tbuckley/cabot-search huggingface dataset:
Effects of Dapagliflozin, an SGLT2 Inhibitor, on HbA1c, Body Weight, and Hypoglycemia Risk in Patients With Type 2 Diabetes Inadequately Controlled on Pioglitazone Monotherapy
Authors: Julio Rosenstock, Marisa Vico, Li Wei, Afshin Salsali, James F. List
Journal: Diabetes Care (2012)

To examine the safety and efficacy of dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, added on to pioglitazone in type 2 diabetes inadequately controlled on pioglitazone.Treatment-naive patients or those receiving metformin, sulfonylurea, or thiazolidinedione entered a 10-week pioglitazone dose-optimization period with only pioglitazone. They were then randomized, along with patients previously receiving pioglitazone ≥30 mg, to 48 weeks of double-blind dapagliflozin 5 (n = 141) or 10 mg (n = 140) or placebo (n = 139) every day plus open-label pioglitazone. The primary objective compared HbA(1c) change from baseline with dapagliflozin plus pioglitazone versus placebo plus pioglitazone at week 24. Primary analysis was based on ANCOVA model using last observation carried forward; all remaining analyses used repeated-measures analysis.At week 24, the mean reduction from baseline in HbA(1c) was -0.42% for placebo versus -0.82 and -0.97% for dapagliflozin 5 and 10 mg groups, respectively (P = 0.0007 and P < 0.0001 versus placebo). Patients receiving pioglitazone alone had greater weight gain (3 kg) than those receiving dapagliflozin plus pioglitazone (0.7-1.4 kg) at week 48. Through 48 weeks: hypoglycemia was rare; more events suggestive of genital infection were reported with dapagliflozin (8.6-9.2%) than placebo (2.9%); events suggestive of urinary tract infection showed no clear drug effect (5.0-8.5% for dapagliflozin and 7.9% for placebo); dapagliflozin plus pioglitazone groups had less edema (2.1-4.3%) compared with placebo plus pioglitazone (6.5%); and congestive heart failure and fractures were rare.In patients with type 2 diabetes inadequately controlled on pioglitazone, the addition of dapagliflozin further reduced HbA(1c) levels and mitigated the pioglitazone-related weight gain without increasing hypoglycemia risk.
Integrating service development with evaluation in telehealthcare: an ethnographic study
Authors: T. Finch
Journal: BMJ (2003)

To identify issues that facilitate the successful integration of evaluation and development of telehealthcare services.Ethnographic study using various qualitative research techniques to obtain data from several sources, including in-depth semistructured interviews, project steering group meetings, and public telehealthcare meetings.Seven telehealthcare evaluation projects (four randomised controlled trials and three pragmatic service evaluations) in the United Kingdom, studied over two years. Projects spanned a range of specialties-dermatology, psychiatry, respiratory medicine, cardiology, and oncology.Clinicians, managers, technical experts, and researchers involved in the projects.Key problems in successfully integrating evaluation and service development in telehealthcare are, firstly, defining existing clinical practices (and anticipating changes) in ways that permit measurement; secondly, managing additional workload and conflicting responsibilities brought about by combining clinical and research responsibilities (including managing risk); and, thirdly, understanding various perspectives on effectiveness and the limitations of evaluation results beyond the context of the research study.Combined implementation and evaluation of telehealthcare systems is complex, and is often underestimated. The distinction between quantitative outcomes and the workability of the system is important for producing evaluative knowledge that is of practical value. More pragmatic approaches to evaluation, that permit both quantitative and qualitative methods, are required to improve the quality of such research and its relevance for service provision in the NHS.
Effect of systemic adjuvant treatment on first sites of breast cancer relapse
Authors: A Goldhirsch, R.D Gelber, K.N Price, M Castiglione, A.S Coates, C-M Rudenstam, J Collins, J Lindtner, A Hacking, G Marini, M Byrne, H Cortés-Funes, G Schnürch, K.W Brunner, M.H.N Tattersall, J Forbes, H-J Senn
Journal: The Lancet (1994)
Should Anticoagulation Therapy Be Withheld in Patients With Active Cancer After 6 Months of Low–Molecular Weight Heparin?
Authors: Edgar Gerardo Urrego, Alberto Carmona-Bayonas, Enrique González-Billalabeitia, Francisco Ayala de la Peña
Journal: Journal of Clinical Oncology (2015)

TO THEEDITOR: Napolitano et al 1 recently published their work evaluating the role of residual vein thrombosis (RVT) to assess the optimal duration of anticoagulation therapy in patients with active cancer and deep vein thrombosis (DVT) of the lower extremities. We agree with the authors that the absence of RVT identified a group at low risk for DVT recurrence. However, we have some methodologic concerns that might hamper the applicability of this trial to our daily practice. Concerning the inferential extensibility, we deem it essential to report whether tumors were truly active at the time of random assignment (6 months from the index DVT), and whether the hypercoagulable states resolved throughout the study period. We base these recommendations on the following observations. Although, in the definition of the study population, the authors established active cancer as an inclusion criterion, 78% of patients did not have metastasis. Strikingly, 63% of the patients did undergo major surgery, and supposedly, many of them were thereafter free of disease. Notably, the low percentage of patients with metastatic or incurable tumors explains the low mortality rate that was reported in this study. Given that the persistence of tumor-related thrombophilia is a key determinant of venous thromboembolism (VTE) recurrence, this fact might limit the applicability of this study to patients with metastatic disease who are seen in daily practice, even in the absence of RVT. We would appreciate if the authors could clarify this point.
Suicidal Destruction of Cytochrome P-450 During Oxidative Drug Metabolism
Authors: P R O Montellano, M A Correia
Journal: The Annual Review of Pharmacology and Toxicology (1983)

Heme oxygenases (HO) catabolize free heme, that is, iron (Fe) protoporphyrin (IX), into equimolar amounts of Fe2+, carbon monoxide (CO), and biliverdin. The stress-responsive HO-1 isoenzyme affords protection against programmed cell death. The mechanism ...Read More
OBSERVATIONS ON ENCEPHALOMYELITIS OF MICE (DA STRAIN)
Authors: Joan B. Daniels, Alwin M. Pappenheimer, Sheila Richardson
Journal: The Journal of Experimental Medicine (1952)

A new agent, DA, has been isolated from a spontaneously paralyzed mouse. Its biological properties and the pathology of lesions in experimental infection indicate close relationship with the Theiler group of encephalomyelitis viruses. Serological studies were inconclusive. The intracerebral neutralization test failed to reveal measurable antibody and other routes of inoculation were unsuitable because of low invasiveness of the agent. Repeated vaccination of females did not render their offspring resistant to homologous intracerebral challenge. The occurrence of early viremia is reported following intracerebral inoculation of the DA strain and also the known Theiler strains, 4727, FA, and GD-VII. The pathology of mice experimentally infected with DA and with known members of the Theiler group is described. Attention is called to the demyelinating lesion of the cord in mice surviving for several months and to the persistence of virus in the CNS of such animals. Another characteristic feature of the pathology was the degeneration of ventral nerve roots and in some mice of the peripheral nerves. Similar changes were not seen with strains of Theiler virus other than DA. Spheroidal bodies of undetermined significance were found in the lesions. Finally the occurrence of myositis after intracerebral inoculation, not only mice infected with the DA virus, but also with the 4727 and FA strains, is described and discussed.
Assessment of the population-level effectiveness of the Avahan HIV-prevention programme in South India: a preplanned, causal-pathway-based modelling analysis
Authors: Michael Pickles, Marie-Claude Boily, Peter Vickerman, Catherine M Lowndes, Stephen Moses, James F Blanchard, Kathleen N Deering, Janet Bradley, Banadakoppa M Ramesh, Reynold Washington, Rajatashuvra Adhikary, Mandar Mainkar, Ramesh S Paranjape, Michel Alary
Journal: The Lancet Global Health (2013)

Avahan, the India AIDS initiative of the Bill & Melinda Gates Foundation, was a large-scale, targeted HIV prevention intervention. We aimed to assess its overall effectiveness by estimating the number and proportion of HIV infections averted across Avahan districts, following the causal pathway of the intervention.We created a mathematical model of HIV transmission in high-risk groups and the general population using data from serial cross-sectional surveys (integrated behavioural and biological assessments, IBBAs) within a Bayesian framework, which we used to reproduce HIV prevalence trends in female sex workers and their clients, men who have sex with men, and the general population in 24 South Indian districts over the first 4 years (2004-07 or 2005-08 dependent on the district) and the full 10 years (2004-13) of the Avahan programme. We tested whether these prevalence trends were more consistent with self-reported increases in consistent condom use after the implementation of Avahan or with a counterfactual (assuming consistent condom use increased at slower, pre-Avahan rates) using a Bayes factor, which gave a measure of the strength of evidence for the effectiveness estimates. Using regression analysis, we extrapolated the prevention effect in the districts covered by IBBAs to all 69 Avahan districts.In 13 of 24 IBBA districts, modelling suggested medium to strong evidence for the large self-reported increase in consistent condom use since Avahan implementation. In the remaining 11 IBBA districts, the evidence was weaker, with consistent condom use generally already high before Avahan began. Roughly 32700 HIV infections (95% credibility interval 17900-61600) were averted over the first 4 years of the programme in the IBBA districts with moderate to strong evidence. Addition of the districts with weaker evidence increased this total to 62800 (32000-118000) averted infections, and extrapolation suggested that 202000 (98300-407000) infections were averted across all 69 Avahan districts in South India, increasing to 606000 (290000-1 193000) over 10 years. Over the first 4 years of the programme 42% of HIV infections were averted, and over 10 years 57% were averted.This is the first assessment of Avahan to account for the causal pathway of the intervention, that of changing risk behaviours in female sex workers and high-risk men who have sex with men to avert HIV infections in these groups and the general population. The findings suggest that substantial preventive effects can be achieved by targeted behavioural HIV prevention initiatives.Bill & Melinda Gates Foundation.
Stent and Artery Geometry Determine Intimal Thickening Independent of Arterial Injury
Authors: Joseph M. Garasic, Elazer R. Edelman, James C. Squire, Philip Seifert, Michael S. Williams, Campbell Rogers
Journal: Circulation (2000)

Background —Clinical trials show that larger immediate postdeployment stent diameters provide greater ultimate luminal size, whereas animal data show that arterial injury and stent design determine late neointimal thickening. At deployment, a stent stretches a vessel, imposing a cross-sectional polygonal luminal shape that depends on the stent design, with each strut serving as a vertex. We asked whether this design-dependent postdeployment luminal geometry affects late neointimal thickening independently of the extent of strut-induced injury. Methods and Results —Stainless steel stents of 3 different configurations were implanted in rabbit iliac arteries for 3 or 28 days. Stents designed with 12 struts per cross section had 50% to 60% less mural thrombus and 2-fold less neointimal area than identical stents with only 8 struts per cross section. Sequential histological sectioning of individual stents showed that immediate postdeployment luminal geometry and subsequent neointimal area varied along the course of each stent subunit. Mathematical modeling of the shape imposed by the stent on the artery predicted late neointimal area, based on the re-creation of a circular vessel lumen within the confines of the initial stent-imposed polygonal luminal shape. Conclusions —Immediate postdeployment luminal geometry, dictated by stent design, determines neointimal thickness independently of arterial injury and may be useful for predicting patterns of intimal growth for novel stent designs.
LSC 2013 abstract - Host defense against pneumonia: The role of the leptin/neutrophil axis?
Authors: Niki Ubags, Juanita H.J. Vernooy, Elianne Burg, Angela Cramer, Jenna Bement, Catherine Hayes, C. Martin, Jan Tavernier, Matthew E. Poynter, Mercedes Rincon, Matthew J. Wargo, Emiel F.M. Wouters, Benjamin T. Suratt
Journal: European Respiratory Journal (2013)

Rationale:  Respiratory infections are an important trigger of COPD exacerbations and a major risk factor for Acute Lung Injury. We have shown that leptin is a key mediator of neutrophil recruitment to the injured lung. However, the importance of leptin in the neutrophilic response to respiratory infection remains unknown. We hypothesize that leptin contributes to development of pulmonary neutrophilia in pneumonia and that defective leptin signaling impairs this response.   Methods:  Leptin staining was performed in human and murine lung tissue infected with bacterial or H1N1-influenza pneumonia and controls by immunohistochemistry. BAL neutrophilia was determined 24h after murine  E.coli  infection and o.p. aspiration of recombinant leptin or buffer. Human blood- and murine bone marrow-derived neutrophils were examined for phosphorylation of STAT3, Erk, p38, Akt, and GSK-3β after leptin stimulation.   Results:  Human and murine pneumonia lung samples showed increased leptin staining compared to controls. BAL neutrophil levels in  E.coli  infected mice significantly increased at 24h in mice treated with leptin compared to controls, whereas in  db/db  mice, these levels were decreased. In human and murine neutrophils stimulated with leptin  ex vivo , increases in P-p38, P-Akt, and P-GSK3β were observed, whereas no P-STAT3 or P-Erk was found, suggesting that neutrophils signal to leptin primarily through the short form of the leptin receptor (ObRa).   Conclusion:  Pulmonary leptin is induced in the infected lung and is effective in neutrophil recruitment to the lung following infection. This response is impaired in ObRb deficient mice. Yet, a paradox is suggested by evidence that neutrophil leptin-response is primarily through ObRa.
Isolation of a lipopolysaccharide-binding acute phase reactant from rabbit serum.
Authors: P S Tobias, K Soldau, R J Ulevitch
Journal: The Journal of Experimental Medicine (1986)

This report describes the purification of an acute phase reactant from acute phase rabbit serum, which endows normal serum with the properties of acute phase serum, insofar as LPS is concerned. The acute phase reactant is referred to as LPS-binding protein, or LBP. LBP was purified approximately 2,000-fold by chromatography of acute phase serum on Bio-Rex 70 and Mono-Q resins. The resulting preparation consisted of two glycoproteins having molecular weights of 60,500 and 58,000; the two were obtained in a variable ratio, usually near 10:1, respectively. After separation by SDS-PAGE, the N-terminal 36 amino acid sequences of the two proteins were identical. From the N-terminal sequence, as well as other properties of LBP, LBP appears to be unrelated to any known acute phase reactants. The direct interaction of LPS and LBP was inferred from two types of evidence: first, immunoprecipitation of [3H]LPS from APRS by anti-LBP sera; and second, by the 125I-labeling of LBP when APRS-containing 125I-labeled 2-(p-azidosalicylamido)ethyl 1,3'-dithiopropionyl-LPS was photolysed. The data presented here support the concept that the 60-kD glycoprotein we have termed LBP is a newly recognized acute phase reactant that may modulate the biochemical and biologic properties of LPS in vivo.
Lipooligosaccharides (LOS) of Neisseria gonorrhoeae and Neisseria meningitidis have components that are immunochemically similar to precursors of human blood group antigens. Carbohydrate sequence specificity of the mouse monoclonal antibodies that recognize crossreacting antigens on LOS and human erythrocytes.
Authors: R E Mandrell, J M Griffiss, B A Macher
Journal: The Journal of Experimental Medicine (1988)

We have used mouse mAbs, 3F11 and 06B4, that are specific for highly conserved epitopes of Neisseria gonorrhoeae lipooligosaccharides (LOS) to identify immunochemically similar structures on human erythrocytes. mAb 3F11 agglutinated erythrocytes from all randomly selected adult humans, while mAb 06B4 agglutinated only 80% of the same specimens. The antibodies had an activity with erythrocytes similar to human cold agglutinins in that agglutination occurred at 4 degrees C and decreased with increasing incubation temperature. Human infant erythrocytes were agglutinated less well, but enzymatic treatment of either infant or adult cells resulted in an increase in expression of the 3F11- and 06B4-defined epitopes. Both antibodies bound to a series of neutral glycosphingolipids from human erythrocytes and neutrophils that have a type 2 (Gal beta 1----4GlcNAc) or N-acetyllactosamine structure. Neither antibody bound to glycosphingolipids from human meconium, which have a type 1 (Gal beta 1----3GlcNAc) structure. The antibodies were unable to bind to N-acetyl-lactosamine glycosphingolipids with a nonreducing terminal sialic acid or a Gala1----3Gal disaccharide. Antibody binding also was blocked by the presence of fucose linked to the penultimate glucosamine residue of N-acetyllactosamine glycosphingolipids. Although both antibodies bound to linear and branched-chain N-acetyllactosamine glycosphingolipids, 3F11 had a higher affinity for branched structures than did 06B4. The activity of 3F11 with human adult and infant treated and untreated erythrocytes with N-acetyllactosamine glycosphingolipids, and with LOS was very similar, if not identical, in specificity to 1B2, an mAb prepared from mice inoculated with a linear N-acetyllactosamine glycosphingolipid.
Infectious Tolerance
Authors: Helmut Jonuleit, Edgar Schmitt, Hacer Kakirman, Michael Stassen, Jürgen Knop, Alexander H. Enk
Journal: The Journal of Experimental Medicine (2002)

Regulatory CD4+CD25+ T cells (Treg) are mandatory for maintaining immunologic self-tolerance. We demonstrate that the cell-cell contact–mediated suppression of conventional CD4+ T cells by human CD25+ Treg cells is fixation resistant, independent from membrane-bound TGF-β but requires activation and protein synthesis of CD25+ Treg cells. Coactivation of CD25+ Treg cells with Treg cell–depleted CD4+ T cells results in anergized CD4+ T cells that in turn inhibit the activation of conventional, freshly isolated CD4+ T helper (Th) cells. This infectious suppressive activity, transferred from CD25+ Treg cells via cell contact, is cell contact–independent and partially mediated by soluble transforming growth factor (TGF)-β. The induction of suppressive properties in conventional CD4+ Th cells represents a mechanism underlying the phenomenon of infectious tolerance. This explains previously published conflicting data on the role of TGF-β in CD25+ Treg cell–induced immunosuppression.
An Imaging Biomarker of Early Treatment Response in Prostate Cancer that Has Metastasized to the Bone
Authors: Kuei C. Lee, Sudha Sud, Charles R. Meyer, Bradford A. Moffat, Thomas L. Chenevert, Alnawaz Rehemtulla, Kenneth J. Pienta, Brian D. Ross
Journal: Cancer Research (2007)

Prostate cancer ranks as the most common lethal malignancy diagnosed and the second leading cause of cancer mortality in American men. Although high response rates are achieved using androgen blockade as first-line therapy, most men progress toward hormone-refractory prostate cancer. Systemic chemotherapies have been shown to improve clinical outcome in hormone refractory prostate cancer patients; however, they are not curative. Due to the high incidence of bone involvement in hormone-refractory prostate cancer, assessment of treatment response in metastatic prostate cancer to the bone remains a major clinical need. In this current study, we investigated the feasibility of using the functional diffusion map (fDM) as an imaging biomarker for assessing early treatment response in a preclinical model of metastatic prostate cancer. The fDM biomarker requires a pretreatment and midtreatment magnetic resonance imaging diffusion map, which is used to quantify spatially distinct therapeutic-induced changes in the Brownian motion (or diffusion) of water within tumor tissue. Because water within tumor cells is in a restricted environment relative to extracellular water, loss of cell membrane integrity and cellular density during therapy will be detected by fDM as an increase in diffusion. Regions of significantly increased diffusion values were detected early using fDM in docetaxel-treated versus untreated metastatic prostate bone tumors at 7 days post treatment initiation (P < 0.05), indicating loss of tumor cell viability. Validation of fDM results was accomplished by histologic analysis of excised tissue. Results from this study show the capability of fDM as a biomarker for detection of bone cancer treatment efficacy, thus warranting clinical evaluation.
Disturbances in Atrial Rhythm and Conduction Following the Surgical Creation of an Atrial Septal Defect by the Blalock-Hanlon Technique
Authors: SANDRA D. HAMILTON, THOMAS D. BARTLEY, ROBERT H. MILLER, GEROLD L. SCHIEBLER, HENRY J. L. MARRIOTT
Journal: Circulation (1968)

Disturbances in atrial conduction or rhythm, or both, were found in 16 of 27 patients undergoing the surgical creation of an atrial septal defect by the Blalock-Hanlon technique. These included P-wave aberrations of intra-atrial block and ectopic atrial rhythm, A-V rhythm, A-V dissociation, sinus bradycardia, atrial flutter, escapecapture bigeminy, and atrial premature beats. Some of these were transient and occurred within 2 weeks after surgery. It seems likely that tissue trauma engendered by the clamp and resection of the atrial septum with possible injury to the internodal conducting pathways may be the genesis of these early postoperative disturbances. Of the eight cases with transient disturbances, six occurred in this period. Later changes, such as intra-atrial block, sinus bradycardia, and atrial flutter, may be atttributed to changes in atrial size secondary to the postoperative pathophysiology. Digitalis intoxication and congestive heart failure cannot be excluded as contributory factors in either the early or the late disturbances. It was not possible to correlate the incidence and nature of these disturbances with morbidity and mortality. In such severely ill, cyanotic infants, irregularities, however slight, may have altered cardiac function significantly and contributed to their deaths.