mediated by SHP-1 phosphatase activity. The macrophage phagocytic response is controlled by an integration of the inhibitory SIRPalpha signal with prophagocytic signals such as from Fcgamma and complement receptor activation. Thus, augmentation of inhibitory CD47-SIRPalpha signaling may prevent or attenuate RBC clearance in AIHA.
Adherence to Long-Term Surveillance Mammography Among Women With Ductal Carcinoma In Situ Treated With Breast-Conserving Surgery
Authors: Larissa Nekhlyudov, Laurel A. Habel, Ninah S. Achacoso, Inkyung Jung, Reina Haque, Laura C. Collins, Stuart J. Schnitt, Charles P. Quesenberry, Suzanne W. Fletcher
Journal: Journal of Clinical Oncology (2009)

PURPOSE Breast-conserving surgery (BCS) is an effective treatment for ductal carcinoma in situ (DCIS) but women who undergo BCS remain at risk for recurrences. Whether mammographic surveillance after BCS occurs and by whom is not known. METHODS We reviewed medical records of women diagnosed with DCIS between 1990 and 2001 and treated with BCS. Using descriptive statistics, generalized estimating, and logistic regression modeling, we examined the rates and predictors of surveillance mammography over a 10-year period after BCS. Results The cohort included 3,037 women observed for a median of 4.8 years (range, 0.5 to 15.7). Of the 2,676 women observed for at least 1 year after BCS, most (79%) had at least one surveillance mammogram during the first year of follow-up; 69% in year 5 and 61% in year 10. Among those observed for 5 years, surveillance mammograms were more likely among women age 60 to 69 years (odds ratio [OR], 1.72; 95% CI, 1.26 to 2.34), users of menopausal hormone therapy at diagnosis (OR, 1.26; 95% CI, 1.01 to 1.57) as well as those treated with adjuvant radiation (OR, 1.28; 95% CI, 1.08 to 1.53) and adjuvant radiation with tamoxifen (OR, 1.61; 95% CI, 1.13 to 2.30). Surveillance mammograms were less likely among obese women (OR, 0.70; 95% CI, 0.56 to 0.86). The findings were similar among women observed for 10 years. Only 34% and 15% of women observed for 5 and 10 years, respectively, had a surveillance mammogram during each year of follow-up. CONCLUSION Surveillance mammography after BCS among insured women with DCIS often did not occur yearly and declined over time after treatment. Patients and providers must remain vigilant about surveillance after BCS.