tbuckley/cabot-search huggingface dataset:
Comparison of addition of theophylline to inhaled steroid with doubling of the dose of inhaled steroid in asthma
Authors: D Ukena, U Harnest, R Sakalauskas, P Magyar, N Vetter, H Steffen, S Leichtl, F Rathgeb, A Keller, VW Steinijans
Journal: European Respiratory Journal (1997)

The anti-asthmatic effects of theophylline may supplement those of inhaled steroids in asthma. The aim of the present trial was to study how the addition of theophylline compares to doubling the dose of inhaled steroid in asthmatics who remain symptomatic on beclomethasone dipropionate (BDP) 400 microg x day(-1). The trial was designed as a randomized, double-blind, parallel-group study in several European countries. Sixty nine patients were treated for 6 weeks with theophylline plus BDP 400 microg x day(-1), compared to 64 patients treated with BDP 800 micro x day(-1). The mean+/-SD serum theophylline concentration was 10.1+/-4.2 mg x L(-1). Lung function measurements were made throughout the study and patients kept daily records of peak expiratory flow (PEF), symptoms and salbutamol usage. Forced expiratory volume in one second and PEF at week 6 were significantly increased by both treatments (p&lt;0.01). PEF variability was reduced by about 30% in both groups. There were significant improvements in asthma symptoms and rescue medication use (p&lt;0.001). There were no significant differences between the treatment groups. The study demonstrated clinical equivalence of theophylline plus beclomethasone dipropionate 400 microg x day(-1) and beclomethasone dipropionate 800 microg x day(-1) in patients whose asthma is not controlled on beclomethasone dipropionate 400 microg x day(-1). The results support the use of theophylline as a steroid-sparing agent. The combination of low-dose inhaled steroid plus theophylline is a suitable treatment for moderate asthma.
Cross-linking the B7 Family Molecule B7-DC Directly Activates Immune Functions of Dendritic Cells
Authors: Loc T. Nguyen, Suresh Radhakrishnan, Bogoljub Ciric, Koji Tamada, Tahiro Shin, Drew M. Pardoll, Lieping Chen, Moses Rodriguez, Larry R. Pease
Journal: The Journal of Experimental Medicine (2002)

B7-DC molecules are known to function as ligands on antigen-presenting cells (APCs), enhancing T cell activation. In this study, cross-linking B7-DC with the monoclonal antibody sHIgM12 directly potentiates dendritic cell (DC) function by enhancing DC presentation of major histocompatibility complex–peptide complexes, promoting DC survival; and increasing secretion of interleukin (IL)-12p70, a key T helper cell type 1 promoting cytokine. Furthermore, ex vivo treatment of DCs or systemic treatment of mice with sHIgM12 increases the number of transplanted DCs that reach draining lymph nodes and increases the ability of lymph node APCs to activate naive T cells. Systemic administration of the antibody has an equivalent effect on DCs transferred at a distant site. These findings implicate B7-DC expressed on DCs in bidirectional communication. In addition to the established costimulatory and inhibitory functions associated with B7-DC, this molecule can also function as a conduit for extracellular signals to DCs modifying DC functions.
Increased Low-Density Lipoprotein Oxidation and Impaired High-Density Lipoprotein Antioxidant Defense Are Associated With Increased Macrophage Homing and Atherosclerosis in Dyslipidemic Obese Mice
Authors: Ann Mertens, Peter Verhamme, John K. Bielicki, Michael C. Phillips, Rozenn Quarck, Wim Verreth, Dominique Stengel, Ewa Ninio, Mohamad Navab, Bharti Mackness, Mike Mackness, Paul Holvoet
Journal: Circulation (2003)

Obesity-associated dyslipidemia in humans is associated with increased low-density lipoprotein (LDL) oxidation. Mice with combined leptin and LDL receptor deficiency are obese and show severe dyslipidemia and insulin resistance. We investigated the association between oxidation of apolipoprotein B-containing lipoproteins, high-density lipoprotein (HDL) antioxidant defense, and atherosclerosis in these mice.LDL receptor knockout (LDLR-/-), leptin-deficient (ob/ob), double-mutant (LDLR-/-;ob/ob), and C57BL6 mice were fed standard chow. Double-mutant mice had higher levels of non-HDL (P<0.001) and HDL (P<0.01) cholesterol and of triglycerides (P<0.001). They also had higher oxidative stress, evidenced by higher titers of autoantibodies against malondialdehyde-modified LDL (P<0.001). C57BL6 and ob/ob mice had no detectable lesions. Lesions covered 20% of total area of the thoracic abdominal aorta in double-mutant mice compared with 3.5% in LDLR-/- mice (P<0.01). Higher macrophage homing and accumulation of oxidized apolipoprotein B-100-containing lipoproteins were associated with larger plaque volumes in the aortic root of double-mutant mice (P<0.01). The activity of the HDL-associated antioxidant enzymes paraoxonase and lecithin:cholesterol acyltransferase (LCAT) (ANOVA; P<0.0001 for both) was lower in double-mutant mice. Adenovirus-mediated LCAT gene transfer in double-mutant mice increased plasma LCAT activity by 64% (P<0.01) and reduced the titer of autoantibodies by 40% (P<0.01) and plaque volume in the aortic root by 42% (P<0.05) at 6 weeks.Dyslipidemia and insulin resistance in obese LDL receptor-deficient mice are associated with increased oxidative stress and impaired HDL-associated antioxidant defense, evidenced by decreased paraoxonase and LCAT activity. Transient LCAT overexpression was associated with a reduction of oxidative stress and atherosclerosis.
Mechanisms of ANCA-Mediated Leukocyte-Endothelial Cell Interactions In Vivo
Authors: Sarah L. Nolan, Neena Kalia, Gerard B. Nash, Dia Kamel, Peter Heeringa, Caroline O.S. Savage
Journal: Journal of the American Society of Nephrology (2008)

Anti-myeloperoxidase (anti-MPO) antibodies have been implicated in the pathogenesis of small-vessel vasculitis, but the molecular mechanisms by which these antibodies contribute to disease are unknown. For determination of how anti-MPO antibodies affect inflammatory cell recruitment in small-vessel vasculitis, intravital microscopy was used to monitor leukocyte behavior in the accessible cremasteric microvessels under various experimental conditions. After local pretreatment of the cremaster muscle with cytokines (TNF-alpha, IL-1beta, or keratinocyte-derived chemokine), administration of anti-MPO IgG to wild-type mice reduced leukocyte rolling in favor of augmented adhesion to and transmigration across the endothelium. This led to a decrease in the number of systemic circulating leukocytes and, similar to the early events in the development of vasculitic lesions, an increase in leukocyte recruitment to renal and pulmonary tissue. TNF-alpha led to the greatest recruitment of inflammatory cells, and IL-1beta led to the least. When anti-CD18 was co-administered, anti-MPO IgG did not affect leukocyte rolling, adhesion, or transmigration; similarly, anti-MPO IgG did not produce these effects in Fc receptor gamma chain-/- mice. This study provides direct in vivo evidence of enhanced leukocyte-endothelial cell interactions in the presence of anti-MPO IgG and highlights the critical roles of Fcgamma receptors and beta2 integrins in mediating these interactions. In addition, it suggests that neutrophils primed by cytokines in the presence of anti-MPO IgG can have systemic effects and target specific vascular beds.
Beneficial effects of SR33805 in failing myocardium
Authors: Younss Ait Mou, Attila Toth, Cécile Cassan, Daniel Czuriga, Pieter P. de Tombe, Zoltan Papp, Alain Lacampagne, Olivier Cazorla
Journal: Cardiovascular Research (2011)

SR33805, a potent Ca(2+) channel blocker, increases cardiac myofilament Ca(2+) sensitivity in healthy rat cardiomyocytes. Therefore, the aim of the present study was to evaluate the effects of SR33805 on contractile properties in ischaemic failing hearts after myocardial infarction (MI) in vivo and in vitro at the cellular level.The effect of SR33805 (10 µM) was tested on the excitation-contraction coupling of cardiomyocytes isolated from rat with end-stage heart failure. Cell shortening and Ca(2+) transients were measured in intact cardiomyocytes, while contractile properties were determined in Triton X-100 permeabilized myocytes. Acute treatment with SR33805 restored the MI-altered cell shortening without affecting the Ca(2+) transient amplitude, suggesting an increase of myofilament Ca(2+) sensitivity in MI myocytes. Indeed, a SR33805-induced sensitization of myofilament activation was found to be associated with a slight increase in myosin light chain-2 phosphorylation and a more significant decrease on troponin I (TnI) phosphorylation. Decreased TnI phosphorylation was related to inhibition of protein kinase A activity by SR33805. Finally, administration of a single intra-peritoneal bolus of SR33805 (20 mg/kg) improved end-systolic strain and fractional shortening of MI hearts.The present study indicates that treatment with SR33805 improved contractility of ischaemic failing hearts after MI in the rat by selectively modulating the phosphorylation status of sarcomeric regulatory proteins, which then sensitized the myofilaments to Ca(2+). Our results gave a proof of concept that manipulation of the Ca(2+) sensitivity of sarcomeric regulatory proteins can be used to improve contractility of a failing heart.
Brain-Derived Neurotrophic Factor and Neuropsychiatric Disorders
Authors: Anita E. Autry, Lisa M. Monteggia
Journal: Pharmacological Reviews (2012)

Brain derived neurotrophic factor (BDNF) is the most prevalent growth factor in the central nervous system (CNS). It is essential for the development of the CNS and for neuronal plasticity. Because BDNF plays a crucial role in development and plasticity of the brain, it is widely implicated in psychiatric diseases. This review provides a summary of clinical and preclinical evidence for the involvement of this ubiquitous growth factor in major depressive disorder, schizophrenia, addiction, Rett syndrome, as well as other psychiatric and neurodevelopmental diseases. In addition, the review includes a discussion of the role of BDNF in the mechanism of action of pharmacological therapies currently used to treat these diseases, such antidepressants and antipsychotics. The review also covers a critique of experimental therapies such as BDNF mimetics and discusses the value of BDNF as a target for future drug development.
Adoptive immunotherapy of prostate cancer bone lesions using redirected effector lymphocytes
Authors: Jehonathan H. Pinthus, Tova Waks, Victoria Malina, Keren Kaufman-Francis, Alon Harmelin, Itzhak Aizenberg, Hannah Kanety, Jacob Ramon, Zelig Eshhar
Journal: Journal of Clinical Investigation (2004)

Prostate cancer is currently the most commonly diagnosed noncutaneous malignancy in American men. When metastatic, usually to the bone, the disease is no longer curable and is usually treated palliatively with androgen ablation. However, after conversion to androgen-independent disease, there is no effective therapy currently available. The "T body" approach, which uses genetically reprogrammed lymphocytes derived from the patient and expressing chimeric receptor genes, combines the effector functions of T lymphocytes and NK cells with the ability of antibodies to recognize predefined surface antigens with high specificity and in a non–MHC-restricted manner. We show here the therapeutic efficacy of human lymphocytes bearing erbB2-specific chimeric receptors on human prostate cancer BM lesions in a SCID mouse model after conditioning of the recipient to allow homing and persistent functioning of the adoptively transferred cells. Induction of stromal cell–derived factor-1 production within the BM using low-dose irradiation or cyclophosphamide combined with IL-2 administration enhanced the homing of systemically delivered T bodies, resulting in decreased tumor growth and prostate-specific antigen secretion, prolongation of survival, and even cure of the treated mice. These preclinical studies strongly support the idea that the T body approach has therapeutic potential in disseminated prostate cancer.
Reply to P.P. Singh et al
Authors: Yu-Tse Tsan, Chang-Hsing Lee, Jung-Der Wang, Pau-Chung Chen
Journal: Journal of Clinical Oncology (2012)

It has been well established that diabetes increases risk of developing hepatocellular carcinoma (HCC). 1 In contrast, antidiabetic therapy may reduce risk of developing HCC in patients with diabetes.The biguanide metformin, which exerts its effects mainly on the liver, is the first-line agent for the treatment of diabetes.Recent studies have raised the possibility that metformin intake for the control of diabetes may decrease risk of HCC as well as thiazolidinediones (TZDs) can. 2-4 Singh and Singh 5 expressed concern about the potential effect of antidiabetic therapy, especially metformin and TZDs, on risk reduction of HCC in patients with hepatitis B virus (HBV).This is an important and interesting issue for us because 61.9% patients in the group with statin use in our HBV-infected cohort had diabetes. 6To investigate the relationship among the use of metformin, TZDs, and statins on reducing HCC risk, we reanalyzed the data by adding the potential medications (Table 1, next page).The adjusted hazard ratios (HRs) were 0.64 (95% CI, 0.43 to 0.97), 0.42 (95% CI, 0.28 to 0.63), and 0.34 (95% CI, 0.18 to 0.67) for statin use of 28 to 90, 91 to 365, and greater than 365 cumulative defined daily doses (cDDDs), respectively, compared with nonusers (Ͻ 28 cDDDs) after adding metformin, TZDs, and sulfonylurea use.These findings were similar to those of our previous analysis; statin use may reduce risk of HCC in patients with HBV infection in a dose-dependent manner. 6 Singh and Singh 5 also suggested that part of the risk reduction may have been attributable to the effect of metformin or TZDs with a synergistic effect on risk reduction of HCC in patients with hepatitis B. 5 To examine the association between HCC and amounts of metformin and TZDs used, we have conducted two Cox proportional hazard models with adjustment for different potential confounders.In model 1, variables, including target medication, age, sex, income, urbanization, diabetes, and liver cirrhosis, were conducted.As a result, we found a protective effect on HCC risk reduction of metformin and TZD use.The adjusted HR was 0.73 (95% CI, 0.54 to 0.98) for metformin use of greater than 365 cDDDs and 0.20 (95% CI, 0.05 to 0.81) for TZD use of greater than 365 cDDDs relative to nonusers, respectively.However, only TZDs use remained a significant HCC risk reduction; the adjusted HR was 0.23 (95% CI, 0.06 to 0.92) for TZD use of greater than 365 cDDDs relative to nonusers after including statin, metformin, TZDs, sulfonylurea use, and other potential confounders in model 2 (Table 1).It was difficult to assess the synergistic effect among statin, metformin, and TZD use because of the relatively small number of HCCs in each stratum of our study.A large-scale study is needed to clarify the association between HCC and the use of statin, metformin, and TZDs.
Late Results Following Emergency Saphenous Vein Bypass Grafting For Unstable Angina
Authors: LAWRENCE I. BONCHEK, SHAHBUDIN H. RAHIMTOOLA, RICHARD P. ANDERSON, JOHN A. MCANULTY, JOSEF ROSCH, J. DAVID BRISTOW, ALBERT STARR
Journal: Circulation (1974)

Fifty-five consecutive patients with intermittent resting chest pain persisting more than 24 hours after hospitalization and accompanied by ECG changes representative of ischemia were operated urgently more than one year ago. Recent cases with shorter follow-up are excluded. Twenty-eight patients had single grafts, 23 had double grafts, three had triple grafts, and one a quadruple graft. There were three operative deaths (5%) and one sudden late death (2%). There were six early Mls and three late Mls. Follow-up ranges from 12 to 52 months (mean 24 months) with nine patients followed for four years. Actuarial analysis indicates a projected survival rate of 93% three years postoperative. Twenty-three survivors are Functional Class (FC) I, 19 are FC II, and eight are FC III. Functional class could not be determined in one survivor. Thirty patients had postoperative angiography one week to 32 months postop. 35/51 grafts were patent. Only three patients had no patent grafts. There were no significant differences between mean preoperative and postoperative left ventricular end-diastolic pressures (assessed in 20 patients) or ejection fractions (assessed in ten patients). The extremely low mortality early and late postop (7%), the low incidence of Ml (16%), and the excellent functional results after extended follow-up indicate that emergency saphenous vein bypass grafting is an effective therapy for unstable angina.
ACROKERATOSIS VERRUCIFORMIS OF HOPF WITH STEATOCYSTOMA MULTIPLEX AND HYPERTKOPHIC LICHEN PLANUS
Authors: JULIAN VERBOV
Journal: British Journal of Dermatology (1972)

SUMMARY.— The case is reported of a woman aged 50 with acrokeratosis verruciformis of Hopf. The patient's father and a sister were said to have similar lesions. The patient also had steatocystoma multiplmx in the presternal region and hypertrophic lichen planus over the elbows.
Lung Cancer Incidence in Never Smokers
Authors: Heather A. Wakelee, Ellen T. Chang, Scarlett L. Gomez, Theresa H. Keegan, Diane Feskanich, Christina A. Clarke, Lars Holmberg, Lee C. Yong, Laurence N. Kolonel, Michael K. Gould, Dee W. West
Journal: Journal of Clinical Oncology (2007)

Purpose Lung cancer is a leading cause of cancer death worldwide. Although smoking remains the predominant cause of lung cancer, lung cancer in never smokers is an increasingly prominent public health issue. However, data on this topic, particularly lung cancer incidence rates in never smokers, are limited. Methods We reviewed the existing literature on lung cancer incidence and mortality rates among never smokers and present new data regarding rates in never smokers from the following large, prospective cohorts: Nurses’ Health Study; Health Professionals Follow-Up Study; California Teachers Study; Multiethnic Cohort Study; Swedish Lung Cancer Register in the Uppsala/Örebro region; and First National Health and Nutrition Examination Survey Epidemiologic Follow-Up Study. Results Truncated age-adjusted incidence rates of lung cancer among never smokers age 40 to 79 years in these six cohorts ranged from 14.4 to 20.8 per 100,000 person-years in women and 4.8 to 13.7 per 100,000 person-years in men, supporting earlier observations that women are more likely than men to have non–smoking-associated lung cancer. The distinct biology of lung cancer in never smokers is apparent in differential responses to epidermal growth factor receptor inhibitors and an increased prevalence of adenocarcinoma histology in never smokers. Conclusion Lung cancer in never smokers is an important public health issue, and further exploration of its incidence patterns, etiology, and biology is needed.
A prospective evaluation of VEGF-targeted treatment cessation in metastatic clear cell renal cancer
Authors: T. Powles, I. Kayani, K. Sharpe, L. Lim, J. Peters, G.D. Stewart, D. Berney, A. Sahdev, S. Chowdhury, E. Boleti, J. Shamash, A.R. Reynolds, R. Jones, C. Blank, J. Haanen, A. Bex
Journal: Annals of Oncology (2013)
QUALITATIVE DIFFERENCES IN THE ANTIGENIC COMPOSITION OF INFLUENZA A VIRUS STRAINS
Authors: William F. Friedewald
Journal: The Journal of Experimental Medicine (1944)

A study of the PR8, Christie, Talmey, W.S., and swine strains of influenza A virus by means of antibody absorption tests revealed the following findings: 1. Serum antibody could be specifically absorbed with allantoic fluid containing influenza virus or, more effectively, with concentrated suspensions of virus obtained from allantoic fluid by high-speed centrifugation or by the red cell adsorption and elution technique. Normal allantoic fluid, or the centrifugalized sediment therefrom, failed to absorb antibodies. Influenza B virus (Lee) caused no detectable absorption of antibody from antisera directed against influenza A virus strains, but it specifically absorbed antibody from Lee antisera. 2. The neutralizing, agglutination-inhibiting, and complement-fixing anti-bodies in ferret antisera were completely absorbed only by the homologous virus strain, even though 2 absorptions were carried out with large amounts of heterologous virus strains. 3. PR8 virus appeared to have the broadest range of specific antigenic components for it completely absorbed the heterologous antibodies in Christie and W.S. antisera and left only those antibodies which reacted with the respective homologous strains. The other virus strains (Christie, Talmey, W.S., swine) were more specific in the absorption of heterologous antibodies and completely removed only those antibodies which reacted with the absorbing virus. 4. The absorption tests revealed a higher degree of specificity and individuality of the virus strains than the various cross reactions previously reported. The strain specificity of PR8 virus was equally manifest in absorption tests with ferret sera and with human sera following vaccination. 5. The amount of homologous antibody remaining in a PR8 ferret serum after absorption with PR8 virus, obtained by the red cell adsorption and elution method, varied inversely as the concentration of virus used for absorption. A given concentration of virus, however, absorbed a greater percentage of neutralizing antibodies than either agglutination-inhibiting or complement-fixing antibodies.
[661] ROLE OF THE CD26/ADA/ADENOSINE SYSTEM IN VIRAL AND AUTOIMMUNE CHRONIC LIVER DISEASES
Authors: G.F. Broelsch, F. Teffe, V. Schlaphoff, B.C. Martinez, A. Ciner, M. Cornberg, M.P. Manns, H. Wedemeyer
Journal: Journal of Hepatology (2007)
Sequence variants within the 3'-UTR of the col5a1 gene alters mrna stability: implications for musculoskeletal soft tissue injuries
Authors: M-J Laguette, S Prince, M Collins
Journal: British Journal of Sports Medicine (2011)

Background COL5A1 encodes the à1 chain of type V collagen, a minor fibrillar collagen that regulates fibrillogenesis within non-cartilaginous connective tissues. A variant within the COL5A1 3'-untranslated region (UTR) is associated with Achilles tendinopathy (AT), Anterior cruciate ligament ruptures in females, flexibility and endurance running performance. Objective To provide functional evidence for these genetic associations, the aim of this study was to identify common variants of the COL5A1 3′-UTR from patients with chronic AT and asymptomatic controls. Functional differences between the different variants were tested using reporter gene constructs. Methods The entire COL5A1 3′-UTR from four AT patients and three controls were cloned, from genomic DNA using nested PCR, within the pGL3-Promoter vector, substituting the poly (A) signal of the firefly-luciferase reporter gene. The constructs were transiently co-transfected with an internal control HT1080 cells. The normalised results were expressed as relative luciferase activity. Results Inter-individual variation was demonstrated with a 2.6-fold difference (p&lt;0.001) in the highest activity for an AT patient (110.5±11.6%) and the lowest activity for an asymptomatic subject (42.8±8.6%). In addition, an overall significantly higher activity (87.5±14.3% vs 67.6±20.0%, p&lt;0.001) was observed for the clones from the AT patients. Two major forms of the COL5A1 3′-UTR were identified when all the cloned 3′-UTRs were sequenced. One form (WT-allele) was predominantly identified in the controls, while the second form (TEN-allele) was predominately identified in AT subjects. The luciferase activity of the WT-allele was also significantly lower than the TEN-allele (68.3±24.9% vs 86.0±18.5%, p=0.007). Conclusion Two major COL5A1 3′-UTR alleles were identified; one from the AT patients and the other from the asymptomatic controls. There was an overall increase in mRNA stability for the TEN-allele. These results demonstrate that the COL5A1 3′-UTR may play an important regulatory role which could results is susceptibility to musculoskeletal soft tissue injures and other phenotypes.