tbuckley/cabot-search huggingface dataset:
Pharmacology, Physiology, and Mechanisms of Action of Dipeptidyl Peptidase-4 Inhibitors
Authors: Erin E. Mulvihill, Daniel J. Drucker
Journal: Endocrine Reviews (2014)

Dipeptidyl peptidase-4 (DPP4) is a widely expressed enzyme transducing actions through an anchored transmembrane molecule and a soluble circulating protein. Both membrane-associated and soluble DPP4 exert catalytic activity, cleaving proteins containing a position 2 alanine or proline. DPP4-mediated enzymatic cleavage alternatively inactivates peptides or generates new bioactive moieties that may exert competing or novel activities. The widespread use of selective DPP4 inhibitors for the treatment of type 2 diabetes has heightened interest in the molecular mechanisms through which DPP4 inhibitors exert their pleiotropic actions. Here we review the biology of DPP4 with a focus on: 1) identification of pharmacological vs physiological DPP4 substrates; and 2) elucidation of mechanisms of actions of DPP4 in studies employing genetic elimination or chemical reduction of DPP4 activity. We review data identifying the roles of key DPP4 substrates in transducing the glucoregulatory, anti-inflammatory, and cardiometabolic actions of DPP4 inhibitors in both preclinical and clinical studies. Finally, we highlight experimental pitfalls and technical challenges encountered in studies designed to understand the mechanisms of action and downstream targets activated by inhibition of DPP4.
Controlled versus Assisted Mechanical Ventilation Effects on Respiratory Motor Output in Sleeping Humans
Authors: Anthony J. Rice, Hideaki C. Nakayama, Hans C. Haverkamp, David F. Pegelow, James B. Skatrud, Jerome A. Dempsey
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

Central apneas occur after cessation of mechanical ventilation despite normocapnic conditions. We asked whether this was due to ventilator-induced increases in respiratory rate or VT. Accordingly, we compared the effects of increased VT (135 to 220% of eupneic VT) with and without increased respiratory rate, using controlled and assist control mechanical ventilation, respectively, upon transdiaphragmatic pressure in sleeping humans. Increasing ventilator frequency +1 per minute and VT to 165–200% of baseline eupnea eliminated transdiaphragmatic pressure during controlled mechanical ventilation and prolonged expiratory time (two to four times control) after mechanical ventilation. During and after assist control mechanical ventilation at 135–220% of eupneic VT, transdiaphragmatic pressure was reduced in proportion to the increase in ventilator volume. However, every ventilator cycle was triggered by an active inspiration, and immediately after mechanical ventilation, expiratory time during spontaneous breathing was prolonged less than 20% of that observed after controlled mechanical ventilation at similar VT. We conclude that both increased frequency and VT during mechanical ventilation significantly inhibited respiratory motor output via nonchemical mechanisms. Controlled mechanical ventilation at increased frequency plus moderate elevations in VT reset respiratory rhythm and inhibited respiratory motor output to a much greater extent than did increased VT alone.
S2554X mutation in the filaggrin gene is associated with allergen sensitization in the Japanese population
Authors: Yoshimasa Imoto, Hisako Enomoto, Shigeharu Fujieda, Masayuki Okamoto, Masafumi Sakashita, Dai Susuki, Masafumi Okada, Tomomitsu Hirota, Mayumi Tamari, Kouji Ebe, Tadao Arinami, Emiko Noguchi
Journal: Journal of Allergy and Clinical Immunology (2010)
Postoperative Antibacterial Prophylaxis for the Prevention of Infectious Complications Associated With Tube Thoracostomy in Patients Undergoing Elective General Thoracic Surgery
Authors: David A. Oxman, Nicolas C. Issa, Francisco M. Marty, Alka Patel, Christia Z. Panizales, Nathaniel N. Johnson, J. Humberto Licona, Shannon S. McKenna, Gyorgy Frendl, Steven J. Mentzer, Michael T. Jaklitsch, Raphael Bueno, Yolonda Colson, Scott J. Swanson, David J. Sugarbaker, Lindsey R. Baden
Journal: JAMA Surgery (2013)

To determine whether extended postoperative antibacterial prophylaxis for patients undergoing elective thoracic surgery with tube thoracostomy reduces the risk of infectious complications compared with preoperative prophylaxis only.Prospective, randomized, double-blind, placebo-controlled trial.Brigham and Women's Hospital, an 800-bed tertiary care teaching hospital in Boston, Massachusetts.A total of 251 adult patients undergoing elective thoracic surgery requiring tube thoracostomy between April 2008 and April 2011.Patients received preoperative antibacterial prophylaxis with cefazolin sodium (or other drug if the patient was allergic to cefazolin). Postoperatively, patients were randomly assigned (at a 1:1 ratio) using a computer-generated randomization sequence to receive extended antibacterial prophylaxis (n = 125) or placebo (n = 126) for 48 hours or until all thoracostomy tubes were removed, whichever came first.The combined occurrence of surgical site infection, empyema, pneumonia, and Clostridium difficile colitis by postoperative day 28.A total of 245 patients were included in the modified intention-to-treat analysis (121 in the intervention group and 124 in the placebo group). Thirteen patients (10.7%) in the intervention group and 8 patients (6.5%) in the placebo group had a primary end point (risk difference, -4.3% [95% CI, -11.3% to 2.7%]; P = .26). Six patients (5.0%) in the intervention group and 5 patients (4.0%) in the placebo group developed surgical site infections (risk difference, -0.93% [95% CI, -6.1% to 4.3%]; P = .77). Seven patients (5.8%) in the intervention group and 3 patients (2.4%) in the placebo group developed pneumonia (risk difference, -3.4% [95% CI, -8.3% to 1.6%]; P = .21). One patient in the intervention group developed empyema. No patients experienced C difficile colitis.Extended postoperative antibacterial prophylaxis for patients undergoing elective thoracic surgery requiring tube thoracostomy did not reduce the number of infectious complications compared with preoperative prophylaxis only.clinicaltrials.gov Identifier: NCT00818766.
Ibrutinib antagonizes rituximab-dependent NK cell–mediated cytotoxicity
Authors: Holbrook E. Kohrt, Idit Sagiv-Barfi, Sarwish Rafiq, Sarah E. M. Herman, Jonathon P. Butchar, Carolyn Cheney, Xiaoli Zhang, Joseph J. Buggy, Natarajan Muthusamy, Ronald Levy, Amy J. Johnson, John C. Byrd
Journal: Blood (2014)
Resistance to hepcidin is conferred by hemochromatosis-associated mutations of ferroportin
Authors: Hal Drakesmith, Lisa M. Schimanski, Emma Ormerod, Alison T. Merryweather-Clarke, Vip Viprakasit, Jon P. Edwards, Emma Sweetland, Judy M. Bastin, Diana Cowley, Yingyong Chinthammitr, Kathryn J. H. Robson, Alain R. M. Townsend
Journal: Blood (2005)
Secretin and cholecystokin/pancreozymin in combination in the inhibition of gastric acid secretion
Authors: B. S. Bedi, H. T. Debas, A. E. O. Wasunna, B. F. Buxton, I. E. Gillespie
Journal: Gut (1971)

Both secretin, and the single substance which possesses both cholecystokinin and pancreozymin activity, have been shown to inhibit gastric acid secretory responses. Since potentiation may occur between pairs of stimulants of gastric secretion, the effects of combining secretin and cholecystokinin/pancreozymin have been studied in Heidenhain pouches stimulated by continuous intravenous pentagastrin. Evidence suggesting potentiation between these two inhibitor agents is presented.
Pulmonary aspergillomas treated with corticosteroids
Authors: D. Davies, A. R. Somner
Journal: Thorax (1972)

The development of an aspergilloma in a damaged lung is often a silent process, though such patients are more likely to have chronic cough and recurrent haemoptysis. Two patients are described who had aspergillomas associated with chronic ill health, weight loss, and copious purulent and often bloodstained sputum. Treatment with antibiotics was ineffective but the response to corticosteroids was striking. Reasons are given for believing that the symptoms were due to an Arthus type of antigen-antibody reaction in the cavity wall.
Effect of Isonicotinic Acid Hydrazide on the Intratumor Injection of BCG2
Authors: Frank C. Sparks, N. Erick Albert, James H. Breeding
Journal: JNCI Journal of the National Cancer Institute (1977)

Rats with established subcutaneous tumors were treated by repeated intratumor injections of BCG over a 5-week period. Isonicotinic acid hydrazide (INH) was given to some rats to determine if this drug decreased the effect of BCG on local tumor growth. INH alone had no effect on either survival or tumor volume. Rats treated with either BCG or BCG and INH had prolonged survivals and smaller tumor volumes than did control rats. In these experiments, INH did not decrease the effect of BCG on local tumor growth. However, the intratumor injection of BCG in rats receiving INH systematically was associated with better survival and smaller tumor volumes compared to the intratumor injection of BCG alone.
Molecular Evolution of the ocnus and janus Genes in the Drosophila melanogaster Species Subgroup
Authors: John Parsch, Colin D. Meiklejohn, Elisabeth Hauschteck-Jungen, Peter Hunziker, Daniel L. Hartl
Journal: Molecular Biology and Evolution (2001)

Genes involved in male fertility are potential targets for sexual selection, and their evolution may play a role in reproductive isolation and speciation. Here we describe a new Drosophila melanogaster gene, ocnus (ocn), that encodes a protein abundant in testes nuclear extracts. RT-PCR indicates that ocn transcription is limited to males and is specific to testes. ocn shares homology with another testis-specific gene, janusB (janB), and is located just distal to janB on chromosome 3. The two genes also share homology with the adjacent janusA (janA) gene, suggesting that multiple duplication events have occurred within this region of the genome. We cloned and sequenced these three genes from species of the D. melanogaster species subgroup. Phylogenetic analysis based on protein-encoding sequences predicts a duplication pattern of janA → janA janB → janA janB ocn, with the latter event occurring after the divergence of the D. melanogaster and Drosophila obscura species groups. We found significant heterogeneity in the rates of evolution among the three genes within the D. melanogaster species subgroup as measured by the ratio of nonsynonymous to synonymous substitutions, suggesting that diversification of gene function followed each duplication event and that each gene evolved under different selective constraints. All three genes showed faster rates of evolution than genes encoding proteins with metabolic function. These results are consistent with previous studies that have detected an increased rate of evolution in genes with reproductive function.
ARF Suppresses Tumor Angiogenesis through Translational Control of <i>VEGFA</i> mRNA
Authors: Hiroyuki Kawagishi, Hideaki Nakamura, Mitsuo Maruyama, Shuki Mizutani, Kazushi Sugimoto, Masatoshi Takagi, Masataka Sugimoto
Journal: Cancer Research (2010)

Vascular endothelial growth factor A (VEGFA) is a specific mitogen for vascular endothelial cells that plays a critical role in cancer neoangiogenesis. Here, we report that the nucleolar tumor suppressor p19(ARF) suppresses VEGFA expression, acting at the level of mRNA translation without affecting the transcription of the VEGFA gene. Translational repression of VEGFA mRNA by p19(ARF) does not require p53, a major target of the ARF tumor suppressor pathway, but instead correlates with binding to nucleophosmin/B23. Maintaining VEGFA expression relies on nucleophosmin/B23, and downregulating this protein by RNAi or p19(ARF) leads to translational repression of VEGFA. p19(ARF) inhibits VEGFA-dependent tumor angiogenesis in nude mice. Additionally, p14(ARF) expression and microvessel density are inversely correlated in human colon carcinomas. Taken together, our results define a mechanism by which the ARF tumor suppressor targets the translational repression of specific oncogenes during neoplastic transformation.
The relation between tender points and fibromyalgia symptom variables: evidence that fibromyalgia is not a discrete disorder in the clinic
Authors: F. Wolfe
Journal: Annals of the Rheumatic Diseases (1997)

<h3>OBJECTIVE</h3> To investigate the relation between measures of pain threshold and symptoms of distress to determine if fibromyalgia is a discrete construct/disorder in the clinic. <h3>METHODS</h3> 627 patients seen at an outpatient rheumatology centre from 1993 to 1996 underwent tender point and dolorimetry examinations. All completed the assessment scales for fatigue, sleep disturbance, anxiety, depression, global severity, pain, functional disability, and a composite measure of distress constructed from scores of sleep disturbance, fatigue, anxiety, depression, and global severity—the rheumatology distress index (RDI). <h3>RESULTS</h3> In regression analyses, the RDI was linearly related to the count of tender points (<i>r</i><sup>2</sup>=0.30). Lesser associations were found between the RDI and dolorimetry measurements (<i>r</i><sup>2</sup>=0.08). The RDI was more strongly correlated with the two measures of pain threshold than any of the individual fibromyalgia symptom variables. In partial correlation analyses, all of the information relating to symptom variables was contained in the tender point count, and dolorimetry was not independently related to symptoms. <h3>CONCLUSION</h3> Tender points are linearly related to fibromyalgia variables and distress, and there is no discrete enhancement or perturbation of fibromyalgia or distress variables associated with very high levels of tender points. Although fibromyalgia is a recognisable clinical entity, there seems to be no rationale for treating fibromyalgia as a discrete disorder, and it would seem appropriate to consider the entire range of tenderness and distress in clinic patients as well as in research studies. The tender point count functions as a ‘sedimentation rate’ for distress, and is a better measure than the dolorimetry score.
Ambiguous External Genitalia in the Newborn and Prepubescent Child
Authors: W. Paul Dmowski
Journal: JAMA (1970)

The sexual makeup of an individual consists of several components both physical and psychological in nature. In the normal being, male or female, all characteristics are expected to be of one gender, harmonious with the chromosomal pattern established in the zygote at the time of fertilization. However, the bisexual potential inherent in everyone may result in the emergence of abnormalities both physical and psychological. Aberrations at any of the stages of development may thus result in the incomplete or faulty differentiation of the particular component and sexual ambiguity. Ambiguous external genitalia is not a syndrome per se, but manifestation of abnormal development common to many disorders. The occurrence is approximately one in every 30,000 newborns. Despite its relative rarity, this condition carries several serious implications and requires careful evaluation when observed neonatally or in the prepubescent child. <h3>Embryogenesis of External Genitalia</h3> External genitalia originate from the same primordial structures in
Molecular Pathways: Targeting the Microenvironment in Chronic Lymphocytic Leukemia—Focus on the B-Cell Receptor
Authors: Elisa ten Hacken, Jan A. Burger
Journal: Clinical Cancer Research (2013)

Abstract Interactions between malignant B lymphocytes and the tissue microenvironment play a major role in the pathogenesis of chronic lymphocytic leukemia (CLL) and other B-cell malignancies. The coexistence and coevolution of CLL cells with their tissue neighbors provided the basis for discovery of critical cellular and molecular drivers of the disease and identification of new therapeutic targets. Bone marrow stromal cells (BMSC), monocyte-derived nurselike cells (NLC), and T cells are key players in the CLL microenvironment, which activate and protect CLL cells within the tissues. CLL surface molecules, such as the B-cell antigen receptor (BCR), chemokine receptors, adhesion molecules, and TNF receptor superfamily members (e.g., CD40, BCMA, and BAFF-R) engage in cross-talk with respective tissue ligands. This cross-talk results in survival and expansion of the CLL clone, and protects CLL cells from conventional cytotoxic drugs. Inhibiting these pathways represents an alternative therapeutic strategy to more conventional chemoimmunotherapy. Here, we review central components of the CLL microenvironment, with a particular emphasis on BCR signaling, and we summarize the most relevant clinical advances with inhibitors that target the BCR-associated spleen tyrosine kinase/SYK (fostamatinib), Bruton's tyrosine kinase/BTK (ibrutinib), and PI3Kδ (idelalisib). Clin Cancer Res; 20(3); 548–56. ©2013 AACR.
Risk factors for advanced neoplasia within subcentimetric polyps: implications for diagnostic imaging
Authors: Frank Thomas Kolligs, Alexander Crispin, Anno Graser, Axel Munte, Ulrich Mansmann, Burkhard Göke
Journal: Gut (2012)

<h3>Objective</h3> Diagnostic imaging by CT colonography and capsule endoscopy is used to detect colonic lesions. Controversy exists regarding the work-up of subcentimetric lesions. The aim of this study was to identify risk indicators for advanced neoplasia (AN) in subcentimetric polyps. <h3>Design</h3> Colonoscopies were classified on the basis of the largest lesion found. AN was defined as high-grade dysplasia, villous histology, or cancer. Logistic regression models were developed to identify risk factors for AN, and validated on separate datasets. A risk index based on the logistic regression was generated, and the number needed to screen (NNS) to detect AN was determined. <h3>Results</h3> 1 077 956 colonoscopies identified 106 270 intermediate (5–9 mm) and 198 954 diminutive (≤4 mm) lesions; 13% of intermediate and 3.7% of diminutive lesions contained AN. The risk of AN was higher in intermediate than in diminutive lesions (OR 3.1; 95% CI 3.0 to 3.3). Age ≥85 versus &lt;45 years was associated with ORs of 2.4 (95% CI 1.8 to 3.1) for intermediate polyps and 3.2 (95% CI 2.3 to 4.5) for diminutive polyps. Pedunculated versus sessile morphology was associated with a higher risk of AN in intermediate (OR 2.0; 95% CI 1.9 to 2.2) and diminutive (OR 3.5; 95% CI 2.9 to 4.1) lesions. In the combined analysis for subcentimetric lesions, ORs were 2.7 (95% CI 2.2 to 3.3) for age ≥85 versus &lt;45 years, 1.1 (95% CI 1.1 to 1.2) for male sex, 1.6 (95% CI 1.4 to 1.7) for occult blood, 1.3 (95% CI 1.2 to 1.5) for overt blood in stool, 1.3 (95% CI 1.2 to 1.4) for more than four lesions, and 2.2 (95% CI 2.1 to 2.3) for pedunculated versus sessile lesions. At median risk index values, the NNS was 9.3 (95% CI 9.1 to 9.5) in individuals with intermediate lesions and 29.4 (95% CI 28.5 to 30.2) in those with diminutive lesions. Compared with the NNS of 15 of the whole cohort, the majority of intermediate, but a minority of diminutive, lesions were deemed at high risk of AN. <h3>Conclusion</h3> This study successfully identified risk factors and established a risk index for subcentimetric lesions. This has implications for the work-up of patients with subcentimetric lesions identified on diagnostic imaging.
Staphylococcus aureus prophylaxis in hemodialysis patients using central venous catheter
Authors: R Sesso, D Barbosa, I L Leme, H Sader, M E Canziani, S Manfredi, S Draibe, A C Pignatari
Journal: Journal of the American Society of Nephrology (1998)

Central venous catheterization is a common technique to establish rapid and temporary access for hemodialysis. However, it is a known risk factor for Staphylococcus aureus infection and bacteremia. Mupirocin is a topical antibiotic with high in vitro anti-staphylococcal activity. A randomized prospective trial was conducted to assess the effectiveness of mupirocin ointment in the prevention of Staphylococcus aureus skin and catheter colonization, and episodes of bacteremia in 136 end-stage renal disease patients. Of these, 67 received skin disinfection at the venous catheter insertion site with povidone iodine (control group), and 69 received the same treatment followed by application of 2% mupirocin ointment at the cannula site after catheter placement and at the end of each dialysis session. Patients were followed until catheter removal and were monitored for the development of Staphylococcus aureus skin/catheter colonization and episodes of bacteremia. Median duration of catheter use was greater in the mupirocin than in the control group (37 versus 20 d, P < 0.01). Patients in the mupirocin group had a significantly lower rate of Staphylococcus aureus isolation from the pericatheter skin (1.76 per 1000 versus 14.27 per 1000 patient-days, P < 0.001) and from the catheter surface (3.17 per 1000 versus 14.27 per 1000 patient-days, P < 0.001). The proportion of patients with Staphylococcus aureus skin infection at the insertion site was lower in the mupirocin group (4.3% versus 23.9%, P = 0.001). Staphylococcus aureus-associated bacteremia was observed in 17 patients (two in the mupirocin group [0.71 episodes per 1000 patient-days] and 15 in the control group [8.92 per 1000 patient-days], P < 0.001). The hazard ratio of developing Staphylococcus aureus bacteremia was 7.2 (95% confidence interval, 1.6 to 31.6) times greater in patients not receiving mupirocin. Mupirocin applied to the insertion site significantly reduces the risk of Staphylococcus aureus skin and catheter colonization, exit-site infection, and Staphylococcus aureus bacteremia in hemodialysis patients.
Diet and Lifestyle Recommendations Revision 2006
Authors: Alice H. Lichtenstein, Lawrence J. Appel, Michael Brands, Mercedes Carnethon, Stephen Daniels, Harold A. Franch, Barry Franklin, Penny Kris-Etherton, William S. Harris, Barbara Howard, Njeri Karanja, Michael Lefevre, Lawrence Rudel, Frank Sacks, Linda Van Horn, Mary Winston, Judith Wylie-Rosett
Journal: Circulation (2006)

Improving diet and lifestyle is a critical component of the American Heart Association’s strategy for cardiovascular disease risk reduction in the general population. This document presents recommendations designed to meet this objective. Specific goals are to consume an overall healthy diet; aim for a healthy body weight; aim for recommended levels of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides; aim for normal blood pressure; aim for a normal blood glucose level; be physically active; and avoid use of and exposure to tobacco products. The recommendations are to balance caloric intake and physical activity to achieve and maintain a healthy body weight; consume a diet rich in vegetables and fruits; choose whole-grain, high-fiber foods; consume fish, especially oily fish, at least twice a week; limit intake of saturated fat to &lt;7% of energy, trans fat to &lt;1% of energy, and cholesterol to &lt;300 mg/day by choosing lean meats and vegetable alternatives, fat-free (skim) or low-fat (1% fat) dairy products and minimize intake of partially hydrogenated fats; minimize intake of beverages and foods with added sugars; choose and prepare foods with little or no salt; if you consume alcohol, do so in moderation; and when you eat food prepared outside of the home, follow these Diet and Lifestyle Recommendations. By adhering to these diet and lifestyle recommendations, Americans can substantially reduce their risk of developing cardiovascular disease, which remains the leading cause of morbidity and mortality in the United States.