tbuckley/cabot-search huggingface dataset:
Predictive Value of Plasma HIV RNA Level on Rate of CD4 T-Cell Decline in Untreated HIV Infection
Authors: Benigno Rodríguez, Ajay K. Sethi, Vinay K. Cheruvu, Wilma Mackay, Ronald J. Bosch, Mari Kitahata, Stephen L. Boswell, W. Christopher Mathews, David R. Bangsberg, Jeffrey Martin, Christopher C. Whalen, Scott Sieg, Suhrida Yadavalli, Steven G. Deeks, Michael M. Lederman
Journal: JAMA (2006)

Plasma human immunodeficiency virus (HIV) RNA level predicts HIV disease progression, but the extent to which it explains the variability in rate of CD4 cell depletion is poorly characterized.To estimate the proportion of variability in rate of CD4 cell loss predicted by presenting plasma HIV RNA levels in untreated HIV-infected persons.Repeated-measures analyses of 2 multicenter cohorts, comprising observations beginning on May 12, 1984, and ending on August 26, 2004. Analyses were conducted between August 2004 and March 2006.Two cohorts of HIV-infected persons: patients followed up at 4 US teaching medical institutions or participating in either the Research in Access to Care for the Homeless Cohort (REACH) or the San Francisco Men's Health Study (SFMHS) cohorts and participants in the Multicenter AIDS Cohort Study (MACS) cohort.Antiretroviral treatment-naive, chronically HIV-infected persons (n = 1289 and n = 1512 for each of the 2 cohorts) untreated during the observation period (> or =6 months) and with at least 1 HIV RNA level and 2 CD4 cell counts available. Approximately 35% were nonwhite, and 35% had risk factors other than male-to-male sexual contact.The extent to which presenting plasma HIV RNA level could explain the rate of model-derived yearly CD4 cell loss, as estimated by the coefficient of determination (R2).In both cohorts, higher presenting HIV RNA levels were associated with greater subsequent CD4 cell decline. In the study cohort, median model-estimated CD4 cell decrease among participants with HIV RNA levels of 500 or less, 501 to 2000, 2001 to 10,000, 10,001 to 40,000, and more than 40,000 copies/mL were 20, 39, 48, 56, and 78 cells/microL, respectively. Despite this trend across broad categories of HIV RNA levels, only a small proportion of CD4 cell loss variability (4%-6%) could be explained by presenting plasma HIV RNA level. Analyses using multiple HIV RNA measurements or restricting to participants with high HIV RNA levels improved this correlation minimally (R2, 0.09), and measurement error was estimated to attenuate these associations only marginally (deattenuated R2 in the 2 cohorts, 0.05 and 0.08, respectively).Presenting HIV RNA level predicts the rate of CD4 cell decline only minimally in untreated persons. Other factors, as yet undefined, likely drive CD4 cell losses in HIV infection. These findings have implications for treatment decisions in HIV infection and for understanding the pathogenesis of progressive immune deficiency.
Sociobehavioral aspects of periodontal disease
Authors: W. Murray Thomson, Aubrey Sheiham, A. John Spencer
Journal: Periodontology 2000 (2012)

Abstract As one of the most common chronic diseases suffered by adults, periodontitis affects sufferers’ day‐to‐day lives and is a threat to the integrity of the dentition. An important part in the condition’s occurrence is played by sociobehavioural factors, the understanding of which is facilitated by using a number of largely complementary theoretical frameworks. Differences among individuals with respect to their periodontal status at any particular point in their life‐course (and particularly once they are into early middle‐age and beyond) are likely to have resulted from prolonged and differential exposure to the various protective and risk factors that determine their periodontal status. Thus, a sound understanding of the psychosocial pathways of the behaviors that are strongly linked to periodontal disease – and how such psychological factors affect the response of the periodontal tissues to pathogens – is essential for improving periodontal health, whether at the personal level or at the population level. Controlling periodontitis in populations therefore requires a number of complementary strategies. The current state of knowledge of its risk factors means that there is sufficient information to enable control of the disease, and public health officials should include it alongside their efforts to control dental caries. Controlling periodontitis has three strategies: (i) a population strategy for altering life practices, particularly those determining smoking behavior and oral self‐care (plaque removal) in the community; (ii) a secondary prevention strategy to detect and treat people with destructive periodontal disease; and (iii) a high‐risk strategy for treating existing disease and preventing further disease in those at special risk. The Common Risk Factor Approach and the health promotion approach are key aspects of these strategies.
Arterial Thromboembolism in Cancer Patients Treated With Cisplatin: A Systematic Review and Meta-analysis
Authors: Tracy Proverbs-Singh, Sophia K. Chiu, Ziyue Liu, Sonia Seng, Guru Sonpavde, Toni K. Choueiri, Che-Kai Tsao, Menggang Yu, Noah M Hahn, William K. Oh, Matthew D. Galsky
Journal: JNCI Journal of the National Cancer Institute (2012)

Cisplatin has been associated with an increased risk of arterial thromboembolic events (ATEs). However, because this association is mostly based on case reports and retrospective studies, we conducted a systemic review and meta-analysis of randomized controlled trials evaluating the incidence and risk of ATEs associated with cisplatin. Eligible studies included prospective randomized phase II and III trials evaluating cisplatin-based vs non-cisplatin-based chemotherapy in patients with solid tumors, which were identified from PubMed articles published between 1990 and 2010. Incidence rates, relative risks (RRs), and 95% confidence intervals (CIs) were calculated using a random effects model. A total of 8216 patients from 38 trials were included. Among patients treated with cisplatin-based chemotherapy, the summary incidence of ATEs was 0.67% (95% CI = 0.40% to 0.95%), and the RR of ATEs was 1.36 (95% CI = 0.86 to 2.17; P = .19). No increase in ATEs was detected in any prespecified subgroup.
Commissioning perhaps shouldn't follow the American way
Authors: John Hughes
Journal: BMJ (2005)

Rationing in response to NHS deficits: rural patients are likely to be affected most See News, p 1426Editor-News that pressing financial problems have caused NHS trusts in Suffolk to set new "thresholds" to treatments such as joint replacements reinforces concerns raised by a recent BMA survey of medical directors of trusts in which over a third of respondents anticipated reductions of key services in response to funding shortfalls. 1 2 What has hitherto escaped comment is how cuts in services are far more likely to be felt in some parts of the country than others.Deficits in the NHS are invariably presented as a problem of financial mismanagement, but the pattern of deficits shows that the current resource allocation model discriminates against particular communities.According to the recently published accounts for 2004-5, 3 89 out of 303 (30%) English primary care trusts ended the year in deficit.The table shows how 301 of these trusts are distributed accorded to fifths of deprivation and rurality.Primary care trusts serving populations that are in both the most rural and the least deprived fifth were most likely to be in financial difficulties.Seventeen of the 25 (68%) in this category were in deficit.These trusts received the lowest funding allocation per head (£995).By contrast, only 3% (one of 34) of the primary care trusts serving populations that are in both the most urban and the most deprived fifths failed to break even in 2004-5.These trusts received the highest funding allocations per head (£1405).This shows that poor financial management can at best only partly explain why some trusts are in deficit.The pattern of deficits implies that NHS funding provides insufficient resources for rural areas, for comparatively affluent areas, and, most particularly, for areas that are both rural and affluent.The risk is that such measures will result in NHS services being subject to a new postcode lottery, in which rural residents are more likely to lose out.
Cancer Incidence Among Those Initiating Insulin Therapy With Glargine Versus Human NPH Insulin
Authors: Til Stürmer, M. Alison Marquis, Haibo Zhou, James B. Meigs, Soo Lim, Lawrence Blonde, Eileen MacDonald, Ray Wang, Lisa M. LaVange, Virginia Pate, John B. Buse
Journal: Diabetes Care (2013)

OBJECTIVE To add to the evidence on comparative long-term effects of insulin analog glargine versus human NPH insulin on the risk for cancer. RESEARCH DESIGN AND METHODS We identified cohorts of initiators of glargine and human NPH without an insulin prescription during the prior 19 months among patients covered by the Inovalon Medical Outcomes Research for Effectiveness and Economics Registry (MORE2 Registry) between January 2003 and December 2010. Patients were required to have a second prescription of the same insulin within 180 days and to be free of cancer. We balanced cohorts on risk factors for cancer outcomes based on comorbidities, comedication, and health care use during the prior 12 months using inverse probability of treatment weighting. Incident cancer was defined as having two claims for cancer (any cancer) or the same cancer (breast, prostate, colon) within 2 months. We estimated adjusted hazard ratios (HRs) and their 95% CI using weighted Cox models censoring for stopping, switching, or augmenting insulin treatment, end of enrollment, and mortality. RESULTS More patients initiated glargine (43,306) than NPH (9,147). Initiators of glargine (NPH) were followed for 1.2 (1.1) years and 50,548 (10,011) person-years; 993 (178) developed cancer. The overall HR was 1.12 (95% CI 0.95–1.32). Results were consistent for breast cancer, prostate cancer, and colon cancer; various durations of treatment; and sensitivity analyses. CONCLUSIONS Patients initiating insulin glargine rather than NPH do not seem to be at an increased risk for cancer. While our study contributes significantly to our evidence base for long-term effects, this evidence is very limited mainly based on actual dynamics in insulin prescribing.
Thrombin plays a pivotal role in vascular re-occlusion after PTCA and coronary thrombolysis
Authors: G. Agnelli
Journal: Cardiovascular Research (1996)

Acute coronary syndromes are the clinical presentations of complex biochemical events which in most cases culminate in intracoronary thrombosis. A central role in the process of intravascular thrombosis is played by thrombin, a glycosylated trypsin-like serine protease with multiple action in vascular biology [l]. In patients with acute coronary syndromes thrombin is generated by the exposure of tissue factor after fissuring or rupture of a coronary plaque. Tissue factor leads to thrombin generation through the activation of the coagulation factors VII and IX and the prothrombinase complex. Once generated, thrombin initiates a positive feed-back autocatalytic loop by directly activating factors V and VIII, thus amplifying its generation by about lOOO-fold. At substrate level, other than activating factors V and VIII, thrombin cleaves fibrinogen to fibrin and activates factor XIII which results in formation of stable, cross-linked fibrin clot. Thrombin binds to a specific receptor on the platelet surface initiating a number of intracellular processes, including ADP and thromboxane A, release and expression of GP IIb/IIIa receptors, which result in platelet aggregation. Thrombin receptors have been cloned from human platelets and vascular smooth muscle cells [2,3]. The activation of thrombin receptor on vascular smooth muscle cells is followed by most of the multiple cellular effects of thrombin, mainly by smooth muscle cell mitogenesis and migration. High concentrations of thrombin are present at the time and the site of mechanical injury or PTCA and persist throughout the period of vascular formation. The restenosis process appears to be triggered by the formation of a “neointima”
TR-14 * A FEASIBILITY AND RANDOMIZED PHASE II STUDY OF VORINOSTAT, BEVACIZUMAB, OR TEMOZOLOMIDE DURING RADIATION FOLLOWED BY MAINTENANCE CHEMOTHERAPY IN NEWLY-DIAGNOSED PEDIATRIC HIGH-GRADE GLIOMA: CHILDREN'S ONCOLOGY GROUP STUDY ACNS0822
Authors: L. M. Hoffman, J. Geller, J. Leach, D. Boue, R. Drissi, L. Chen, M. Krailo, A. P. Panandiker, L. Chow, D. Haas-Kogan, S. Jogal, M. Nelson, R. Jakacki, M. Kieran, K. Cohen, I. Pollack, A. Gajjar, M. Fouladi
Journal: Neuro-Oncology (2015)

BACKGROUND: High-grade gliomas (HGGs) in children consistently demonstrate poor outcome despite multi-modal therapy. ACNS0822 was a feasibility and phase II trial in newly-diagnosed pediatric HGG. METHODS: In the feasibility study, patients received vorinostat 230 mg/m2/dose daily during radiation therapy (RT). In the phase II study, patients were randomized to one of three radiosensitizing agents during RT: Arm A [vorinostat 230 mg/m2/dose on Days 1-5 weekly], Arm B [temozolomide (TMZ) 90 mg/m2/dose daily], and Arm C [bevacizumab (BEV) 10 mg/kg/dose on Days 22 and 36]. All patients received BEV (10 mg/kg/dose every 2 weeks) + TMZ (200 mg/m2/dose on Days 1-5 q 28 days) for maintenance therapy × 12 cycles. The primary objectives were to determine 1) the feasibility of administering vorinostat during RT and 2) the 1-year event-free survival (EFS) of vorinostat or BEV with RT versus TMZ with RT as the historical control followed by maintenance chemotherapy. RESULTS: Six eligible patients were enrolled on the feasibility study; none experienced a dose limiting toxicity. The 95 patients enrolled (92 eligible) on the phase II study, were randomized to Arm A (vorinostat, n = 31), Arm B (TMZ, n = 29), and Arm C (BEV, n = 32). One-year EFS for Arms A, B, and C were 36.1 ± 10.4%, 54.8± 10.2%, 38.5 ± 10.1%, respectively. All chemoradiotherapy arms, and the maintenance arm were well-tolerated. The most common grade 3/4 toxicities in maintenance therapy included thrombocytopenia (9.6%), neutropenia (7%), and leukopenia (3.6%). Intracranial hemorrhage possibly attributable to BEV was reported in 2 patients in maintenance cycles 2 [grade 3] and 7 [grade 2]. There were no therapy-related deaths. CONCLUSION: Vorinostat (230 mg/m2/dose weekly) was tolerable during RT, as was maintenance therapy with BEV + TMZ. However, neither vorinostat, nor BEV proved superior to TMZ as a radiosensitizer in pediatric HGG.
Ongoing outbreak of Shigella flexneri serotype 3a in men who have sex with men in England and Wales, data from 2009–2011
Authors: M L Borg, A Modi, A Tostmann, M Gobin, J Cartwright, C Quigley, P D Crook, N Boxall, J Paul, T Cheasty, N Gill, G Hughes, I Simms, I Oliver
Journal: Eurosurveillance (2012)

Diagnoses of Shigella flexneri in the United Kingdom (UK) are usually travel-related. However, since 2009, there has been an overall increase in UK-acquired cases. The Health Protection Agency has been investigating a national outbreak of S. flexneri detected in 2011 and which is still ongoing. Cases occurred mostly in men who have sex with men and were of serotype 3a. The investigation aimed at obtaining epidemiological data to inform targeted outbreak management and control.
Major Histocompatibility Complex Class II–Positive Cortical Epithelium Mediates the Selection of Cd4+25+ Immunoregulatory T Cells
Authors: Steven J. Bensinger, Antonio Bandeira, Martha S. Jordan, Andrew J. Caton, Terri M. Laufer
Journal: The Journal of Experimental Medicine (2001)

CD4+25+ T cells are a unique population of immunoregulatory T cells which are critical for the prevention of autoimmunity. To address the thymic selection of these cells we have used two models of attenuated thymic deletion. In K14-Aβb mice, major histocompatibility complex (MHC) class II I-Ab expression is limited to thymic cortical epithelium and deletion by hematopoietic antigen-presenting cells does not occur. In H2-DMα–deficient mice, MHC class II molecules contain a limited array of self-peptides resulting in inefficient clonal deletion. We find that CD4+25+ T cells are present in the thymus and periphery of K14-Aβb and H2-DMα–deficient mice and, like their wild-type counterparts, suppress the proliferation of cocultured CD4+25− effector T cells. In contrast, CD4+25+ T cells from MHC class II–deficient mice do not suppress responder CD4+ T cells in vitro or in vivo. Thus, development of regulatory CD4+25+ T cells is dependent on MHC class II-positive thymic cortical epithelium. Furthermore, analysis of the specificities of CD4+25+ T cells in K14-Aβb and H2-DMα–deficient mice suggests that a subset of CD4+25+ T cells is subject to negative selection on hematopoietic antigen-presenting cells.
Myeloid TGF-β Responsiveness Promotes Metastases
Authors: Fernando Souza-Fonseca-Guimaraes, Mark J. Smyth
Journal: Cancer Discovery (2013)

Abstract Summary: Tumor-induced immune suppression is a major impediment to many potentially effective cancer therapies. TGF-β has previously been described as having both tumor-promoting and tumor-suppressive characteristics. In this issue of Cancer Discovery, Pang and colleagues show that myeloid-specific TGF-β signaling is a critical mediator in tumor metastasis. These findings point to a more specific means to reduce cancer immunosuppression, prevent metastasis, and minimize treatment-related adverse events. Cancer Discov; 3(8); 846–8. ©2013 AACR. See related article by Pang et al., p. 936
RIP3, a kinase promoting necroptotic cell death, mediates adverse remodelling after myocardial infarction
Authors: Mark Luedde, Matthias Lutz, Natalie Carter, Justyna Sosna, Christoph Jacoby, Mihael Vucur, Jérémie Gautheron, Christoph Roderburg, Nadine Borg, Florian Reisinger, Hans-Joerg Hippe, Andreas Linkermann, Monika J. Wolf, Stefan Rose-John, Renate Lüllmann-Rauch, Dieter Adam, Ulrich Flögel, Mathias Heikenwalder, Tom Luedde, Norbert Frey
Journal: Cardiovascular Research (2014)

Programmed necrosis (necroptosis) represents a newly identified mechanism of cell death combining features of both apoptosis and necrosis. Like apoptosis, necroptosis is tightly regulated by distinct signalling pathways. A key regulatory role in programmed necrosis has been attributed to interactions of the receptor-interacting protein kinases, RIP1 and RIP3. However, the specific functional role of RIP3-dependent signalling and necroptosis in the heart is unknown. The aims of this study were thus to assess the significance of necroptosis and RIP3 in the context of myocardial ischaemia.Immunoblots revealed strong expression of RIP3 in murine hearts, indicating potential functional significance of this protein in the myocardium. Consistent with a role in promoting necroptosis, adenoviral overexpression of RIP3 in neonatal rat cardiomyocytes and stimulation with TNF-α induced the formation of a complex of RIP1 and RIP3. Moreover, RIP3 overexpression was sufficient to induce necroptosis of cardiomyocytes. In vivo, cardiac expression of RIP3 was up-regulated upon myocardial infarction (MI). Conversely, mice deficient for RIP3 (RIP3(-/-)) showed a significantly better ejection fraction (45 ± 3.6 vs. 32 ± 4.4%, P < 0.05) and less hypertrophy in magnetic resonance imaging studies 30 days after experimental infarction due to left anterior descending coronary artery ligation. This was accompanied by a diminished inflammatory response of infarcted hearts and decreased generation of reactive oxygen species.Here, we show that RIP3-dependent necroptosis modulates post-ischaemic adverse remodelling in a mouse model of MI. This novel signalling pathway may thus be an attractive target for future therapies that aim to limit the adverse consequences of myocardial ischaemia.
Percutaneous sclerotherapy of a giant mediastinal lymphangioma
Authors: A. Desir, B. Ghaye, B. Duysinx, R. F. Dondelinger
Journal: European Respiratory Journal (2008)

The present study reports a case of percutaneous sclerotherapy of a giant mediastinal cystic lymphangioma using Ethibloc® (Ethicon, Norderstedt, Germany) and absolute ethanol in a 59-yr-old female. The tumour, situated predominantly in a retrocardiac location, caused dyspnoea and dysphagia by compression and was considered unresectable. Follow-up computed tomography 3 yrs after treatment showed a 90% volume reduction of the tumour. The patient is currently asymptomatic. To the best of the present authors’ knowledge, percutaneous transthoracic sclerotherapy of a mediastinal lymphangioma has not previously been reported in the literature available in English.
Cellular and Humoral Immune Responses in Type 1 Diabetic Patients Participating in a Phase III GAD-alum Intervention Trial
Authors: Stina Axelsson, Mikael Chéramy, Linda Åkerman, Mikael Pihl, Johnny Ludvigsson, Rosaura Casas
Journal: Diabetes Care (2013)

OBJECTIVE GAD formulated in aluminum hydroxide (GAD-alum) has previously been shown to induce preservation of residual insulin secretion in recent-onset type 1 diabetes, but recent phase II and III GAD-alum trials failed to reach primary outcomes. The European phase III study was therefore closed after 15 months, and only a minority of patients completed the 30 months of follow-up. RESEARCH DESIGN AND METHODS This study aimed to characterize cellular and humoral responses in the Swedish patients (n = 148) participating in the phase III trial, receiving four (4D) or two (2D) GAD-alum doses or placebo. Serum GAD65 antibody (GADA) levels, GADA IgG1–4 subclass distribution, cytokine secretion, and proliferative responses in peripheral blood mononuclear cells (PBMCs) were analyzed. RESULTS The GAD65-induced cytokine profile tended to switch toward a predominant Th2-associated profile over time both in the 2D and 4D group. The groups also displayed increased GADA levels and PBMC proliferation compared with placebo, whereas GADA IgG subclass distribution changed in 4D patients. CONCLUSIONS Both 2D and 4D patients displayed GAD65-specifc cellular and humoral effects after GAD-alum treatment, but at different time points and magnitudes. No specific immune markers could be associated with treatment efficacy.
INITIATION OF ANTIBODY RESPONSES BY DIFFERENT CLASSES OF LYMPHOCYTES
Authors: Samuel Strober
Journal: The Journal of Experimental Medicine (1972)

The life-span and migratory characteristics of rat thoracic duct cells which initiate the adoptive primary and secondary antibody response to diphtheria toxoid (DT) and horse spleen ferritin (HSF) were investigated. The experimental results show that thoracic duct lymphocytes from normal (unimmunized) donors are able to restore the adoptive response of irradiated hosts to HSF. Thoracic duct cells passaged through an intermediate host (intravenous injection and subsequent collection in the thoracic duct lymph) showed a marked reduction in their restorative action as compared with unpassaged cells. In addition, the restorative action of cells from donors treated with thymidine-(3)H for 48 hr before cannulation of the thoracic duct was markedly decreased. This indicates that a population of lymphocytes involved in the adoptive primary response is unable to recirculate from the blood to the lymph and is turning over rapidly (short lived). The nonrecirculating, short-lived lymphocytes are proably "B" cells, since a combination of spleen cells from neonatally thymectomized rats and passaged or thymidine-(3)H-treated cells restores a vigorous response to HSF. On the other hand, passaged or thymidine-(3)H-treated thoracic duct cells from donors immunized to DT or HSF are able to restore a vigorous adoptive secondary antibody response. Experiments with the hapten-protein conjugate, DNP-DT, show that the majority of both helper ("T") and precursor ("B") cells are able to recirculate and are slowly turning over (long lived). The findings suggest that T lymphocytes involved in both the primary and secondary antibody response are recirculating, long-lived cells. However, B lymphocytes involved in the primary response are nonrecirculating, short-lived cells ("B(1)" cells) which undergo a fundamental physiological change to recirculating, long-lived cells ("B(2)" cells) involved in the secondary antibody response.