tbuckley/cabot-search huggingface dataset:
Incretin-Based Therapies for the Treatment of Type 2 Diabetes: Evaluation of the Risks and Benefits
Authors: Daniel J. Drucker, Steven I. Sherman, Fred S. Gorelick, Richard M. Bergenstal, Robert S. Sherwin, John B. Buse
Journal: Diabetes Care (2010)

Type 2 diabetes is a complex metabolic disorder characterized by hyperglycemia arising from a combination of insufficient insulin secretion together with resistance to insulin action. The incidence and prevalence of type 2 diabetes are rising steadily, fuelled in part by a concomitant increase in the worldwide rates of obesity. As longitudinal studies of type 2 diabetes provide evidence linking improved glycemic control with a reduction in the rates of diabetes-associated complications, there is considerable interest in the therapy of type 2 diabetes (Fig. 1), with a focus on the development and use of new agents that exhibit improved efficacy and safety relative to current available medicines.



Figure 1 
Relative comparison of properties exhibited by different classes of agents approved for the treatment of type 2 diabetes. CVD, cardiovascular disease; TG, triglycerides; CHF, congestive heart failure. A1C reduction depends on starting A1C.



Although the number of patients with type 2 diabetes that successfully achieve target levels of A1C is steadily improving, a substantial number of subjects continue to fall short of acceptable treatment goals, leaving them at high risk for development of diabetes-associated complications (1). More importantly, a large number of subjects with type 2 diabetes fail to achieve target values for glucose, lipids, and blood pressure, with only 12.2% of patients meeting target values despite recent improvements in therapeutic agents targeting hyperglycemia, dyslipidemia, and hypertension (2). The development of multiple new agents for the treatment of type 2 diabetes has broadened the options for patient-specific therapy. However, no currently available agents exhibit the ideal profile of exceptional glucose-lowering efficacy to safely achieve target levels of glycemia in a broad range of patients. Hence, highly efficacious agents that exhibit unimpeachable safety, excellent tolerability, and ease of administration to ensure long-term adherence and that also clearly reduce common comorbidities and complications of diabetes are …
Research alone is not sufficient to prevent sports injury
Authors: Dale Hanson, John P Allegrante, David A Sleet, Caroline F Finch
Journal: British Journal of Sports Medicine (2012)

This journal aims to promote, publish and promulgate high-quality, innovative research. As laudable as this is, it is not enough. Unless this research culminates in practical and cost-effective interventions capable of attracting the political and social support required to allow effective implementation, it will not prevent harm or save lives.1

The Public Health Model has been proposed as a framework to promote the progression of sports medicine research towards real-world application.2 ,3 In this four-stage model, research progresses in a stepwise manner from problem identification to adoption of effective interventions:4 

Unfortunately, most sports injury research does not result in adequate dissemination or widespread use of effective interventions.5 ,6 The problem is not unique to sports medicine. In a review of 1210 articles published in 12 leading public health and health promotion journals, Oldenburg et al 7 found that 63% of publications were descriptive (Stages 1 and 2), 11% were concerned with method development and 16% were intervention-based (Stage 3), and only 5% were concerned with institutionalisation or policy implementation research, with less than 1% containing diffusion research (Stage 4).

While researchers have generated considerable knowledge from surveillance, risk factor identification and efficacy and effectiveness studies, this knowledge needs to be adopted by those who can use it to improve sports medicine practice (eg, clinicians, coaches and sporting bodies).1 ,8

Several gaps between injury prevention research and safety promotion practice hamper our efforts:9 

These gaps stem from the contrasting approaches that researchers, policy makers, practitioners and the community take to the scientific, practical and social challenges posed by …
Somatostatin receptor scintigraphy versus chromogranin A assay in the management of patients with neuroendocrine tumors of different types: clinical role
Authors: M. Cimitan, A. Buonadonna, R. Cannizzaro, V. Canzonieri, E. Borsatti, R. Ruffo, L. De Apollonia
Journal: Annals of Oncology (2003)
Ebola crisis has alerted politicians to global health threats, debate hears
Authors: A. Gulland
Journal: BMJ (2015)

The Ebola virus epidemic has led to a “seismic political shift” in international attitudes to global health security, says Brian McCloskey, adviser to the United Nations’ special envoy on Ebola.

McCloskey, who is on secondment from his job as director of global health at Public Health England, told a debate at the London School of Hygiene and Tropical Medicine that Ebola had “galvanised politicians to realise that health crises go beyond health . . . Ebola was a major risk to the global economy.”

He said that the Ebola outbreak has been different from the H1N1 influenza pandemic, in that governments did not fear that H1N1 would threaten international financial markets. “Ebola has brought down the economy of west Africa …
TRINUCLEOTIDE INSTABILITY: A Repeating Theme in Human Inherited Disorders
Authors: James F. Gusella, Ph.D, Marcy E. MacDonald, Ph.D
Journal: Annual Review of Medicine (1996)

▪ Abstract In recent years, a completely new mechanism of mutation has emerged in a number of disorders that display perplexing and paradoxical features of genetic inheritance. This mechanism involves the expansion and intergenerational instability of stretches of consecutive identical nucleotide triplets that also exist as shorter stable segments on normal chromosomes. The unstable nature of the trinucleotide segments has solved many of the genealogic puzzles in these disorders and has provided a new tool for predictive testing. Treatments for the disorders await a better understanding of the different pathogenic processes that are triggered by various expanded repeats. The existence of numerous other disorders with peculiarities of genetic inheritance suggests that this mutational mechanism may be a major cause of human inherited disease.
Inactivation of the Glycine Transporter 1 Gene Discloses Vital Role of Glial Glycine Uptake in Glycinergic Inhibition
Authors: Jesús Gomeza, Swen Hülsmann, Koji Ohno, Volker Eulenburg, Katalin Szöke, Diethelm Richter, Heinrich Betz
Journal: Neuron (2003)

The glycine transporter subtype 1 (GlyT1) is widely expressed in astroglial cells throughout the mammalian central nervous system and has been implicated in the regulation of N-methyl-D-aspartate (NMDA) receptor activity. Newborn mice deficient in GlyT1 are anatomically normal but show severe motor and respiratory deficits and die during the first postnatal day. In brainstem slices from GlyT1-deficient mice, in vitro respiratory activity is strikingly reduced but normalized by the glycine receptor (GlyR) antagonist strychnine. Conversely, glycine or the GlyT1 inhibitor sarcosine suppress respiratory activity in slices from wild-type mice. Thus, during early postnatal life, GlyT1 is essential for regulating glycine concentrations at inhibitory GlyRs, and GlyT1 deletion generates symptoms found in human glycine encephalopathy.
Role of ADAM17 in endotoxin-induced pulmonary inflammation
Authors: Daniela Dreymueller, Christian Martin, Tanja Kogel, Franz Martin Hess, Carl P. Blobel, Keisuke Horiuchi, Stefan Uhlig, Andreas Ludwig
Journal: European Respiratory Journal (2011)

Acute lung inflammation is associated with enhanced vascular permeability and leukocyte recruitment. Several proinflammatory, soluble and surface-expressed mediators, including TNFα, TNFR1/2, amphiregulin, IL-6R, IL-1R, L-selectin, CX3CL1, and JAMs may become released by the activity of the metalloproteinases ADAM10 and ADAM17. We examined the role of these proteases in vascular permeability and leukocyte transmigration in vitro by pharmacological inhibition and lentiviral-mediated siRNA knockdown of ADAM10 and ADAM17. The in vivo role of these proteases was studied in a murine model of LPS-induced lung injury by pharmacological inhibition. The relevance of ADAM17 was further analyzed by knockout of ADAM17 in endothelial or smooth muscle cells. The BAL protein levels and the wet/dry-ratio served as markers of vascular permeability and edema formation. Cell recruitment to the alveolar space and lung tissue was analyzed by flow cytometry; cytokines were determined by ELISA. In vitro, transmigration of neutrophils to IL-8 through pulmonary endothelial cells was reduced by pharmacological inhibition as well as knockdown of ADAM10 or ADAM17. LPS-mediated induction of permeability was reduced by pharmacological inhibition, but not by ADAM10 knockdown, indicating a predominant role of ADAM17 in the regulation of endothelial permeability. In vivo, LPS challenge increased the wet/dry-ratio as well as the BAL levels of protein, TNFα, IL-6 and leukocytes. All these effects were largely prevented by inhibitor application or by knockout of ADAM17 in smooth muscle or endothelial cells. These results indicate that local ADAM17 is involved in the onset of inflammation and tissue injury during endotoxin-induced lung inflammation.
In vitro modeling of the microvascular occlusion and thrombosis that occur in hematologic diseases using microfluidic technology
Authors: Michelle Tsai, Ashley Kita, Joseph Leach, Ross Rounsevell, James N. Huang, Joel Moake, Russell E. Ware, Daniel A. Fletcher, Wilbur A. Lam
Journal: Journal of Clinical Investigation (2011)

In hematologic diseases, such as sickle cell disease (SCD) and hemolytic uremic syndrome (HUS), pathological biophysical interactions among blood cells, endothelial cells, and soluble factors lead to microvascular occlusion and thrombosis. Here, we report an in vitro "endothelialized" microfluidic microvasculature model that recapitulates and integrates this ensemble of pathophysiological processes. Under controlled flow conditions, the model enabled quantitative investigation of how biophysical alterations in hematologic disease collectively lead to microvascular occlusion and thrombosis. Using blood samples from patients with SCD, we investigated how the drug hydroxyurea quantitatively affects microvascular obstruction in SCD, an unresolved issue pivotal to understanding its clinical efficacy in such patients. In addition, we demonstrated that our microsystem can function as an in vitro model of HUS and showed that shear stress influences microvascular thrombosis/obstruction and the efficacy of the drug eptifibatide, which decreases platelet aggregation, in the context of HUS. These experiments establish the versatility and clinical relevance of our microvasculature-on-a-chip model as a biophysical assay of hematologic pathophysiology as well as a drug discovery platform.
6-Month Androgen Suppression Plus Radiation Therapy vs Radiation Therapy Alone for Patients With Clinically Localized Prostate Cancer
Authors: Anthony V. D'Amico, Judith Manola, Marian Loffredo, Andrew A. Renshaw, Alyssa DellaCroce, Philip W. Kantoff
Journal: JAMA (2004)

ContextSurvival benefit in the management of high-grade clinically localized prostate cancer has been shown for 70 Gy radiation therapy combined with 3 years of androgen suppression therapy (AST), but long-term AST is associated with many adverse events.ObjectiveTo assess the survival benefit of 3-dimensional conformal radiation therapy (3D-CRT) alone or in combination with 6 months of AST in patients with clinically localized prostate cancer.Design, Setting, and PatientsA prospective randomized controlled trial of 206 patients with clinically localized prostate cancer who were randomized to receive 70 Gy 3D-CRT alone (n = 104) or in combination with 6 months of AST (n = 102) from December 1, 1995, to April 15, 2001. Eligible patients included those with a prostate-specific antigen (PSA) of at least 10 ng/mL, a Gleason score of at least 7, or radiographic evidence of extraprostatic disease.Main Outcome MeasuresTime to PSA failure (PSA &gt;1.0 ng/mL and increasing &gt;0.2 ng/mL on 2 consecutive visits) and overall survival.ResultsAfter a median follow-up of 4.52 years, patients randomized to receive 3D-CRT plus AST had a significantly higher survival (P = .04), lower prostate cancer–specific mortality (P = .02), and higher survival free of salvage AST (P = .002). Kaplan-Meier estimates of 5-year survival rates were 88% (95% confidence interval [CI], 80%-95%) in the 3D-CRT plus AST group vs 78% (95% CI, 68%-88%) in the 3D-CRT group. Rates of survival free of salvage AST at 5 years were 82% (95% CI, 73%-90%) in the 3D-CRT plus AST group vs 57% (95% CI, 46%-69%) in the 3D-CRT group.ConclusionThe addition of 6 months of AST to 70 Gy 3D-CRT confers an overall survival benefit for patients with clinically localized prostate cancer.
Revised International Pediatric Non-Hodgkin Lymphoma Staging System
Authors: Angelo Rosolen, Sherrie L. Perkins, C. Ross Pinkerton, R. Paul Guillerman, John T. Sandlund, Catherine Patte, Alfred Reiter, Mitchell S. Cairo
Journal: Journal of Clinical Oncology (2015)

Treatment and prognosis of pediatric non-Hodgkin lymphoma (NHL) have improved dramatically in the last 30 years. However, the St Jude NHL staging classification for pediatric NHL was developed more than 35 years ago. The most recent Lugano lymphoma staging classification focused on adult lymphoma. Furthermore, major limitations of the current pediatric NHL staging classification include lack of consideration of new distinct pediatric NHL histologic entities; absence of recognition of frequent skin, bone, kidney, ovarian, and other organ involvement; and lack of newer precise methods to detect bone marrow and CNS involvement, minimal disease quantification, and highly sensitive imaging technologies.An international multidisciplinary expert panel convened in Frankfurt, Germany, in 2009 at the Third International Childhood, Adolescent and Young Adult NHL Symposium to develop a revised international pediatric NHL staging system (IPNHLSS), addressing limitations of the current pediatric NHL staging system and creating a revised classification. Evidence-based disease distribution and behavior were reviewed from multiple pediatric cooperative group NHL studies.A revised IPNHLSS was developed incorporating new histologic entities, extranodal dissemination, improved diagnostic methods, and advanced imaging technology.This revised IPNHLSS will facilitate more precise staging for children and adolescents with NHL and facilitate comparisons of efficacy across different treatment strategies, various institutions, multicenter trials, and cooperative groups by allowing for reproducible pediatric-based staging at diagnosis and relapse.
Use of Glucocorticoids and Risk of Venous Thromboembolism
Authors: Sigrun A. Johannesdottir, Erzsébet Horváth-Puhó, Olaf M. Dekkers, Suzanne C. Cannegieter, Jens Otto L. Jørgensen, Vera Ehrenstein, Jan P. Vandenbroucke, Lars Pedersen, Henrik Toft Sørensen
Journal: JAMA Internal Medicine (2013)

Importance: Excess endogenous cortisol has been linked to venous thromboembolism (VTE) risk, but whether this relationship applies to exogenous glucocorticoids remains uncertain.Because the prevalence of glucocorticoid use and the incidence of VTE are high, an increased risk of VTE associated with glucocorticoid use would have important implications.Background: To examine the association between glucocorticoid use and VTE.Design: Population-based case-control study using nationwide databases.Setting: Denmark (population 5.6 million).Participants: We identified 38 765 VTE cases diagnosed from January 1, 2005, through December 31, 2011, and 387 650 population controls included through riskset sampling and matched by birth year and sex.The VTE diagnosis date for the case was the index date for cases and matched controls.Exposure: We classified individuals who filled their most recent glucocorticoid prescription 90 days or less, 91 to 365 days, and more than 365 days before the index date as present, recent, and former users, respectively.Present users were subdivided into new (first-ever prescription 90 days or less before the index date) and continuing users (others). Main Outcomes and Measures:We used conditional logistic regression adjusted for VTE risk factors to estimate incidence rate ratios (IRRs) and 95% CIs for glucocorticoid users vs nonusers.Results: Systemic glucocorticoids increased VTE risk among present (adjusted IRR,2.31;95% CI, 2.18-2.45),new (3.06;2.77-3.38),continuing (2.02; 1.88-2.17),and recent (1.18; 1.10-1.26)users but not among former users (0.94; 0.90-0.99).The adjusted IRR increased from 1.00 (95% CI, 0.93-1.07)for a prednisolone-equivalent cumulative dose of 10 mg or less to 1.98 (1.78-2.20)for more than 1000 to 2000 mg, and to 1.60 (1.49-1.71)for doses higher than 2000 mg.New use of inhaled (adjusted IRR, 2.21; 95% CI, 1.72-2.86)and intestinalacting (2.17; 1.27-3.71)glucocorticoids also increased VTE risk. Conclusions and Relevance:The risk of VTE is increased among glucocorticoid users.Although residual confounding may partly explain this finding, we consider a biological mechanism likely because the association followed a clear temporal gradient, persisted after adjustment for indicators of severity of underlying disease, and existed also for noninflammatory conditions.Hence, our observations merit clinical attention.
The role of multiple toll-like receptor signalling cascades on interactions between biomedical polymers and dendritic cells
Authors: Behnaz Shokouhi, Cevayir Coban, Vasif Hasirci, Erkin Aydin, Anandhan Dhanasingh, Nian Shi, Shohei Koyama, Shizuo Akira, Martin Zenke, Antonio S. Sechi
Journal: Biomaterials (2010)
Impaired lung function and serum leptin in men and women with normal body weight: a population based study
Authors: D D Sin
Journal: Thorax (2003)

Impaired lung function is a risk factor for cardiovascular morbidity. Whether circulating factors are responsible for this association is unknown. A study was undertaken to determine whether leptin, a hormone that can promote atherothrombosis, is raised in individuals with impaired lung function.Data from non-obese participants in the Third National Health, Nutrition, and Examination Survey (n=2808) were analysed to determine the relationship between circulating leptin levels and forced expiratory volume in 1 second (FEV(1)) values divided into quintiles (quintile 1, FEV(1) predicted < or =85.2%; quintile 2, 85.3-94.3%; quintile 3, 94.4-101.4%; quintile 4, 101.5-110.0%; and quintile 5, > or =110.1%).Serum leptin levels changed along the FEV(1) gradient. The highest leptin levels were found in quintile 1 (geometric mean (GM) 5.42; interquartile range (IQR) 3.00-9.60 fg/l) and the lowest in quintile 5 (GM 4.94; IQR 2.80-9.10 fg/l). Adjustments for age, body mass index, and other confounders strengthened this relationship. Compared with quintile 5, the odds of having an increased serum leptin level in quintiles 1, 2, 3, and 4 were 2.26 (95% confidence interval (CI) 1.54 to 3.31), 2.20 (95% CI 1.52 to 3.17), 1.46 (95% CI 1.01 to 2.09), and 1.28 (95% CI 0.90 to 1.83), respectively.Individuals with impaired lung function have raised serum leptin levels. Leptin may play a role in the pathogenesis of cardiovascular morbidity and mortality related to impaired lung function.
CELLULAR RESPONSES TO INTERFERON-γ
Authors: U. Boehm, T. Klamp, M. Groot, J. C. Howard
Journal: Annual Review of Immunology (1997)

The phytohemagglutinin-induced virus-inhibitor may, however, be produced in white cells in response to a stimulation of cellular RNA synthesis and may be a feedback mechanism for control of RNA synthesis. E. Frederick Wheelock (1965) ▪ Abstract Interferons are cytokines that play a complex and central role in the resistance of mammalian hosts to pathogens. Type I interferon (IFN-α and IFN-β) is secreted by virus-infected cells. Immune, type II, or γ-interferon (IFN-γ) is secreted by thymus-derived (T) cells under certain conditions of activation and by natural killer (NK) cells. Although originally defined as an agent with direct antiviral activity, the properties of IFN-γ include regulation of several aspects of the immune response, stimulation of bactericidal activity of phagocytes, stimulation of antigen presentation through class I and class II major histocompatibility complex (MHC) molecules, orchestration of leukocyte-endothelium interactions, effects on cell proliferation and apoptosis, as well as the stimulation and repression of a variety of genes whose functional significance remains obscure. The implementation of such a variety of effects by a single cytokine is achieved by complex patterns of cell-specific gene regulation: Several IFN-γ-regulated genes are themselves components of transcription factors. The IFN-γ response is itself regulated by interaction with responses to other cytokines including IFN-α/β, TNF-α, and IL-4. Over 200 genes are now known to be regulated by IFN-γ and they are listed in a World Wide Web document that accompanies this review. However, much of the cellular response to IFN-γ can be described in terms of a set of integrated molecular programs underlying well-defined physiological systems, for example the induction of efficient antigen processing for MHC-mediated antigen presentation, which play clearly defined roles in pathogen resistance. A promising approach to the complexity of the IFN-γ response is to extend the analysis of the less understood IFN-γ-regulated genes in terms of molecular programs functional in pathogen resistance.
1235 HIGH PRE-TRANSPLANT HEV SEROPREVALENCE IN HCV INFECTED LIVER TRANSPLANT RECIPIENTS; EVIDENCE FOR HCV TREATMENT PROTECTION AGAINST DEVELOPMENT OF CHRONIC HEV INFECTION
Authors: L. Koning, M.R. Charlton, S.D. Pas, J.K. Heimbach, A.D.M.E. Osterhaus, K.D. Watt, H.L.A. Janssen, R.J. de Knegt, A.A. van der Eijk
Journal: Journal of Hepatology (2013)
The role of stretching in tendon injuries
Authors: E Witvrouw, N Mahieu, P Roosen, P McNair
Journal: British Journal of Sports Medicine (2007)

The function of tendons can be classified into two categories: tensile force transmission, and storage and release of elastic energy during locomotion. The action of tendons in storing and releasing energy is mainly seen in sports activities with stretch-shortening cycles (SSCs). The more intense the SSC movements are (jumping-like activities), the more frequently tendon problems are observed. High SSC movements impose high loads on tendons. Consequently, tendons that frequently deal with high SSC motion require a high energy-absorbing capacity to store and release this large amount of elastic energy. As the elasticity of tendon structures is a leading factor in the amount of stored energy, prevention and rehabilitation programmes for tendon injuries should focus on increasing this tendon elasticity in athletes performing high SSC movements. Recently, it has been shown that ballistic stretching can significantly increase tendon elasticity. These findings have important clinical implications for treatment and prevention of tendon injuries.