tbuckley/cabot-search huggingface dataset:
Heart in Diabetes: Not Only a Macrovascular Disease
Authors: Bernd Stratmann, Diethelm Tschoepe
Journal: Diabetes Care (2011)

The importance of diabetes as a cause of mortality and morbidity is well known. The number of patients increases alongside aging of the population, raising the prevalence of obesity and a sedentary lifestyle. As a disease that is strongly associated with both micro- and macrovascular complications, diabetes results in organ and tissue damage. Cardiovascular disease (CVD) causes up to 70% of all deaths in people with diabetes. The epidemic of diabetes will thus be followed by an epidemic of diabetes-related vascular diseases. Almost two of three patients who present with symptomatic chronic heart disease have abnormal glucose homeostasis. Although the mortality from coronary artery disease (CAD) in patients without diabetes has declined over the past 20 years, the mortality in men with type 2 diabetes has not changed significantly. Moreover, diabetes is an independent risk factor for heart failure, and there are a substantial number of patients with diabetes and heart failure. The main macrovascular complications, for which diabetes has been a well-established risk factor throughout the cardiovascular system, are CAD, peripheral vascular disease, increased intima-media thickness, and stroke. Ischemic heart disease and stroke account for the highest proportion of comorbid diseases associated with diabetes.

The joint guidelines of the European Society of Cardiology and the European Association of Diabetes take into account the close reciprocal relationship between diagnostics and therapeutics in cardiology and diabetology.

Patients with diabetes and CVD have an unfavorable prognosis (1). Mortality rates due to heart disease are two to four times higher among people with diabetes compared with those without diabetes after correction for traditional risk factors for CVD such as age, obesity, smoking, dyslipidemia, and hypertension. It appears, however, that the presence of even one of these risk factors leads to poorer outcomes among people with diabetes compared with those without diabetes. People with …
Risk of Subsequent Malignant Neoplasms in Long-Term Hereditary Retinoblastoma Survivors After Chemotherapy and Radiotherapy
Authors: Jeannette R. Wong, Lindsay M. Morton, Margaret A. Tucker, David H. Abramson, Johanna M. Seddon, Joshua N. Sampson, Ruth A. Kleinerman
Journal: Journal of Clinical Oncology (2014)

Hereditary retinoblastoma (Rb) survivors have increased risk of subsequent malignant neoplasms (SMNs). Previous studies reported elevated radiotherapy (RT) -related SMN risks, but less is known about chemotherapy-related risks.In a long-term follow-up study of 906 5-year hereditary Rb survivors diagnosed from 1914 to 1996 and observed through 2009, treatment-related SMN risks were quantified using cumulative incidence analyses and multivariable Cox proportional hazards regression models with age as the underlying time scale.Nearly 90% of Rb survivors were treated with RT, and almost 40% received alkylating agent (AA) -containing chemotherapy (predominantly triethylenemelamine). Median follow-up time to first SMN diagnosis was 26.3 years. Overall SMN risk was not significantly elevated among survivors receiving AA plus RT versus RT without chemotherapy (hazard ratio [HR], 1.27; 95% CI, 0.99 to 1.63). AA-related risks were significantly increased for subsequent bone tumors (HR, 1.60; 95% CI, 1.03 to 2.49) and leiomyosarcoma (HR, 2.67; 95% CI, 1.22 to 5.85) but not for melanoma (HR, 0.74; 95% CI, 0.36 to 1.55) or epithelial tumors (HR, 0.89; 95% CI, 0.48 to 1.64). Leiomyosarcoma risk was significantly increased for survivors who received AAs at age < 1 (HR, 5.17; 95% CI, 1.76 to 15.17) but not for those receiving AAs at age ≥ 1 year (HR, 1.75; 95% CI, 0.68 to 4.51). Development of leiomyosarcoma was significantly more common after AA plus RT versus RT (5.8% v 1.6% at age 40 years; P = .01).This comprehensive quantification of SMN risk after chemotherapy and RT among hereditary Rb survivors also demonstrates an AA-related contribution to risk. Although triethylenemelamine is no longer prescribed, our findings warrant further follow-up to investigate potential SMN risks associated with current chemotherapies used for Rb.
V(D)J-mediated Translocations in Lymphoid Neoplasms: A Functional Assessment of Genomic Instability by Cryptic Sites
Authors: Rodrig Marculescu, Trang Le, Paul Simon, Ulrich Jaeger, Bertrand Nadel
Journal: The Journal of Experimental Medicine (2002)

Most lymphoid malignancies are initiated by specific chromosomal translocations between immunoglobulin (Ig)/T cell receptor (TCR) gene segments and cellular proto-oncogenes. In many cases, illegitimate V(D)J recombination has been proposed to be involved in the translocation process, but this has never been functionally established. Using extra-chromosomal recombination assays, we determined the ability of several proto-oncogenes to target V(D)J recombination, and assessed the impact of their recombinogenic potential on translocation rates in vivo. Our data support the involvement of 2 distinct mechanisms: translocations involving LMO2, TAL2, and TAL1 in T cell acute lymphoblastic leukemia (T-ALL), are compatible with illegitimate V(D)J recombination between a TCR locus and a proto-oncogene locus bearing a fortuitous but functional recombination site (type 1); in contrast, translocations involving BCL1 and BCL2 in B cell non-Hodgkin’s lymphomas (B-NHL), are compatible with a process in which only the IgH locus breaks are mediated by V(D)J recombination (type 2). Most importantly, we show that the t(11;14)(p13;q32) translocation involving LMO2 is present at strikingly high frequency in normal human thymus, and that the recombinogenic potential conferred by the LMO2 cryptic site is directly predictive of the in vivo level of translocation at that locus. These findings provide new insights into the regulation forces acting upon genomic instability in B and T cell tumorigenesis.
Effect of chronic theophylline treatment on the methacholine dose-response curve in allergic asthmatic subjects
Authors: CP Page, T Cotter, S Kilfeather, P Sullivan, D Spina, JF Costello
Journal: European Respiratory Journal (1998)

Theophylline is a bronchodilator and immunomodulator drug which has recently been demonstrated to attenuate the recruitment and activation of inflammatory cells into lungs of asthmatics. This study investigated the effect of chronic treatment with theophylline for its ability to alter airway responsiveness, as indicated by changes in airway sensitivity and reactivity to inhaled methacholine. The subjects studied were mild asthmatics who relied on beta-agonist medication only and who were randomized into two groups, one receiving theophylline (median dose 250 mg twice daily; range 250-375 mg twice daily) and the other placebo. A number of parameters was measured before and after treatment, including baseline forced expiratory volume in one second (FEV1), the provocative concentration of methacholine causing a 20% fall in FEV1 (PC20; sensitivity), dose-response slope (reactivity) and percentage eosinophils, eosinophil cationic protein and T-cell markers in peripheral blood (by flow cytometry). After 2 months of treatment with theophylline there was a significant lowering of airway reactivity (slope) to methacholine and improvement in methacholine sensitivity (PC20). However, such changes were not associated with any significant change in the number or activation status of eosinophils and lymphocytes in peripheral blood. In conclusion, chronic treatment with theophylline reduces the reactivity of the airways to methacholine, which might be beneficial in the treatment of persistent asthma. The cellular mechanisms of this improvement remain to be clarified.
Value of High-Cost Cancer Care: A Behavioral Science Perspective
Authors: Kevin P. Weinfurt
Journal: Journal of Clinical Oncology (2007)

Concerns about the high costs of cancer care have led to a renewed interest in understanding how patients value the outcomes of care. Psychologists, economists, and others have highlighted some of the ways in which patients and caregivers perceive and make treatment decisions. Prospect theory is the predominant framework for understanding decisions made in situations where the outcomes of each choice are uncertain. Prospect theory assumes that a patient values the outcomes of care not in absolute terms, such as years of life saved, but as deviations from the patient's point of reference. This article discusses some of the implications of this notion, along with discussing differences among people in their reference points. These and other considerations from the psychology of decision making help to clarify why some patients might be inclined to seek expensive or risky treatments in the hopes of achieving benefits that others might consider not worthwhile. An appreciation of these psychological issues might improve the quality of debates concerning the rising costs of cancer care.
Reversal of Metabolic Block in Glycolysis by Enzyme Replacement in Triosephosphate Isomerase–Deficient Cells
Authors: Art Ationu, Ann Humphries, Michel R.A. Lalloz, Roopen Arya, Barbara Wild, Joanne Warrilow, Jennifer Morgan, Alastair J. Bellingham, D. Mark Layton
Journal: Blood (1999)
Pegylated interferon-α-2b reduces corticosteroid requirement in patients with Behçet's disease with upregulation of circulating regulatory T cells and reduction of Th17
Authors: S Lightman, S R J Taylor, C Bunce, H Longhurst, W Lynn, R Moots, M Stanford, O Tomkins-Netzer, D Yang, V L Calder, D O Haskard
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Objective</h3> To determine whether the addition of 26 weeks of subcutaneous peginterferon-α-2b could reduce the requirement for systemic corticosteroids and conventional immunosuppressive medication in patients with Behçet9s disease (BD). <h3>Methods</h3> We conducted a multicentre randomised trial in patients with BD requiring systemic therapy. Patients were randomised to 26 weeks of peginterferon-α-2b in addition to their standard care or to standard care only and followed 6-monthly for 3 years with BD activity scores and quality of life questionnaires. Patients at one centre had blood taken to measure regulatory T cells (Tregs) and Th17 cells. <h3>Results</h3> 72 patients were included. At months 10–12, while among the entire patient population there was no difference in the corticosteroid dose or immunosuppression use between the treatment groups (adjusted OR 1.04, 95% CI 0.34 to 3.19), <i>post hoc</i> analysis revealed that in patients who were on corticosteroids at baseline the corticosteroid requirement was significantly lower in the peginterferon-α-2b (6.5 (5–15) mg/day) compared with the non-interferon group (10 (8.25–16.5) mg/day, p=0.039). Furthermore, there was a trend towards an improved quality of life that became significant by 36 months (p=0.008). This was associated with a significant rise in Tregs and a decrease in Th17 cells which was still present at 1 year and 6 months after the interferon was stopped. The safety profile was similar with adverse events in 10% in both groups. <h3>Conclusions</h3> The addition of peginterferon-α-2b to the drug regime of BD patients did not significantly reduce their corticosteroid dose required at 1 year. However, in those on corticosteroids at baseline <i>post hoc</i> analysis demonstrated that the addition of peginterferon-α-2b did result in a significant reduction in corticosteroid dose with a significantly improved quality of life and trend to reduce other required immunosuppressive agents. This effect was seen at 1 year and associated with a rise in Tregs suggesting a possible mode for interferon action. <h3>Trial registration number</h3> ISRCTN 36354474; EudraCT 2004-004301-18.
New methods in arthroscopy: preliminary investigations.
Authors: L Frizziero, F Zizzi, R Leghissa, A Ferruzzi
Journal: Annals of the Rheumatic Diseases (1986)

The microhysteroscope, which affords direct in vivo observation of otherwise inaccessible surfaces, can be used to great advantage in arthroscopy. Although conventional arthroscopy can distinguish between 'inflammatory' and 'reactive' (post-traumatic) synovial changes, the microendoscope offers the possibility of more precise differentiation. Synovial membranes, joint cartilage, and menisci were studied at four different magnifications, including microscopic observation of vitally stained cells. Frankly pathological synovia (e.g., rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis) were compared and distinguished from examples of less florid synovial changes. The fibrocartilaginous structure of the menisci and secondary undulations and tertiary depression of joint cartilage become visible in vivo with the microendoscope; these may well point to early damage to these structures. The authors believe that the three dimensional images at the magnifications provided by this microendoscope go some way towards bridging the gap between the conventional arthroscope, the light microscope, and the scanning electron microscope. This report presents preliminary findings with this new technique.
Sarcoidosis and MIF gene polymorphism: a case-control study in an Irish population
Authors: B. J. Plant, S. Ghani, M. J. O'Mahony, L. Morgan, C. M. O'Connor, K. Morgan, J. A. Baugh, S. C. Donnelly
Journal: European Respiratory Journal (2006)

Macrophage migration inhibitory factor is a key pro-inflammatory mediator. A 5-CATT repeat functional polymorphism within the promoter of the gene was previously associated with the lowest promoter activity. It was hypothesised that patients exhibiting a 5-CATT allele would have a less aggressive inflammatory response with an associated less severe clinical phenotype in sarcoidosis. Irish Caucasian sarcoidosis patients (n = 173) followed up for 1–39 yrs and a control group (n = 166) were genotyped for the CATT repeat polymorphism. Disease severity at the time of diagnosis and at the time of elaboration of the present study was assessed by the presence of thoracic and extrathoracic symptoms, erythema nodosum, radiographic interstitial changes (chest radiograph score equal to stage II or greater, or high-resolution computed tomography confirmed), pulmonary function tests, steroid use, erythrocyte sedimentation rate, C-reactive protein and angiotensin-converting enzyme levels. In the Irish population studied, no evidence was found of a significant association between either sarcoidosis susceptibility and disease severity and the 5-CATT repeat functional polymorphism in the macrophage migration inhibitory gene. The present study found no significant association between the 5-CATT repeat macrophage migration inhibitory factor gene polymorphism and sarcoidosis, and did not support the overriding role for macrophage migration inhibitory factor in driving sarcoidosis pathogenesis.
Mast cell dipeptidyl peptidase I mediates survival from sepsis
Authors: Jon Mallen–St. Clair, Christine T.N. Pham, S. Armando Villalta, George H. Caughey, Paul J. Wolters
Journal: Journal of Clinical Investigation (2004)

Sepsis is a common, life-threatening disease for which there is little treatment. The cysteine protease dipeptidyl peptidase I (DPPI) activates granule-associated serine proteases, several of which play important roles in host responses to bacterial infection. To examine DPPI's role in sepsis, we compared DPPI–/– and DPPI+/+ mice using the cecal ligation and puncture (CLP) model of septic peritonitis, finding that DPPI–/– mice are far more likely to survive sepsis. Outcomes of CLP in mice lacking mast cell DPPI reveal that the absence of DPPI in mast cells, rather than in other cell types, is responsible for the survival advantage. Among several cytokines surveyed in peritoneal fluid and serum, IL-6 is highly and differentially expressed in DPPI–/– mice compared with DPPI+/+ mice. Remarkably, deleting IL-6 expression in DPPI–/– mice eliminates the survival advantage. The increase in IL-6 in septic DPPI–/– mice, which appears to protect these mice from death, may be related to reduced DPPI-mediated activation of mast cell tryptase and other peptidases, which we show cleave IL-6 in vitro. These results indicate that mast cell DPPI harms the septic host and that DPPI is a novel potential therapeutic target for treatment of sepsis.
Immunopathogenesis of IBD: insufficient suppressor function in the gut?
Authors: I L Huibregtse, A U van Lent, S J H van Deventer
Journal: Gut (2006)

The intestinal immune system is in a constant state of controlled inflammation, and there is substantial evidence that loss of control is an important pathogenic mechanism in inflammatory bowel diseases (IBD). A major current working hypothesis defines Crohn’s disease as a dysregulated immune response towards components of the intestinal flora, leading to chronic intestinal inflammation.1 The causes for this inappropriate response can be attributed to (a combination of) defects in the epithelial barrier, the innate immune response or the adaptive immune response.

Animal experiments as well as clinical data indicate that the immunopathogenesis of Crohn’s disease and ulcerative colitis differ at the level of T cell differentiation and activation although the governing mechanisms responsible for these differences have been incompletely defined. In both diseases, activation of T cells is evident but pathogenic T cells in Crohn’s disease predominantly produce interferon γ (membrane bound), tumour necrosis factor (TNF)α and interleukin (IL)-23 whereas ulcerative colitis is characterised by production of IL-5 and IL-13.2,3

The increased production of “Th1” type cytokines in Crohn’s disease is probably related to increased activation of mucosal dendritic cells and macrophages, and the pivotal function of membrane associated (Toll-like receptor (TLR)) and intracellular (nucleotide oligomerisation domain (NOD) family) receptors in the activation of these antigen presenting cells (APC) has now been well established. Both receptors are key mediators of innate host defence, crucially involved in maintaining intestinal homeostasis.4 In healthy subjects, the colonic mucosa harbours “non-inflammatory” dendritic cells, expressing low levels of TLR2 and TLR4 and producing cytokines such as IL-10, contributing to a non-inflammatory environment,5,6 but in the mucosa of patients with Crohn’s disease the production of IL-12 is greatly increased.7–9 Dendritic cells in both ulcerative colitis and Crohn’s disease have an activated phenotype with higher levels of the …
Standardisation of the quantitative determination of antinuclear antibodies (ANAs) with a homogeneous pattern.
Authors: T E Feltkamp, F Klein, M B Janssens
Journal: Annals of the Rheumatic Diseases (1988)

The results of antinuclear antibody tests using the indirect immunofluorescence technique may be reported as a description of the pattern and the intensity of fluorescence obtained at a certain dilution. If quantitative results are required titration is necessary. Such titrations may vary greatly between different laboratories. The present study involving 26 laboratories shows an improvement of interlaboratory comparability for the homogeneous fluorescence pattern when a common reference serum is used. Cultured cells as substrate appear to give better quantitative agreement than rat liver sections. National reference sera should be standardised in items of the appropriate WHO reference preparation.
Hope and Persuasion by Physicians During Informed Consent
Authors: Victoria A. Miller, Melissa Cousino, Angela C. Leek, Eric D. Kodish
Journal: Journal of Clinical Oncology (2014)

To describe hopeful and persuasive messages communicated by physicians during informed consent for phase I trials and examine whether such communication is associated with physician and parent ratings of the likelihood of benefit, physician and parent ratings of the strength of the physician's recommendation to enroll, parent ratings of control, and parent ratings of perceived pressure.Participants were children with cancer (n = 85) who were offered a phase I trial along with their parents and physicians. Informed consent conferences (ICCs) were audiotaped and coded for physician communication of hope and persuasion. Parents completed an interview (n = 60), and physicians completed a case-specific questionnaire.The most frequent hopeful statements related to expectations of positive outcomes and provision of options. Physicians failed to mention no treatment and/or palliative care as options in 68% of ICCs and that the disease was incurable in 85% of ICCs. When physicians mentioned no treatment and/or palliative care as options, both physicians and parents rated the physician's strength of recommendation to enroll in the trial lower.Hopes and goals other than cure or longer life were infrequently mentioned, and a minority of physicians communicated that the disease was incurable and that no treatment and/or palliative care were options. These findings are of concern, given the low likelihood of medical benefit from phase I trials. Physicians have an important role to play in helping families develop alternative goals when no curative options remain.
RE: Prostate Cancer Mortality in Areas With High and Low Prostate Cancer Incidence
Authors: Paul F. Pinsky
Journal: JNCI Journal of the National Cancer Institute (2014)

Stattin et al. present intriguing findings from an ecologic study that attempts to ascertain the relationship between PSA screening intensity and prostate cancer (PCa) mortality in the counties of Sweden (1). As a surrogate for PSA intensity, they utilize the change in PCa incidence in the county over two relevant time periods. They classify the 24 Swedish counties into three groups—low, medium, and high change in prostate cancer incidence—and then compare PCa mortality in the “high” counties (n = 8) vs the “low” (n = 6) counties, finding a statistically significant rate ratio of 0.87 (95% confidence interval = 0.81 to 0.95). However, their analysis, including the stated confidence interval, was based solely on the combined number of PCa deaths (and person years) in the “high” counties and the combined number of PCa deaths (and person years) in the “low” counties, an analysis that would be appropriate if the “exposure” was known at the individual (person) level for all subjects, as in a randomized trial.

For an ecologic study, though, where the exposure can only be classified at the aggregate level, which is the case here where the level is the county and the exposure is change in incidence in the county, the unit of analysis must be at that same level and not the level of the individual (2). The effective sample size of the Stattin et al. study therefore should be 14 (8 + 6), and the analysis should compare the distribution of PCa mortality rates in the eight high counties vs that in the six low counties, statistically testing whether the two distributions are different (note: statistical adjustments can be performed to account for the fact that the underlying PCa mortality rates are not known but only estimated from the observed counts). Such an analysis could make it considerably more difficult to find a statistically significant result.

Further, to preclude the necessity of somewhat arbitrarily defining cutoffs to determine high vs low counties, a regression analysis of change in incidence vs PCa mortality over all (24) counties would be a standard statistical method for such an ecologic study. For example, a study of ultraviolet (UV) light (among other factors) and bladder cancer takes the mean UV index value (averaged over time) for each of the 50 states and regresses these against the states’ corresponding bladder cancer incidence rates (3).

Until the standard analyses appropriate for ecologic studies are performed, and the results shared, readers will not have confidence in the authors’ stated conclusion of a statistically significant relationship between PCa mortality and change in PCa incidence.