tbuckley/cabot-search huggingface dataset:
Association Between Severe Hypoglycemia, Adverse Macrovascular Events, and Inflammation in the Edinburgh Type 2 Diabetes Study
Authors: Rachel Bedenis, Anna H. Price, Christine M. Robertson, Jo R. Morling, Brian M. Frier, Mark W.J. Strachan, Jackie F. Price
Journal: Diabetes Care (2014)

To determine whether a history of severe hypoglycemia was associated with an increased risk of subsequent macrovascular events in people with type 2 diabetes and to explore possible mediation of this association by inflammation.A cohort of 1,066 adults aged 60-75 years with type 2 diabetes was evaluated prospectively. Baseline history of severe hypoglycemia and plasma levels of the inflammatory markers C-reactive protein, fibrinogen, interleukin-6, and tumor necrosis factor-α were recorded. Their association with incident macrovascular events after 4 years was explored.At baseline, 87 participants (8.2%) reported one or more episodes of severe hypoglycemia within the preceding year, and at follow-up 99 participants (9.3%) had suffered a new macrovascular event. Hypoglycemia was associated with increased odds of macrovascular events (odds ratio [OR] 2.11 [95% CI 1.06, 4.21], P = 0.035), including coronary heart events (OR 2.44 [95% CI 1.13, 5.26], P = 0.023), largely due to increased myocardial infarction (OR 4.02 [95% CI 1.54, 10.48], P = 0.004). Hypoglycemia was also associated with increased levels of inflammatory markers, including a general inflammation factor derived using principal-components analysis (P = 0.030, after adjustment for cardiometabolic risk factors). However, the significant association between hypoglycemia and macrovascular events persisted after adjustment for inflammatory markers.The odds of suffering a macrovascular event were higher in patients with type 2 diabetes who had a history of severe hypoglycemia. There was no evidence that a proinflammatory state had a major role in mediating this association.
Heterozygosity for a Loss-of-Function Mutation in GALNT2 Improves Plasma Triglyceride Clearance in Man
Authors: Adriaan G. Holleboom, Helen Karlsson, Ruei-Shiuan Lin, Thomas M. Beres, Jeroen A. Sierts, Daniel S. Herman, Erik S.G. Stroes, Johannes M. Aerts, John J.P. Kastelein, Mohammad M. Motazacker, Geesje M. Dallinga-Thie, Johannes H.M. Levels, Aeilko H. Zwinderman, Jonathan G. Seidman, Christine E. Seidman, Stefan Ljunggren, Dirk J. Lefeber, Eva Morava, Ron A. Wevers, Timothy A. Fritz, Lawrence A. Tabak, Mats Lindahl, G. Kees Hovingh, Jan Albert Kuivenhoven
Journal: Cell Metabolism (2011)
Spreading tolerance by converting
Authors: Hema Bashyam
Journal: The Journal of Experimental Medicine (2008)

Unlike some religious leaders, suppressive T cells need more than just charisma to spread messages of tolerance: the cells rely on a cell surface cytokine complex to convert others, according to Andersson et al. (page 1975).






Figure 1

Naive-turned-suppressor cells dampen colitis (left).




Regulatory T (T reg) cells suppress other T cells in part via the cytokine TGF-β, which can convert naive CD4+ T cells into suppressor cells. Andersson et al. now find that naive CD4+ T cells turn into suppressor cells only when they bump into T reg cells that have an inactive TGF-β complex on their surface. Proteolysis of the inactive complex, which liberates soluble protein, was required for conversion. Inhibiting the protease or swamping the cells with inactive complex prevented cleavage and thus conversion. The converted cells could suppress gut inflammation when transferred into mice suffering from colitis.

Other immune cells also secrete soluble TGF-β, but they do not seem to force conversion—at least in this system. Previous experiments showed that naive T cells cultured with T reg cell–depleted spleen cells, which secrete TGFβ, fail to convert. Non-T reg cells don't express the inactive surface complex, so perhaps its cleavage is needed to trigger other conversion-supporting signals.

The latent TGF-β complex was present only on T reg cells that had been stimulated via their T cell receptors. This specificity might allow T reg cells to limit conversion by delivering the TGF-β signal only to T cells bound to the same antigen-presenting cell and thus on the verge of being activated. “We wouldn't want T reg cells to run amok and convert all naive T cells,” says lead author Ethan Shevach. How often T reg cells rely on this mechanism and its impact on the induction of tolerance in vivo are unknown.
c-Myc and Cancer Metabolism
Authors: Donald M. Miller, Shelia D. Thomas, Ashraful Islam, David Muench, Kara Sedoris
Journal: Clinical Cancer Research (2012)

The processes of cellular growth regulation and cellular metabolism are closely interrelated. The c-Myc oncogene is a "master regulator" which controls many aspects of both of these processes. The metabolic changes which occur in transformed cells, many of which are driven by c-Myc overexpression, are necessary to support the increased need for nucleic acids, proteins, and lipids necessary for rapid cellular proliferation. At the same time, c-Myc overexpression results in coordinated changes in level of expression of gene families which result in increased cellular proliferation. This interesting duality of c-Myc effects places it in the mainstream of transformational changes and gives it a very important role in regulating the "transformed phenotype." The effects induced by c-Myc can occur either as a "primary oncogene" which is activated by amplification or translocation or as a downstream effect of other activated oncogenes. In either case, it appears that c-Myc plays a central role in sustaining the changes which occur with transformation. Although efforts to use c-Myc as a therapeutic target have been quite frustrating, it appears that this may change in the next few years.
Outpatient Nephrology Referral Rates after Acute Kidney Injury
Authors: Edward D. Siew, Josh F. Peterson, Svetlana K. Eden, Adriana M. Hung, Theodore Speroff, T. Alp Ikizler, Michael E. Matheny
Journal: Journal of the American Society of Nephrology (2011)

AKI associates with an increased risk for the development and progression of CKD and mortality. Processes of care after an episode of AKI are not well described. Here, we examined the likelihood of nephrology referral among survivors of AKI at risk for subsequent decline in kidney function in a US Department of Veterans Affairs database. We identified 3929 survivors of AKI hospitalized between January 2003 and December 2008 who had an estimated GFR (eGFR) <60 ml/min per 1.73 m(2) 30 days after peak injury. We analyzed time to referral considering improvement in kidney function (eGFR ≥60 ml/min per 1.73 m(2)), dialysis initiation, and death as competing risks over a 12-month surveillance period. Median age was 73 years (interquartile range, 62-79 years) and the prevalence of preadmission kidney dysfunction (baseline eGFR <60 ml/min per 1.73 m(2)) was 60%. Overall mortality during the surveillance period was 22%. The cumulative incidence of nephrology referral before dying, initiating dialysis, or experiencing an improvement in kidney function was 8.5% (95% confidence interval, 7.6-9.4). Severity of AKI did not affect referral rates. These data demonstrate that a minority of at-risk survivors are referred for nephrology care after an episode of AKI. Determining how to best identify survivors of AKI who are at highest risk for complications and progression of CKD could facilitate early nephrology-based interventions.
The Social Brain, Stress, and Psychopathology
Authors: Tor D. Wager, Peter J. Gianaros
Journal: JAMA Psychiatry (2014)

these domains are prominent with NMDA-channel blockade. As a phase 2 exploratory study, these results are quite encouraging and consistent with a priori hypotheses. And now the bad news. On January 21, 2014, Roche announced that 2 phase 3 trials of bitopertin for negative symptoms failed to achieve primary endpoints. Once again,we are faced with the dilemma of an initial rigorous trial providing support for a compound that is well grounded in preclinical andclinical studies, followedbya failure to replicate.Wemust wait until more information is available about the more recentnegativestudies todeterminewhether the failure to replicate can be understood by aspects of study design or implementation or by participant heterogeneity. It is clear that advances in basic neuroscience and drug developmentmust be matched by improved clinical trial methods including identificationofbiomarkers to reduce theproblemofpatientheterogeneity. Otherwise, promising new agents associated with moderate therapeutic effects may be abandoned despite the potential for largeandconsistenteffects if apersonalizedmedicine approach can be achieved.
Itchy folliculitis and human immunodeficiency virus infection: clinicopathological and immunological features, pathogenesis and treatment
Authors: None Fearfield, None Rowe, None Francis, None Bunker, None Staughton
Journal: British Journal of Dermatology (1999)

The predominant itchy folliculitis associated with human immunodeficiency virus (HIV) infection appears to be an eosinophilic folliculitis (EF). This is characterized by lytic degeneration of sebaceous glands and an inflammatory infiltrate in which eosinophils and CD8+ T lymphocytes predominate. All patients have low CD4 counts and present late on in their HIV disease. Lesional distribution is mainly truncal, with a significant proportion also having facial involvement. Our prospective survey has shown that it is impossible to differentiate clinically between infective folliculitis and EF, and we recommend therefore that all cases are biopsied. We review the clinicopathological and immunological aspects of HIV-associated itchy folliculitis, in particular HIV-associated EF as well as current theories on pathogenesis and treatment. We suggest that HIV-associated EF is an autoimmune disease with the sebocyte or some constituent of sebum acting as the autoantigen.
Clinical and cost effectiveness of mobile phone supported self monitoring of asthma: multicentre randomised controlled trial
Authors: D. Ryan, D. Price, S. D. Musgrave, S. Malhotra, A. J. Lee, D. Ayansina, A. Sheikh, L. Tarassenko, C. Pagliari, H. Pinnock
Journal: BMJ (2012)

To determine whether mobile phone based monitoring improves asthma control compared with standard paper based monitoring strategies.Multicentre randomised controlled trial with cost effectiveness analysis.UK primary care.288 adolescents and adults with poorly controlled asthma (asthma control questionnaire (ACQ) score ≥ 1.5) from 32 practices.Participants were centrally randomised to twice daily recording and mobile phone based transmission of symptoms, drug use, and peak flow with immediate feedback prompting action according to an agreed plan or paper based monitoring.Changes in scores on asthma control questionnaire and self efficacy (knowledge, attitude, and self efficacy asthma questionnaire (KASE-AQ)) at six months after randomisation. Assessment of outcomes was blinded. Analysis was on an intention to treat basis.There was no significant difference in the change in asthma control or self efficacy between the two groups (ACQ: mean change 0.75 in mobile group v 0.73 in paper group, mean difference in change -0.02 (95% confidence interval -0.23 to 0.19); KASE-AQ score: mean change -4.4 v -2.4, mean difference 2.0 (-0.3 to 4.2)). The numbers of patients who had acute exacerbations, steroid courses, and unscheduled consultations were similar in both groups, with similar healthcare costs. Overall, the mobile phone service was more expensive because of the expenses of telemonitoring.Mobile technology does not improve asthma control or increase self efficacy compared with paper based monitoring when both groups received clinical care to guidelines standards. The mobile technology was not cost effective.Clinical Trials NCT00512837.
REG-γ associates with and modulates the abundance of nuclear activation-induced deaminase
Authors: Yasuhiro Uchimura, Lance F. Barton, Cristina Rada, Michael S. Neuberger
Journal: The Journal of Experimental Medicine (2011)

Activation-induced deaminase (AID) acts on the immunoglobulin loci in activated B lymphocytes to initiate antibody gene diversification. The abundance of AID in the nucleus appears tightly regulated, with most nuclear AID being either degraded or exported back to the cytoplasm. To gain insight into the mechanisms regulating nuclear AID, we screened for proteins interacting specifically with it. We found that REG-γ, a protein implicated in ubiquitin- and ATP-independent protein degradation, interacts in high stoichiometry with overexpressed nuclear AID as well as with endogenous AID in B cells. REG-γ deficiency results in increased AID accumulation and increased immunoglobulin class switching. A stable stoichiometric AID-REG-γ complex can be recapitulated in co-transformed bacteria, and REG-γ accelerates proteasomal degradation of AID in in vitro assays. Thus, REG-γ interacts, likely directly, with nuclear AID and modulates the abundance of this antibody-diversifying but potentially oncogenic enzyme.
Lessons Learned from the Management of a Rare Genetic Cancer
Authors: Gilbert J. Cote, Robert F. Gagel
Journal: New England Journal of Medicine (2003)

Less than a decade after the identification of activating mutations of the rearranged during transfection (RET) proto-oncogene in multiple endocrine neoplasia type 2 (MEN-2), a clinical syndrome characterized by medullary thyroid carcinoma, pheochromocytoma, and hyperparathyroidism, germ-line genetic testing has become the basis for therapeutic decisions in affected patients. Indeed, consensus was reached at the International Multiple Endocrine Neoplasia meeting in Gubbio, Italy, in 1999 that the decision to perform a thyroidectomy in a young child should be based on the presence or absence of a germ-line RET mutation.1 Such rapid progress to consensus is remarkable in any scientific . . .
mTOR Inhibitors Synergize on Regression, Reversal of Gene Expression, and Autophagy in Hepatocellular Carcinoma
Authors: Hala Elnakat Thomas, Carol A. Mercer, Larissa S. Carnevalli, Jongsun Park, Jesper B. Andersen, Elizabeth A. Conner, Kazuhiro Tanaka, Tomoo Matsutani, Akio Iwanami, Bruce J. Aronow, Liu Manway, S. Michel Maira, Snorri S. Thorgeirsson, Paul S. Mischel, George Thomas, Sara C. Kozma
Journal: Science Translational Medicine (2012)

Combination therapy causes gene reprogramming, autophagy, and tumor regression in a mouse model approximating human HCC.
Impact of Three Courses of Intensified CHOP Prior to High-Dose Sequential Therapy Followed by Autologous Stem-Cell Transplantation As First-Line Treatment in Poor-Risk, Aggressive Non-Hodgkin's Lymphoma: Comparative Analysis of Dutch-Belgian Hemato-Oncology Cooperative Group Studies 27 and 40
Authors: Gustaaf W. van Imhoff, Bronno van der Holt, Marius A. MacKenzie, Mars B. van′t Veer, Pierre W. Wijermans, Gerrit J. Ossenkoppele, Harry C. Schouten, Pieter Sonneveld, Monique M.C. Steijaert, Philip M. Kluin, Hanneke C. Kluin-Nelemans, Leo F. Verdonck
Journal: Journal of Clinical Oncology (2005)

Timing, appropriate amount, and composition of treatment before high-dose therapy and autologous stem-cell transplantation (ASCT) in patients with poor-risk, aggressive non-Hodgkin's lymphoma (NHL) are still unknown. We conducted two consecutive multicenter phase II trials with up-front, high-dose, sequential chemotherapy and ASCT in poor-risk, aggressive NHL. Both trials had identical inclusion criteria and only differed in amount and duration of induction treatment before ASCT.Between 1994 and 2001, 147 newly diagnosed, poor-risk, aggressive NHL patients, age < or = 65 years with stage III to IV and lactate dehydrogenase (LDH) more than 1.5x upper limit of normal (ULN), entered the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON) -27 and HOVON-40 trials. Treatment in HOVON-27 consisted of two up-front, high-dose induction courses followed by carmustine, etoposide, cytarabine, and melphalan plus ASCT in responding patients. In HOVON-40, the same treatment was preceded by three intensified courses of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP).Patient characteristics in both trials were comparable: 80% had diffuse large B-cell lymphoma, 77% had stage IV disease, and median LDH levels were 3.1x ULN. Complete remission (CR) in both trials was 45% to 51%. Before ASCT, CR was 14% in HOVON-27 versus 28% in HOVON-40 (P = .03). Treatment failure was similar (27%). Four-year survival estimates in HOVON-27 compared with HOVON-40 were overall survival, 21% v 50% (P = .007); event-free survival, 15% v 49% (P = .0001); and disease-free survival, 34% v 74% (P = .008). This different outcome favoring HOVON-40 remained highly significant when correcting for competing risk factors in multivariate analysis.In patients with poor-risk, aggressive NHL, addition of intensified CHOP before up-front, high-dose, sequential therapy and ASCT significantly improved the duration of response and survival.
286. Conditionally Replicating Adenoviral Vectors for Glioblastoma Treatment
Journal: Molecular Therapy (2004)

Metargidin, a transmembrane protein of the adamalysin family, and integrins, e.g. a5b1 and av, are preferentially expressed on endothelial cells upon angiogenesis. Furthermore, metargidin interacts with these integrins via its disintegrin domain. In this study, recombinant human disintegrin domain (RDD) was produced in Escherichia coli by subcloning its cDNA into the pGEX-2T vector, and the effect of purified RDD on different steps of angiogenesis was evaluated. At concentrations of 2–10 μg/ml, RDD exhibited inhibitory activities in a variety of in vitro functional assays, including endothelial cell proliferation and adhesion on the integrin substrates, fibronectin, vitronectin or fibrinogen. RDD (10 μg/ml) totally abrogated endothelial cell migration and blocked most capillary formation in a tridimensional fibrin gel. To test RDD efficacy in vivo, the RDD gene inserted into pBi vector containing a tetracycline-inducible promoter was eletrotransferred into nude mouse muscle. RDD was successfully synthesized by muscle cells in vivo as shown by immunolabeling and Western blotting. In addition, 78% less MDA-MB-231 tumor growth, associated with strong inhibition of tumor angiogenesis, was observed in athymic mice bearing electrotransferred RDD. Moreover, in the presence of RDD, 74% fewer B16F10 melanoma lung metastases were found in C57BL/6 mice. Taken together, these results identified this RDD as a potent intrinsic inhibitor of angiogenesis, tumor growth and metastasis, making it a promising tool for use in anticancer treatment.
Is doxycycline the right choice to treat an acute respiratory chlamydia psittaci infection
Authors: Annette Prohl, Carola Ostermann, Markus Lohr, Angela Berndt, Elisabeth Liebler-Tenorio, Michael Rothe, Konrad Sachse, Petra Reinhold
Journal: European Respiratory Journal (2013)

Introduction: Although tetracycline has been known as a front-line antibiotic for treatment of Chlamydia infections, information about its efficacy is contradictory.

Objectives: The aim of this study was to assess the effects of doxycycline treatment in a bovine model of respiratory Chlamydia psittaci (Cp) infection. To address aspects of both human and veterinary medicine, doses were adjusted to humans and cattle.

Animals & Methods: Eighteen calves aged 6-8 weeks were inoculated with Cp as described previously [1]. With appearance of the first clinical signs (about 30 hours after inoculation), doxycycline was applied orally for 13 days (dosis: either 5 mg/kg/day or 10 mg/kg/day). In addition to the two treatment groups (each n=6), six infected calves served as untreated controls. All animals were clinically examined on a daily basis. Broncho-alveolar lavage was performed at days 5 and 9 after inoculation (dpi). At 14 dpi, all animals were sacrificed.

Results : Treatment with doxycycline did not improve clinical outcome. In BALF, no significant differences in cytology, total protein or eicosanoids were found between the groups at any time point. At necropsy, neither the percentage of lung affected nor the morphology of pulmonary lesions differed significantly between the groups. Using quantitative real-time PCR, the amount of chlamydial genome copies detected in the affected lung areas did not differ significantly.

In conclusion , results do not support the use of doxycycline for successful antimicrobial treatment of acute Chlamydia psittaci infection.

Reference: [1] Reinhold et al. (2012) A bovine model of respiratory Chlamydia psittaci infection: challenge-dose titration. PLoS ONE 7, 1:e30125.
Psychopathology in Patients with Severe Asthma Is Associated with Increased Health Care Utilization
Authors: ANNEKE ten BRINKE, MARIJE E. OUWERKERK, AEILKO H. ZWINDERMAN, PHILIP SPINHOVEN, ELISABETH H. BEL
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

Severe asthma accounts for the majority of health costs for this disease, which is mainly related to the treatment of failed control. Several psychosocial factors have been associated with poor asthma control, but the question remains whether psychiatric disorder in patients with severe asthma predisposes for increased health care utilization. In the present study we compared outpatients with severe asthma with and without psychological dysfunctioning with respect to health care utilization. All patients used high dose inhaled corticosteroids and long-acting bronchodilators for more than 1 yr, and had difficult-to-control asthma, requiring one or more courses of corticosteroids during the past year or maintenance therapy with prednisone. Medical history was taken and health care utilization questionnaires were completed. The General Health Questionnaire (GHQ) was used to identify psychiatric cases (GHQ-12 score of ⩾ 6). There were no differences between the psychiatric cases (n = 21) and the noncases (n = 77) with respect to demographic and objective disease characteristics. However, the psychiatric cases had increased odds ratios (OR) for frequent visits to GP (OR = 5.9), frequent emergency visits (OR = 5.3), frequent exacerbations (OR = 12.4), and frequent hospitalizations (OR = 4.8) as compared with the nonpsychiatric patients. The present findings suggest that the morbidity and costs of asthma might be related to the level of psychological dysfunctioning in patients with severe asthma rather than to asthma severity per se, thereby identifying an area of potential intervention.