tbuckley/cabot-search huggingface dataset:
Markers of joint destruction: principles, problems, and potential
Authors: S A YOUNG-MIN
Journal: Annals of the Rheumatic Diseases (2001)

Twenty years ago, Verna Wright commented, “clinicians may all too easily spend years writing ‘doing well’ in the notes of patients who become progressively more crippled before their eyes.” Thankfully much of this has changed. Clinicians increasingly understand the advantages of early intervention, particularly in inflammatory joint diseases,1 2 and we now have better, more targeted treatments. During this time, however, our methods of objectively assessing and quantifying joint damage have remained largely unchanged. As a result, it is likely that early joint damage in patients goes undetected and untreated.

Although magnetic resonance imaging initially promised much, it has delivered little outside highly specialised centres, where software, coils, and scan sequences change with every passing season. The “gold standard” for assessing joint damage is still the plain radiograph. This mainly images only the bone and is insensitive to change, with reliable differences requiring at least 12 months to evolve. The scoring of radiographs is also time consuming and it does not lend itself to routine monitoring. Importantly, all imaging techniques also only provide a historical view of damage that has already occurred. Even after repeated measures, they are of limited use in informing the clinician of continuing or future damage. Existing serological measures, such as erythrocyte sedimentation rate or C reactive protein, also fall short of requirements.3 They are neither specific to joint disease nor of much use in non-inflammatory conditions. Known genetic and environmental factors that have been associated with various arthritic diseases might also be considered to be markers, but they are often not modifiable nor do they provide any direct information on the extent of joint disease. There is an urgent need for reliable, quantitative, and dynamic tests that will detect damage early and allow the response of treatments targeted at joint destruction to be …
Kupffer cell–derived cytokines induce the synthesis of a leukocyte chemotactic peptide, interleukin-8, in human hepatoma and primary hepatocyte cultures
Authors: Amanda J. Thornton, John Ham, Steven L. Kunkel
Journal: Hepatology (1991)

Communication circuits operating between activated monocytes/macrophages and adjacent hepatocytes in the liver effect important alterations in hepatocyte function. We demonstrate here that primary human hepatocytes and hepatoma cells are able to function as effector cells in the recruitment of inflammatory cells in hepatic disease and inflammatory states by synthesizing a neutrophil/lymphocyte chemotactic factor, interleukin-8. We have further investigated the possibility that endogenous factors elaborated by activated peripheral blood monocytes and Kupffer cells in the liver are mediators of hepatocytederived interleukin-8 expression. Twenty-four-hour conditioned medium from lipopolysaccharidestimulated peripheral blood monocytes and nonparenchymal human liver cells enriched for Kupffer cells induced a time-dependent increase in interleukin-8 messenger RNA levels in SK-hepatoma cells over a 24-hr period, similar to that seen for tumor necrosis factor-α or interleukin-1β induction of interleukin-8 in primary hepatocytes. Exogenously added lipopolysaccharide or recombinant interleukin-6 had no effect. Cell-associated interleukin-8 antigen was present in SK-hepatoma and primary hepatocytes that had been incubated with macrophage-conditioned medium, tumor necrosis factor or interleukin-1β. Similarly, neutrophil chemotactic activity was secreted by SKhepatoma cells, a significant proportion of which could be blocked with interleukin-8–specific antiserum. Preincubation of macrophage-conditioned medium with neutralizing antibodies to tumor necrosis factor-α or interleukin-1β reduced its interleukin-8 messenger RNA-inducing capacity. Exposure of SK-hepatoma to conditioned medium followed by removal of the stimulus resulted in a rapid down-regulation of interleukin-8 messenger RNA to 50% of the maximum level within the first hour. These data suggest that products derived from activated Kupffer cells can modulate hepatoma cells and primary hepatocyte interleukin-8 gene expression. In addition, macrophage/monocyte-derived tumor necrosis factor-α and interleukin-1β have major roles in the positive regulatory component of this modulation. (HEPATOLOGY 1992;15:1112–1122.)
Achieving a Healthy Weight Gain During Pregnancy
Authors: Christine M. Olson
Journal: Annual Review of Nutrition (2008)

This review uses the 1990 U.S. Institute of Medicine (IOM) gestational weight gain recommendations to examine the question, what is a healthy pregnancy weight gain? The relationship of gestational weight gain to infant size at birth; pregnancy, labor, and delivery complications; neonatal, infant, and child outcomes; and maternal weight and health outcomes in U.S. and European populations are discussed. Pregnancy weight gains within the IOM recommendations are associated with better outcomes. The possible exception is very obese women, who may benefit from weight gains less than the 7 kg (15 pounds) recommended. Only about 33% to 40% of U.S. women gain within IOM recommendations. Excessive gestational weight gain is more prevalent than inadequate gain. Women's gestational weight gains tend to follow the recommendations of health care providers. Current interventions demonstrate efficacy in influencing gestational weight gain in low-income women with normal and overweight body mass index in the United States and obese women in Scandinavia.
Diagnosis of Sleep-Related Breathing Disorders by Visual Analysis of Transthoracic Impedance Signals in Pacemakers
Authors: Christoph Scharf, Yong K. Cho, Konrad E. Bloch, Corinna Brunckhorst, Firat Duru, Kryzstof Balaban, Nancy Foldvary, Lynn Liu, Richard C. Burgess, Reto Candinas, Bruce L. Wilkoff
Journal: Circulation (2004)

Background— Minute ventilation sensors of cardiac pacemakers measure ventilation by means of transthoracic impedance changes between the pacemaker case and the electrode tip. We investigated whether this technique might detect sleep-related breathing disorders. Methods and Results— In 22 patients, analog waveforms of the transthoracic impedance signal measured by the pacemaker minute ventilation sensor over the course of a night were visualized, scored for apnea/hypopnea events, and compared with simultaneous polysomnography. Analysis of transthoracic impedance signals correctly identified the presence or absence of moderate to severe sleep apnea (apnea/hypopnea index, AHI &gt;20 h −1 ) in all patients (receiver operating characteristics, ROC=1.0). The ROC for AHI scores of ≥5 h −1 and ≥10 h −1 showed an area under the curve of 0.95, P &lt;0.005, and 0.97, P &lt;0.0001, respectively. Accuracy over time assessed by comparing events per 5-minute epochs was high (Cronbach α reliability coefficient, 0.85; intraclass correlation, 0.73). Event-by-event comparison within ±15 seconds revealed agreement in 81% (κ, 0.77; P &lt;0.001). Conclusions— Detection of apnea/hypopnea events by pacemaker minute ventilation sensors is feasible and accurate compared with laboratory polysomnography. This technique might be useful to screen and monitor sleep-related breathing disorders in pacemaker patients.
Regional myocardial function and dimensions early and late after myocardial infarction in the unanesthetized dog.
Authors: P Theroux, J Ross, D Franklin, J W Covell, C M Bloor, S Sasayama
Journal: Circulation Research (1977)

Pairs of ultrasonic dimension gauges and a micromanometer implanted in the subendocardium of the left ventricles of unanesthetized dogs were used to analyze serial changes in hemodynamic status and segmental function for up to 4 weeks after permanent circumflex coronary artery occlusion. Regional function was studied in control segments and in segments identified as marginal (hypokinetic) and ischemic. In three dogs, after transient regional dysfunction, no myocardial infarction developed, whereas in five dogs regional dysfunction at 3 hours after occlusion was followed by the development of persistent dysfunction and infarction. Left ventricular end-diastolic segment length (EDL) changes over time; EDL of the control segments increased progressively, but in marginal segments EDL was 12% below control and in the ischemic segments 30% below control by 4 weeks. Progressive increases in percent active shortening occurred in control segments; but holosystolic bulging was replaced by akinesia in ischemic segments, and persistent reduction in shortening was present in marginal segments at 4 weeks. Correlations were found between percent scar and reductions in percent shortening, EDL, and the ratio of change in diastolic length to change in diastolic pressure. These methods have detected hyperfunction in normal regions and variable segmental loss of contractile function, together with reduction of subendocardial dimensions and changes that may reflect decreased diastolic compliance in ischemic regions. We conclude that this model for the conscious animals may be useful for studying the influence of therapy on the extent of myocardial damage after experimental coronary occlusion.
RhoGDI2 suppresses lung metastasis in mice by reducing tumor versican expression and macrophage infiltration
Authors: Neveen Said, Marta Sanchez-Carbayo, Steven C. Smith, Dan Theodorescu
Journal: Journal of Clinical Investigation (2012)

Half of patients with muscle-invasive bladder cancer develop metastatic disease, and this is responsible for most of the deaths from this cancer. Low expression of RhoGTP dissociation inhibitor 2 (RhoGDI2; also known as ARHGDIB and Ly-GDI) is associated with metastatic disease in patients with muscle-invasive bladder cancer. Moreover, a reduction in metastasis is observed upon reexpression of RhoGDI2 in xenograft models of metastatic cancer. Here, we show that RhoGDI2 suppresses lung metastasis in mouse models by reducing the expression of isoforms V1 and V3 of the proteoglycan versican (VCAN; also known as chondroitin sulfate proteoglycan 2 [CSPG2]). In addition, we found that high versican levels portended poor prognosis in patients with bladder cancer. The functional importance of tumor expression of versican in promoting metastasis was established in in vitro and in vivo studies in mice that implicated a role for the chemokine CCL2 (also known as MCP1) and macrophages. Further analysis indicated that RhoGDI2 suppressed metastasis by altering inflammation in the tumor microenvironment. In summary, we demonstrate what we believe to be a new mechanism of metastasis suppression that works by reducing host responses that promote metastatic colonization of the lung. Therapeutic targeting of these interactions may provide a novel adjuvant strategy for delaying the appearance of clinical metastasis in patients.
The Evolving Landscape of HER2 Targeting in Breast Cancer
Authors: Mark M. Moasser, Ian E. Krop
Journal: JAMA Oncology (2015)

The development of human epidermal growth factor receptor 2 (HER2)-targeting agents for the treatment of HER2-amplified breast cancer has dramatically improved outcomes for patients with this disease. The value of HER2 as a therapeutic target encompasses 2 entirely different mechanistic dimensions. The first approach exploits the fact that HER2 is clearly a disease-driving oncogene to deliver HER2 kinase inhibitors, apparently a highly rational approach to the treatment of HER2-amplified cancers. However, the functionally relevant HER2-HER3 complex has proven much more difficult to inhibit than had been anticipated, and because of its modest efficacy, the HER2 inhibitor lapatinib is currently used predominantly in combinations and in very advanced stages of disease. The second approach exploits the massive cell surface expression of HER2 and delivers of a variety of cytotoxic or immunologic effectors with great selectivity to these cancer cells. This approach has proven transformative, with 3 such drugs introduced into practice to date. The HER2-specific antibody trastuzumab, in combination with chemotherapy, has shown substantial effect in the management of HER2-amplifed breast cancer at all stages of disease and lines of therapy-and the addition of the second HER2 antibody pertuzumab substantially increases the magnitude of this effect in all of the contexts tested thus far. While the immunologic effectors stimulated by these naked HER2 antibodies provide only modest activity as monotherapy, the toxin-carrying antibody trastuzumab-emtansine provides substantial single-agent activity and is being developed for both early- and late-stage disease. The diverse mechanistic landscape afforded by the target HER2 has proven to be fertile ground for drug development, but it has also created complexity and misconception in understanding these agents' modes of action, undermining the development of clinically useful predictive biomarkers. This accounts for the failure of signaling-based biomarkers to predict clinical trastuzumab resistance and shifted the focus to markers of immunologic activity with greater success. The evolving world of HER2 targeting is reviewed herein.
Evaluating antirheumatic treatments using synovial biopsy: a recommendation for standardisation to be used in clinical trials
Authors: Marleen G H van de Sande, Danielle M Gerlag, Beatrijs M Lodde, Lisa G M van Baarsen, Stefano Alivernini, Veronica Codullo, Ioana Felea, Elsa Vieira-Sousa, Ursula Fearon, Richard Reece, Carlomaurizio Montecucco, Douglas J Veale, Costantino Pitzalis, Paul Emery, Lars Klareskog, Iain B McInnes, Paul P Tak
Journal: Annals of the Rheumatic Diseases (2010)

Inflammation of synovium is one of the hallmarks of rheumatoid arthritis (RA). Analysis of synovial tissue has increased our understanding of RA pathogenesis, aided in identifying potential therapeutic targets and has been used in the response and mechanistic evaluation of antirheumatic treatments. In addition, studies are ongoing, aimed at the identification of diagnostic and prognostic biomarkers in the synovium. This paper outlines the currently used procedures for sampling and processing of synovial tissue, and presents a standardised recommendation to support multicentre translational research.
Prognostic Role of <i>Thymidylate Synthase</i> Polymorphisms in Gastric Cancer Patients Treated with Surgery and Adjuvant Chemotherapy
Authors: Kazuyuki Kawakami, Francesco Graziano, Go Watanabe, Annamaria Ruzzo, Daniele Santini, Vincenzo Catalano, Renato Bisonni, Federica Arduini, Italo Bearzi, Stefano Cascinu, Pietro Muretto, Giuseppe Perrone, Carla Rabitti, Lucio Giustini, Giuseppe Tonini, Francesca Pizzagalli, Mauro Magnani
Journal: Clinical Cancer Research (2005)

Abstract Purpose: To investigate the prognostic role of thymidylate synthase (TS) polymorphisms in gastric cancer patients treated with radical surgery and fluorouracil-based adjuvant chemotherapy. Experimental Design: Ninety gastric cancer cases were identified among 187 patients previously enrolled in prospective case-control studies for disease susceptibility. Patients were genotyped for a G/C nucleotide change within a triple 28 bp variable number of tandem repeat sequence in the TS 5′-untranslated region (5′-UTR) and a 6 bp deletion in the TS 3′-untranslated region (3′-UTR). According to available functional data, patients with 5′-UTR 2R/2R, 2R/3C, 3C/3C genotypes were classified as low TS producers (5′-UTRlow) and patients with 5′-UTR 3G/3G, 3G/3C, 2R/3G genotypes as high TS producers (5′UTRhigh). Patients with 3′-UTR del6/del6 and del6/ins6 genotypes were classified as low TS producers (3′-UTRlow) and patients with 3′-UTR ins6/ins6 genotype as high TS producers (3′-UTRhigh). The prognostic analysis was based on 5′-UTR/3′-UTR combined genotypes. Results: Ten patients (11%) were 5′-UTRhigh/3′-UTRhigh, 36 patients were 5′-UTRhigh/3′-UTRlow, 19 patients were 5′-UTRlow/3′-UTRhigh, and 25 patients were 5′-UTRlow/3′-UTRlow. 5′-UTRlow/3′-UTRlow patients showed the best outcome and the threshold of statistical significance was achieved in the comparison of disease-free survival and overall survival with 5′-UTRhigh/3′-UTRlow patients and 5′-UTRhigh/3′-UTRhigh patients. The presence of at least one high TS expression genotype showed independent adverse prognostic role in multivariate analysis. Conclusions: The prognostic role of TS polymorphisms in gastric cancer deserves further investigation because the adverse effect of high TS expression genotypes may be a relevant information to improve adjuvant chemotherapeutic strategies.
Pattern of developing the performance template
Authors: C Foster, K J Hendrickson, K Peyer, B Reiner, J J deKoning, A Lucia, R A Battista, F J Hettinga, J P Porcari, G Wright
Journal: British Journal of Sports Medicine (2009)

The pattern of energy expenditure during sustained high-intensity exercise is influenced by several variables. Data from athletic populations suggest that a pre-exercise conceptual model, or template, is a central variable relative to controlling energy expenditure.The aim of this study was to make systematic observations regarding how the performance template develops in fit individuals who have limited specific experience with sustained high-intensity exercise (eg, time trials).The study was conducted in four parts and involved measuring performance (time and power output) during: (A) six 3 km cycle time trials, (B) three 2 km rowing time trials, (C) four 2 km rowing time trials with a training period between trials 2 and 3, and (D) three 10 km cycle time trials. All time trials were self-paced with feedback to the subjects regarding previous performances and momentary pace.In all four series of time trials there was a progressive pattern of improved performance averaging 6% over the first three trials and 10% over six trials. In all studies improvement was associated with increased power output during the early and middle portions of the time trial and a progressively greater terminal rating of perceived exertion. Despite the change in the pattern of energy expenditure, the subjects did not achieve the pattern usually displayed by athletes during comparable events.This study concludes that the pattern of learning the performance template is primarily related to increased confidence that the trial can be completed without unreasonable levels of exertion or injury, but that the process takes more than six trials to be complete.
Measuring the Impact of Medical Research: Moving From Outputs to Outcomes
Authors: Anthony P. Weiss
Journal: American Journal of Psychiatry (2007)

Billions of dollars are spent every year to support medical research, with a substantial percentage coming from charitable foundations. To justify these expenditures, some measure of the return on investment would be useful, particularly one aligned with the intended ultimate outcome of this scientific effort: the amelioration of disease. The current mode of reporting on the success of medical research is output based, with an emphasis on measurable productivity. This approach falls short in many respects and may be contributing to the well-described efficacy-effectiveness gap in clinical care. The author argues for an outcomes-based approach and describes the steps involved, using an adaptation of the logic model. A shift in focus to the outcomes of our work would provide our funders with clearer mission-central return-on-investment feedback, would make explicit the benefits of science to an increasingly skeptical public, and would serve as a compass to guide the scientific community in playing a more prominent role in reducing the efficacy-effectiveness gap. While acknowledging the enormous complexity involved with the implementation of this approach on a large scale, the author hopes that this essay will encourage some initial steps toward this aim and stimulate further discussion of this concept.
NHS staff stage nationwide strike but limit the impact
Authors: A. O'Dowd
Journal: BMJ (2014)

Many thousands of NHS staff took part in a four hour staged industrial action on Monday 24 November across England and Northern Ireland but ensured that its effect on patients was limited.

The strike, involving trade unions such as Unite, Unison, the GMB, and the Royal College of Midwives, was held to protest against the government’s refusal to implement the consolidated 1% pay rise for all NHS staff recommended by the Review Body on Doctors’ and Dentists’ Remuneration (DDRB). The …
Unstable variant of NADH methemoglobin reductase in puerto ricans with hereditary methemoglobinemia
Authors: Joel M. Schwartz, Philip S. Paress, Jonathan M. Ross, Frank DiPillo, Rafael Rizek
Journal: Journal of Clinical Investigation (1972)

The electrophoretic mobility of erythrocyte NADH methemoglobin reductase in five hereditary methemoglobinemia patients from three Puerto Rican kindreds was 118% of normal at pH 8.6. The methemoglobin ferrocyanide reductase activity of the enzyme in erythrocyte hemolysates was 3.2-6.4% of normal. Electrophoresis of hemolysates prepared from the blood of patients from two different families at six pH values between 4.6 and 9.3 did not differentiate between the variant enzymes. Examination of the deficient enzymes extracted from the erythrocytes of one patient from each kindred revealed altered affinity for NADH and dichloroindophenol dye and decreased thermal stability. The quantitative similarity of the abnormal findings, together with the Puerto Rican origin of the kindreds, suggested that the cyanotic patients possessed the same abnormal enzyme and were thus homozygous for the same rare mutant gene. Consanguinity of the kindreds could not be established. The rates of decline of the normal and variant NADH methemoglobin reductase enzymes in vivo were measured in erythrocyte fractions of increasing cell age. The rate of decline of the variant enzyme was increased 20-fold by comparison with the normal enzyme. The methemoglobin percentage in erythrocyte fractions of increasing cell age correlated inversely with the activity of the variant. The variant enzyme averaged 37% of normal mean activity in young cells and 1% in old cells. The normal enzyme, on the other hand, lost only one-sixth of its activity as the cells aged, and the methemoglobin content in old normal cells did not rise. These observations support the hypothesis that the deficient activity and the heterogeneous pattern of methemoglobin accumulation in vivo arise principally from the accelerated inactivation of variant NADH methemoglobin reductase during the life-span of the red blood cell.