tbuckley/cabot-search huggingface dataset:
Reduction of Vertebral Fracture Risk in Postmenopausal Women With Osteoporosis Treated With Raloxifene&lt;SUBTITLE&gt;Results From a 3-Year Randomized Clinical Trial&lt;/SUBTITLE&gt;
Authors: Bruce Ettinger
Journal: JAMA (1999)

ContextRaloxifene hydrochloride, a selective estrogen receptor modulator, prevents bone loss in postmenopausal women, but whether it reduces fracture risk in these women is not known.ObjectiveTo determine the effect of raloxifene therapy on risk of vertebral and nonvertebral fractures.DesignThe Multiple Outcomes of Raloxifene Evaluation (MORE) study, a multicenter, randomized, blinded, placebo-controlled trial.Setting and ParticipantsA total of 7705 women aged 31 to 80 years in 25 countries who had been postmenopausal for at least 2 years and who met World Health Organization criteria for having osteoporosis. The study began in 1994 and had up to 36 months of follow-up for primary efficacy measurements and nonserious adverse events and up to 40 months of follow-up for serious adverse events.InterventionsParticipants were randomized to 60 mg/d or 120 mg/d of raloxifene or to identically appearing placebo pills; in addition, all women received supplemental calcium and cholecalciferol.Main Outcome MeasuresIncident vertebral fracture was determined radiographically at baseline and at scheduled 24- and 36-month visits. Nonvertebral fracture was ascertained by interview at 6-month-interim visits. Bone mineral density was determined annually by dual-energy x-ray absorptiometry.ResultsAt 36 months of the evaluable radiographs in 6828 women, 503 (7.4%) had at least 1 new vertebral fracture, including 10.1% of women receiving placebo, 6.6% of those receiving 60 mg/d of raloxifene, and 5.4% of those receiving 120 mg/d of raloxifene. Risk of vertebral fracture was reduced in both study groups receiving raloxifene (for 60-mg/d group: relative risk [RR], 0.7; 95% confidence interval [CI], 0.5-0.8; for 120-mg/d group: RR, 0.5; 95% CI, 0.4-0.7). Frequency of vertebral fracture was reduced both in women who did and did not have prevalent fracture. Risk of nonvertebral fracture for raloxifene vs placebo did not differ significantly (RR, 0.9; 95% CI, 0.8-1.1 for both raloxifene groups combined). Compared with placebo, raloxifene increased bone mineral density in the femoral neck by 2.1% (60 mg) and 2.4% (120 mg) and in the spine by 2.6% (60 mg) and 2.7% (120 mg) P&lt;0.001 for all comparisons). Women receiving raloxifene had increased risk of venous thromboembolus vs placebo (RR, 3.1; 95% CI, 1.5-6.2). Raloxifene did not cause vaginal bleeding or breast pain and was associated with a lower incidence of breast cancer.ConclusionsIn postmenopausal women with osteoporosis, raloxifene increases bone mineral density in the spine and femoral neck and reduces risk of vertebral fracture.
Carmustine, etoposide, cytarabine and melphalan as a preparative regimen for allogeneic transplantation for high-risk malignant lymphoma
Authors: D. Przepiorka, K. van Besien, I. Khouri, F. Hagemeister, B. Samuels, J. Folloder, N.T. Ueno, J. Molldrem, R. Mehra, M. Körbling, S. Giralt, J. Gajewski, M. Donato, K. Cleary, D. Claxton, I. Braunschweig, B. Andersson, P. Anderlini, R. Champlin
Journal: Annals of Oncology (1999)
Exercise testing to predict outcome in idiopathic<i>versus</i>associated pulmonary arterial hypertension
Authors: Gaël Deboeck, Cristina Scoditti, Sandrine Huez, Jean-Luc Vachiéry, Michel Lamotte, Linda Sharples, Christian Melot, Robert Naeije
Journal: European Respiratory Journal (2012)

We tested the ability of exercise testing to predict not only survival, but also time to clinical worsening (TTCW) in idiopathic versus associated pulmonary arterial hypertension (PAH). 136 patients with PAH (85 idiopathic and 51 with associated conditions) underwent cardiopulmonary exercise testing and a 6-min walk test. Death or transplantation, and clinical worsening events were recorded. 32 patients died and four had lung transplantation. In a univariate analysis, PAH patients survival was associated with oxygen uptake (V'(O(2))) at peak exercise and at the anaerobic threshold, ventilatory equivalent for carbon dioxide (minute ventilation (V'(E))/carbon dioxide production (V'(CO(2))) at the anaerobic threshold ((at))), V'(E)/V'(CO(2)) slope and distance walked. TTCW was associated with peak V'(O(2)) and V'(O(2),at), V'(E)/V'(CO(2),at), end-tidal carbon dioxide tension measured at the anaerobic threshold, peak oxygen pulse, increase in oxygen pulse and distance walked. In a multivariable analysis, distance walked and V'(E)/V'(CO(2),at) predicted survival, and only peak V'(O(2)) predicted TTCW. The receiver operating characteristic curve-derived cut-off values were 305 m for the 6-min walk distance, 54 for V'(E)/V'(CO(2),at) and 11.6 mL·kg(-1)·min for peak V'(O(2)). In the subgroup with associated PAH, no variable independently predicted either survival or clinical worsening. We conclude that several exercise variables predict survival and clinical stability in idiopathic PAH. Exercise variables are less accurate predictors of outcome in associated PAH.
Human Glioma Cell Sensitivity to the Sequence-Specific Alkylating Agent Methyl-Lexitropsin
Authors: Michael S. Bobola, Sridhar Varadarajan, Nolan W. Smith, Ryan D. Goff, Douglas D. Kolstoe, A. Blank, Barry Gold, John R. Silber
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Defining the cytotoxicity of individual adducts in DNA is necessary for mechanistic understanding of human brain tumor resistance to therapeutic alkylating agents and for design of DNA repair-related antiresistance strategies. Our purpose is to characterize the sensitivity of human glioma cells to methyl-lexitropsin (Me-lex), a sequence-specific alkylator that produces 3-methyladenine (3-meA) as the predominant (&amp;gt;90%) DNA lesion. Experimental Design: We quantitated the Me-lex cytotoxicity of 10 human glioma cell lines that differ in O6-methylguanine (O6-meG)-DNA methyltransferase (MGMT) and mismatch repair activity. We used antisense suppression of alkyladenine DNA glycosylase (AAG) and Ape1 to assess the contribution of 3-meA and abasic sites to lethality and measured abasic sites. Results: (a) The LD10 for Me-lex varied widely among the cell lines. (b) MGMT-proficient lines were more resistant than MGMT-deficient lines, an unexpected finding because Me-lex produces very little O6-meG. (c) Suppression of AAG increased Me-lex killing and reduced abasic site content. (d) Suppression of Ape1 increased Me-lex killing and increased abasic site content. (e) Ablation of MGMT had no effect on Me-lex cytotoxicity. Conclusions: (a) Me-lex is cytotoxic in human glioma cells and AAG promotes resistance, indicating that 3-meA is a lethal lesion in these cells. (b) Abasic sites resulting from 3-meA repair are cytotoxic and Ape1 promotes resistance to these derivative lesions. (c) A factor(s) associated with MGMT expression, other than repair of O6-meG, contributes to Me-lex resistance. (d) Me-lex may have clinical utility in the adjuvant therapy of gliomas. (e) AAG and Ape1 inhibitors may be useful in targeting alkylating agent resistance.
RELATION BETWEEN DEGREE OF IMMUNITY OF MICE FOLLOWING VACCINATION WITH ST. LOUIS ENCEPHALITIS VIRUS AND THE TITRE OF THE PROTECTIVE ANTIBODIES OF THE SERUM
Authors: H. L. Hodes, L. T. Webster
Journal: The Journal of Experimental Medicine (1938)

Vaccination of susceptible mice with St. Louis encephalitis virus induced an acquired immunity to intracerebral inoculation which appeared within 1 week. When first demonstrable this immunity was at a very high level and it remained so for about 6 weeks, after which time it declined and disappeared completely between the 12th and 20th week after vaccination. Humoral antibodies of significant titre could not be demonstrated during the first 6 weeks after vaccination when actual immunity to intracerebral inoculation was at its highest level. Antibodies were first detected 8 weeks after vaccination, when immunity was decreasing. The humoral antibody titre reached its peak at 23 weeks, at which time immunity had completely disappeared. A high level of circulating antibody was still present 37 weeks after vaccination. The evidence presented leads to the conclusion that humoral antibodies do not play a major part in the immunity acquired by susceptible mice after vaccination against St. Louis encephalitis virus.
Principles of endocrinology
Authors: Binnaz Leblebicioglu, John Connors, Angelo Mariotti
Journal: Periodontology 2000 (2012)

The endocrine system plays a major role in human survival. Endocrine glands secrete chemical messengers or hormones that affect every tissue of the body, including the periodontium, during the life of the individual. As the endocrine system influences a broad assortment of biological activities necessary for life, a general understanding of the principal components and functions of this system is essential. A fundamental assessment of hormone structure, mechanism of action and hormone transport, as well as influence on homeostasis is reviewed. A concise evaluation of the functions of the central endocrine glands, the functions of the major peripheral endocrine glands (other than gonadal tissues) and the known relationships of these hormones to the periodontium is examined.
Neuropilin-2–Mediated Tumor Growth and Angiogenesis in Pancreatic Adenocarcinoma
Authors: Nikolaos A. Dallas, Michael J. Gray, Ling Xia, Fan Fan, George van Buren, Puja Gaur, Shaija Samuel, Sherry J. Lim, Thiruvengadam Arumugam, Vijaya Ramachandran, Huamin Wang, Lee M. Ellis
Journal: Clinical Cancer Research (2008)

Abstract Purpose. Neuropilin-2 (NRP-2) is a coreceptor for vascular endothelial growth factor (VEGF) on endothelial cells. NRP-2 is overexpressed in pancreatic ductal adenocarcinoma (PDAC) cells relative to nonmalignant ductal epithelium. This study determined the role of NRP-2 in PDAC cells. Experimental Design. NRP-2 expression was reduced in PDAC cells with stable short-hairpin RNA (shRNA) transfection. Western blotting was done to evaluate signaling intermediates. Migration and invasion studies were carried out in Boyden chambers. Anchorage-independent growth was assessed by soft-agar colony formation. In vivo growth was evaluated using murine subcutaneous and orthotopic xenograft models. Immunohistochemical analysis evaluated in vivo proliferation and angiogenesis. Results. shRNA-NRP-2 decreased NRP-2 levels without affecting neuropilin-1 levels. Akt activation was decreased in clones with reduced NRP-2 (shRNA-NRP-2). shRNA-NRP-2 cells showed decreased migration, invasion, and anchorage-independent growth compared with control cells. In vitro proliferation rates were similar in control- and shRNA-transfected cells. Subcutaneous and orthotopic xenografts from shRNA-transfected cells were significantly smaller than those resulting from control-transfected cells (P &amp;lt; 0.05). Furthermore, shRNA-NRP-2 tumors exhibited less cellular proliferation and decreased microvascular area relative to control tumors (P &amp;lt; 0.05). Constitutive expression of the angiogenic mediator Jagged-1 was reduced in shRNA-NRP-2 cells, whereas vascular endothelial growth factor levels were unchanged. Conclusion. Reduction of NRP-2 expression in PDAC cells decreased survival signaling, migration, invasion, and ability to grow under anchorage-independent conditions. In vivo, reduction of NRP-2 led to decreased growth of xenograft tumors and decreased vascular area, which was associated with decreased Jagged-1 levels. NRP-2 is a potential therapeutic target on PDAC cells.
Routes of spread of pathogens into the pancreas in a feline model of acute pancreatitis.
Authors: A L Widdison, N D Karanjia, H A Reber
Journal: Gut (1994)

The routes of spread of pathogens into the pancreas in acute pancreatitis were investigated. Four experiments were performed: (1) cats with and without acute pancreatitis were given 10(7) Escherichia coli (E coli) intravenously, (2) in cats with acute pancreatitis 10(8) E coli was placed in the colon. In half of them the colon was then enclosed in an impermeable bag to prevent transmural spread. (3) E coli (10(4)) was placed in the pancreatic duct in cats with and without acute pancreatitis. (4) In cats with acute pancreatitis 10(5) E coli was placed in the gall bladder. In half of them the common bile duct was ligated to prevent biliary-pancreatic reflux. After 24 hours, intravenous E coli infected the pancreas in six of nine cats with acute pancreatitis and three of 10 controls. After 72 hours E coli spread to the pancreas from the colon in six of nine cats with acute pancreatitis. This was prevented by enclosing the colon in an impermeable bag (p = 0.02). In five of six cats with acute pancreatitis and five of six controls E coli placed in the pancreatic duct colonised the pancreas within 24 hours. Pancreatic colonisation from the gall bladder occurred in five of six cats with a patent common bile duct and in three of six with an obstructed common bile duct. In conclusion, in cats E coli can spread to the pancreas by the blood stream, transmurally from the colon, and by reflux into the pancreatic duct.
Effect of resolvin D1 on leukotriene D4-induced constriction of rat and human bronchioles
Authors: Melanie Jannaway, Christopher Torrens, Jane Warner, Antony Sampson
Journal: European Respiratory Journal (2013)

Introduction:  Leukotrienes are key inflammatory and contractile mediators in the human airway, while the importance of resolvins in the resolution of inflammation is increasingly apparent. However, the ability of resolvins to modulate bronchoconstriction is unknown.   Aim:  To investigate whether resolvin D 1  (RvD 1 ) can modulate the constriction of isolated rat and human bronchioles induced by leukotriene D 4  (LTD 4 ) or the muscarinic agonist carbachol (CCh).   Method:  Rat bronchioles (0.4 mm diameter) were isolated and mounted on a wire myograph, bathed in Krebs solution and continually gassed with 95% O 2  and 5% CO 2  under a resting tension of 1.5 g. Contractile responses to LTD 4  (1 nM – 1 μM) and CCh (10 nM – 10 μM) were recorded in the absence or presence of RvD 1  (10 nM). Human bronchioles from two lobectomy patients were similarly investigated.   Results:  Dose-dependent constriction of rat bronchioles induced by LTD 4  (EC 50  8 nM, n=6) was abolished by RvD 1  (EC 50  >100 nM, p 1  similarly inhibited LTD 4 -induced constriction in human bronchioles (EC 50  >100 nM), compared with LTD 4  alone (EC 50  1.8 nM, n=2). In contrast, CCh-induced constriction in rat bronchioles was unaffected by RvD 1  (n=6).   Conclusion:  These results show for the first time that resolvin D 1  is a potent and selective inhibitor of LTD 4 -induced, but not CCh-induced, constriction in rat and human airway smooth muscle. Resolvins may provide novel approaches to treating bronchoconstriction and inflammation in airway disease. (Funded by the Gerald Kerkut Charitable Trust).
Role of Protein Kinase CK2 in the Regulation of Tumor Necrosis Factor–Related Apoptosis Inducing Ligand–Induced Apoptosis in Prostate Cancer Cells
Authors: Guixia Wang, Kashif A. Ahmad, Khalil Ahmed
Journal: Cancer Research (2006)

Abstract Protein kinase CK2 (formerly casein kinase 2 or II) is a ubiquitous and highly conserved protein Ser/Thr kinase that plays diverse roles such as in cell proliferation and apoptosis. With respect to the latter, we originally showed that elevated CK2 could suppress various types of apoptosis in prostate cancer cells; however, the downstream pathways that respond to CK2 for mediating the suppression of apoptosis have not been fully elucidated. Here, we report studies on the role of CK2 in influencing activities associated with tumor necrosis factor–related ligand (TRAIL/Apo2-L)–mediated apoptosis in prostate carcinoma cells. To that end, we show that both androgen-insensitive (PC-3) and androgen-sensitive (ALVA-41) prostate cancer cells are sensitized to TRAIL by chemical inhibition of CK2 using its specific inhibitor 4,5,6,7-tetrabromobenzotriazole (TBB). Furthermore, we have shown that overexpression of CK2α using pcDNA6-CK2α protected prostatic cancer cells from TRAIL-mediated apoptosis by affecting various activities associated with this process. Thus, overexpression of CK2 resulted in the suppression of TRAIL-induced apoptosis via its effects on the activation of caspases, DNA fragmentation, and downstream cleavage of lamin A. In addition, the overexpression of CK2 blocked the mitochondrial apoptosis machinery engaged by TRAIL. These findings define the important role of CK2 in TRAIL signaling in androgen-sensitive and -insensitive prostatic carcinoma cells. Our data support the potential usefulness of anticancer strategies that may involve the combination of TRAIL and down-regulation of CK2. (Cancer Res 2006; 66(4): 2242-9)
Bronchial casts associated with hilar lymphatic and pulmonary lymphoid abnormalities.
Authors: J Wiggins, E Sheffield, P K Jeffery, D M Geddes, B Corrin
Journal: Thorax (1989)

A patient who has expectorated bronchial casts for 23 years is reported. The casts contained mucus, fibrin, and lymphocytes, and the resected middle lobe showed dilated lymphatics with thickened walls at the hilum and lymphoid aggregates in the terminal bronchioles.
Corticotropin-releasing factor receptors and stress-related alterations of gut motor function
Authors: Yvette Taché, Bruno Bonaz
Journal: Journal of Clinical Investigation (2007)

Over the past few decades, corticotropin-releasing factor (CRF) signaling pathways have been shown to be the main coordinators of the endocrine, behavioral, and immune responses to stress. Emerging evidence also links the activation of CRF receptors type 1 and type 2 with stress-related alterations of gut motor function. Here, we review the role of CRF receptors in both the brain and the gut as part of key mechanisms through which various stressors impact propulsive activity of the gastrointestinal system. We also examine how these mechanisms translate into the development of new approaches for irritable bowel syndrome, a multifactorial disorder for which stress has been implicated in the pathophysiology.
Exhaled nitric oxide during infancy as a risk factor for asthma and airway hyperreactivity
Authors: Daniel Chang, Weiguo Yao, Christina J. Tiller, Jeffrey Kisling, James E. Slaven, Zhangsheng Yu, Mark H. Kaplan, Robert S. Tepper
Journal: European Respiratory Journal (2014)

Childhood asthma is often characterised by elevated exhaled nitric oxide (eNO), decreased lung function, increased airway reactivity and atopy; however, our understanding of when these phenotypic airway characteristics develop remains unclear. This study evaluated whether eNO, lung function, airway reactivity and immune characteristics during infancy are risk factors of asthma at age 5 years. Infants with eczema, enrolled prior to wheezy illness (n=116), had eNO, spirometry, airway reactivity and allergen sensitisation assessed at entry to the study and repeated at age 5 years (n=90). Increasing eNO at entry was associated with an increased risk of asthma (p=0.037) and increasing airway reactivity (p=0.015) at age 5 years. Children with asthma at 5 years of age had a greater increase in eNO between infancy and age 5 years compared with those without asthma (p=0.002). Egg sensitisation at entry was also associated with an increased risk of asthma (p=0.020), increasing eNO (p = 0.002) and lower forced expiratory flows (p=0.029) as a 5 year-old. Our findings suggest that, among infants at high risk for developing asthma, eNO early in life may provide important insights into the subsequent risk of asthma and its airway characteristics.
N-linked Glycosylation Is Required for Optimal Function of Kaposi's Sarcoma Herpesvirus–encoded, but Not Cellular, Interleukin 6
Authors: Charles S. Dela Cruz, Yoomi Lee, Srinivas R. Viswanathan, Ayman S. El-Guindy, Jennifer Gerlach, Sarah Nikiforow, Duane Shedd, Lyn Gradoville, George Miller
Journal: The Journal of Experimental Medicine (2004)

Kaposi's sarcoma–associated herpesvirus interleukin-6 (vIL-6) is a structural and functional homologue of the human cytokine IL-6 (hIL-6). hIL-6 and vIL-6 exhibit similar biological functions and both act via the gp130 receptor subunit to activate the Janus tyrosine kinase (JAK)1 and signal transducer and activator of transcription (STAT)1/3 pathway. Here we show that vIL-6 is N-linked glycosylated at N78 and N89 and demonstrate that N-linked glycosylation at site N89 of vIL-6 markedly enhances binding to gp130, signaling through the JAK1-STAT1/3 pathway and functions in a cytokine-dependent cell proliferation bioassay. Although hIL-6 is also N-glycosylated at N73 and multiply O-glycosylated, neither N-linked nor O-linked glycosylation is necessary for IL-6 receptor α–dependent binding to gp130 or signaling through JAK1-STAT1/3. As distinct from vIL-6, unglycosylated hIL-6 is as potent as glycosylated hIL-6 in stimulating B cell proliferation. These findings highlight distinct functional roles of N-linked glycosylation in viral and cellular IL-6.
Short-term Intravenous Milrinone for Acute Exacerbation of Chronic Heart Failure&lt;SUBTITLE&gt;A Randomized Controlled Trial&lt;/SUBTITLE&gt;
Authors: Michael S. Cuffe
Journal: JAMA (2002)

Little randomized evidence is available to guide the in-hospital management of patients with an acute exacerbation of chronic heart failure. Although intravenous inotropic therapy usually produces beneficial hemodynamic effects and is labeled for use in the care of such patients, the effect of such therapy on intermediate-term clinical outcomes is uncertain.To prospectively test whether a strategy that includes short-term use of milrinone in addition to standard therapy can improve clinical outcomes of patients hospitalized with an exacerbation of chronic heart failure.Prospective, randomized, double-blind, placebo-controlled trial conducted from July 1997 through November 1999.Seventy-eight community and tertiary care hospitals in the United States.A total of 951 patients admitted with an exacerbation of systolic heart failure not requiring intravenous inotropic support (mean age, 65 years; 92% with baseline New York Heart Association class III or IV; mean left ventricular ejection fraction, 23%).Patients were randomly assigned to receive a 48-hour infusion of either milrinone, 0.5 microg/kg per minute initially (n = 477), or saline placebo (n = 472).Cumulative days of hospitalization for cardiovascular cause within 60 days following randomization.The median number of days hospitalized for cardiovascular causes within 60 days after randomization did not differ significantly between patients given milrinone (6 days) compared with placebo (7 days; P =.71). Sustained hypotension requiring intervention (10.7% vs 3.2%; P<.001) and new atrial arrhythmias (4.6% vs 1.5%; P =.004) occurred more frequently in patients who received milrinone. The milrinone and placebo groups did not differ significantly in in-hospital mortality (3.8% vs 2.3%; P =.19), 60-day mortality (10.3% vs 8.9%; P =.41), or the composite incidence of death or readmission (35.0% vs 35.3%; P =.92)These results do not support the routine use of intravenous milrinone as an adjunct to standard therapy in the treatment of patients hospitalized for an exacerbation of chronic heart failure.