tbuckley/cabot-search huggingface dataset:
Abstract 19791: Echocardiography Derived Velocity Time Integral is Associated with Double Switch Outcomes in Congenitally Corrected Transposition of the Great Arteries
Authors: Shreya Moodley, Sowmya Balasubramanian, Theresa Tacy, Frank Hanley, Frandics Chan, Rajesh Punn
Journal: Circulation (2014)

Introduction:  Congenitally corrected transposition of the great arteries (CCTGA) is a rare form of congenital heart disease characterized by atrioventricular and ventriculoarterial discordance. Management is controversial; options include observation, physiologic repair and anatomic repair by the double switch operation (DSO). Assessment of morphologic left ventricle (LV) preparedness is key in determining DSO timing, although exact criteria are lacking. Cardiac MRI is the current standard technique to assess LV adequacy prior to DSO. The purpose of our study was to determine if echocardiographic (echo) or MRI measures of the LV predict outcomes.   Methods:  A retrospective review of CCTGA patients eligible for DSO at Lucile Packard Children’s Hospital from 2000-2014 was conducted. Inclusion criteria were: 1) age &lt18 years, 2) adequate pre-surgical echo and MRI images and 3) clinical follow-up information available. Post-processing of echo images was performed to obtain measurements of LV structure and function. Measurements included 5/6 and 2/3 area-length ejection fraction (EF) and mass, LV eccentricity index, LV posterior wall thickness, LV tissue Doppler velocities, tricuspid valve regurgitation severity, pulmonary artery (PA) pressure gradient and PA velocity time integral (VTI). MRI measurements included LV mass and EF. Outcomes included achieving DSO and freedom from death, transplant and heart failure at last follow up.   Results:  31 patients met inclusion criteria (7.3 ± 7.8 years). Peak PA VTI correlated significantly with outcomes. Receiver operating curve analysis showed that a VTI of &gt 1.17cm predicted successful DSO and freedom from death, transplant and heart failure at last follow up, with a respective sensitivity of 80% and 83% and specificity of 86% and 78% (AUC 0.88-0.92, p &lt 0.0001). Inter and intra-observer variability for VTI measurements was excellent (intraclass correlation coefficients &gt 0.95). MRI and other echo measurements of LV mass and function as well as PA pressure gradient did not correlate with outcome.   Conclusion:  PA VTI is a readily available and highly reproducible measurement that reflects morphologic LV performance and predicts outcomes in CCTGA patients better than conventional MRI assessment.
B7DC/PDL2 Promotes Tumor Immunity by a PD-1–independent Mechanism
Authors: Xingluo Liu, Jian Xin Gao, Jing Wen, Lijie Yin, Ou Li, Tao Zuo, Thomas F. Gajewski, Yang-Xin Fu, Pan Zheng, Yang Liu
Journal: The Journal of Experimental Medicine (2003)

B7H1 (PDL1) and B7DC (PDL2) are two new members of the B7 family that can interact with PD-1, a putative negative regulator for immune function. Recent studies have provided evidence for inhibitory functions of both members via PD-1. Meanwhile, compelling evidence exists for costimulatory function of both members. Here we demonstrate that expression of B7DC on the tumor cells promotes CD8 T cell–mediated rejection of tumor cells, at both the induction and effector phase of antitumor immunity. Moreover, B7DC binds to PD-1(−/−) cells and enhances T cell killing in a PD-1–independent mechanism. Our results demonstrate a novel pathway for B7DC to promote tumor immunity and may reconcile the apparently contradictory findings on the function of B7DC.
Cutaneous vasculitis complicating coeliac disease.
Authors: S Meyers, S Dikman, H Spiera, N Schultz, H D Janowitz
Journal: Gut (1981)

A 38 year old female, with chronic uncontrolled coeliac disease, presented with the rare complication of cutaneous leucocytoclastic vasculitis. Detailed study failed to identify any cause for the vasculitis, other than the underlying coeliac disease. Haematuria and proteinuria with mesangial nephritis were also demonstrated on renal biopsy with electron microscopic study. It is speculated that exogenous or endogenous antigens permeated the abnormal small bowel mucosa leading to formation of circulating immune complexes. Subsequent tissue deposition of these complexes then resulted in vasculitis and nephritis. The skin lesions cleared completely after treatment with a strict gluten free diet.
Comparative analysis of the therapeutic potential of two inducible Treg cell populations in experimental model of arthritis
Authors: Delphine Martire, Julie Quentin, Anne-Laure Mausset-Bonnefont, Hélène Asnagli, Nathalie Belmonte, Arnaud Foussat, Christian Jorgensen, Pascale Louis-Plence
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Backgroundand objectives</h3> Adoptive cell transfer of T regulatory (Treg) cells is a promising approach to restore tolerance in autoimmune disease. However the various type of Tregs, their doses of injection and their in vivo-suppressive mechanism need to be precisely define to clearly establish which Tregs will be able to dampen efficiently the immune response in the various settings. In this study, the authors compared the therapeutic potential of two IL10-secreting Tregs: Tr1 and CD49b-induced Tregs. The authors previously demonstrated that a single injection of iDC-induced CD49b T cells reversed clinical symptoms of arthritis. This inducible CD49b Treg population shares several phenotypic markers as well as immunosuppressive properties compared with the in vitro-expanded IL-10-secreting Tr1 cells. More recently, the authors provide evidence that injections of Tr1 cells, after the onset of the disease, could protect mice from severe arthritis. In the present study the authors perform adoptive cell transfer experiments of these two inducible Treg cells in order to compare their impact on the immune response. <h3>Materials and methods</h3> CD49b Treg cells were generated in naive mice following repetitive injections of iDC. The purification was based on the negative selection of CD4 T cells isolated from the spleen and liver of the iDC-vaccinated mice. Cell sorting experiments were realised to obtain 98% pure CD49b T cells. Collagen type II (bCII) specific Tr1 clones were obtained from TCR transgenic mice and expanded in vitro. Selected clones showed in vitro antigen specificity, Tr1 cytokine profile and IL10- and tumour necrosis factor β-dependent suppressive activity. <h3>Results</h3> Several doses of CD49b or Tr1 cells were injected intravenously at day 28 in established collagen-induced arthritis. Clinical signs of arthritis were scored, as well as biological parameters such as the level of anti-bCII antibodies in sera and the cytokine profile of bCII specific T cells. The authors defined for both Treg cell populations the dose effect in curative settings experiments. One single dose of 3×106 or 1×106 of Tr1 cell administration could reduce the incidence and severity of CIA. Interestingly, higher dose of 10M of Tr1 cells did not improve the disease. In the same manner, the dose of 105 CD4CD49b<sup>+</sup> cells reverse clinical symptom with a lack of efficacy of higher doses. The homing ability and plasticity of Tr1 cells was also investigated. <h3>Conclusions</h3> These results suggest that even if the Treg cells present some similarities, one should precisely define the dose and type of Treg that will be efficient in each experimental setting.
Passenger Mutations Confound Interpretation of All Genetically Modified Congenic Mice
Authors: Tom Vanden Berghe, Paco Hulpiau, Liesbet Martens, Roosmarijn E. Vandenbroucke, Elien Van Wonterghem, Seth W. Perry, Inge Bruggeman, Tatyana Divert, Sze Men Choi, Marnik Vuylsteke, Valery I. Shestopalov, Claude Libert, Peter Vandenabeele
Journal: Immunity (2015)
High prevalence of vertebral deformities in elderly patients with early rheumatoid arthritis: Table 1
Authors: J Ursum, K Britsemmer, D van Schaardenburg, P T A Lips, B A C Dijkmans, W Lems
Journal: Annals of the Rheumatic Diseases (2009)

Generalised osteoporosis and local bone loss is a well-known complication of rheumatoid arthritis (RA). Vertebral fractures are the most common type of osteoporotic fracture and are associated with increased mortality and morbidity.1 The presence of vertebral fractures increases the risk of new vertebral and non-vertebral fractures.2 The prevalence of vertebral deformities in the Dutch population aged over 55 years in women and men is 15% and 12%, respectively.3 For patients with established RA (mean duration 16.6 years), an odds ratio for vertebral deformities of 2.0 was found,4 leading to an expected prevalence of vertebral deformities in elderly RA patients of 30% and 24% for women and men, respectively. As data …
Therapeutic Implications for the Induced Levels of Chk1 in Myc-Expressing Cancer Cells
Authors: Andreas Höglund, Lisa M. Nilsson, Somsundar Veppil Muralidharan, Lisa A. Hasvold, Philip Merta, Martina Rudelius, Viktoriya Nikolova, Ulrich Keller, Jonas A. Nilsson
Journal: Clinical Cancer Research (2011)

The transcription factor c-Myc (or "Myc") is a master regulator of pathways driving cell growth and proliferation. MYC is deregulated in many human cancers, making its downstream target genes attractive candidates for drug development. We report the unexpected finding that B-cell lymphomas from mice and patients exhibit a striking correlation between high levels of Myc and checkpoint kinase 1 (Chk1).By in vitro cell biology studies as well as preclinical studies using a genetically engineered mouse model, we evaluated the role of Chk1 in Myc-overexpressing cells.We show that Myc indirectly induces Chek1 transcript and protein expression, independently of DNA damage response proteins such as ATM and p53. Importantly, we show that inhibition of Chk1, by either RNA interference or a novel highly selective small molecule inhibitor, results in caspase-dependent apoptosis that affects Myc-overexpressing cells in both in vitro and in vivo mouse models of B-cell lymphoma.Our data suggest that Chk1 inhibitors should be further evaluated as potential drugs against Myc-driven malignancies such as certain B-cell lymphoma/leukemia, neuroblastoma, and some breast and lung cancers.
IMC-EB10, an Anti-FLT3 Monoclonal Antibody, Prolongs Survival and Reduces Nonobese Diabetic/Severe Combined Immunodeficient Engraftment of Some Acute Lymphoblastic Leukemia Cell Lines and Primary Leukemic Samples
Authors: Obdulio Piloto, Bao Nguyen, David Huso, Kyu-Tae Kim, Yiwen Li, Larry Witte, Daniel J. Hicklin, Patrick Brown, Donald Small
Journal: Cancer Research (2006)

Abstract The class III receptor tyrosine kinase FLT3 is expressed on the blasts of &amp;gt;90% of patients with B-lineage acute lymphoblastic leukemias (ALL). In addition, it is expressed at extremely high levels in ALL patients with mixed lineage leukemia rearrangements or hyperdiploidy and is sometimes mutated in these same patients. In this report, we investigate the effects of treating ALL cell lines and primary samples with human anti-FLT3 monoclonal antibodies (mAb) capable of preventing binding of FLT3 ligand. In vitro studies, examining the ability of two anti-FLT3 mAbs (IMC-EB10 and IMC-NC7) to affect FLT3 activation and downstream signaling in ALL cell lines and primary blasts, yielded variable results. FLT3 phosphorylation was consistently inhibited by IMC-NC7 treatment, but in some cell lines, IMC-EB10 actually stimulated FLT3 activation, possibly as a result of antibody-mediated receptor dimerization. Through antibody-dependent, cell-mediated cytotoxicity, such an antibody could still prove efficacious against leukemia cells in vivo. In fact, IMC-EB10 treatment significantly prolonged survival and/or reduced engraftment of several ALL cell lines and primary ALL samples in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. This occurred even when IMC-EB10 treatment resulted in FLT3 activation in vitro. Moreover, fluorescence-activated cell sorting and PCR analysis of IMC-EB10-treated NOD/SCID mice surviving 150 days post-leukemic cell injection revealed that FLT3 immunotherapy reduced leukemic engraftment below the level of detection in these assays (&amp;lt;0.001%). Furthermore, in vivo IMC-EB10 treatment did not select for resistant cells, because cells surviving IMC-EB10 treatment remain sensitive to IMC-EB10 cytotoxicity upon retransplantation. In vivo studies involving either partial depletion or activation of natural killer (NK) cells show that most of the cytotoxic effect of IMC-EB10 is mediated through NK cells. Therefore, such an antibody, either naked or conjugated to radioactive isotopes or cytotoxic agents, may prove useful in the therapy of infant ALL as well as childhood and adult ALL patients whose blasts typically express FLT3. (Cancer Res 2006; 66(9): 4843-51)
Response-guided peginterferon therapy in hepatitis B e antigen-positive chronic hepatitis B using serum hepatitis B surface antigen levels
Authors: Milan J. Sonneveld, Bettina E. Hansen, Teerha Piratvisuth, Ji-Dong Jia, Stefan Zeuzem, Edward Gane, Yun-Fan Liaw, Qing Xie, Jenny E. Heathcote, Henry L.-Y. Chan, Harry L.A. Janssen
Journal: Hepatology (2013)

On-treatment levels of hepatitis B surface antigen (HBsAg) may predict response to peginterferon (PEG-IFN) therapy in chronic hepatitis B (CHB), but previously proposed prediction rules have shown limited external validity. We analyzed 803 HBeAg-positive patients treated with PEG-IFN in three global studies with available HBsAg measurements. A stopping-rule based on absence of a decline from baseline was compared to a prediction-rule that uses HBsAg levels of &lt;1,500 IU/mL and &gt;20,000 IU/mL to identify patients with high and low probabilities of response. Patients with an HBsAg level &lt;1,500 IU/mL at week 12 achieved response (HBeAg loss with HBV DNA &lt;2,000 IU/mL at 6 months posttreatment) in 45%. At week 12, patients without a decline in HBsAg achieved a response in 14%, compared to only 6% of patients with HBsAg &gt;20,000 IU/mL, but performance varied across HBV genotype. In patients treated with PEG-IFN monotherapy (n = 465), response rates were low in patients with genotypes A or D if there was no decline of HBsAg by week 12 (negative predictive value [NPV]: 97%-100%), and in patients with genotypes B or C if HBsAg at week 12 was &gt;20,000 IU/mL (NPV: 92%-98%). At week 24, nearly all patients with HBsAg &gt;20,000 IU/mL failed to achieve a response, irrespective of HBV genotype (NPV for response and HBsAg loss 99% and 100%). Conclusion : HBsAg is a strong predictor of response to PEG-IFN in HBeAg-positive CHB. HBV genotype-specific stopping-rules may be considered at week 12, but treatment discontinuation is indicated in all patients with HBsAg &gt;20,000 IU/mL at week 24, irrespective of HBV genotype. (Hepatology 2013;53:872–880)
The Master Switch: The Role of Mast Cells in Autoimmunity and Tolerance
Authors: Blayne A. Sayed, Alison Christy, Mary R. Quirion, Melissa A. Brown
Journal: Annual Review of Immunology (2008)

There are many parallels between allergic and autoimmune responses. Both are considered hypersensitivity responses: pathologies that are elicited by an exuberant reaction to antigens that do not pose any inherent danger to the organism. Although mast cells have long been recognized as central players in allergy, only recently has their role in autoimmunity become apparent. Because of the commonalities of these responses, much of what we have learned about the underlying mast cell–dependent mechanisms of inflammatory damage in allergy and asthma can be used to understand autoimmunity. Here we review mast cell biology in the context of autoimmune disease. We discuss the huge diversity in mast cell responses that can exert either proinflammatory or antiinflammatory activity. We also consider the myriad factors that cause one response to predominate over another in a particular immune setting.
Glomerular Hyperfiltration and the Salt Paradox in Early Type 1 Diabetes Mellitus
Authors: Volker Vallon, Roland C. Blantz, Scott Thomson
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Diabetes mellitus contributes greatly to morbidity, mortality, and overall health care costs. In major part, these outcomes derive from the high incidence of progressive kidney dysfunction in patients with diabetes making diabetic nephropathy a leading cause of end-stage renal disease. A better understanding of the early dysfunctions observed in the diabetic kidney may permit the development of new strategies to prevent diabetic nephropathy. This review proposes a "tubulo-centric" view of glomerular function in early type I diabetes mellitus. The following are particularly discussed (1) the primary role of an increase in reabsorption by the proximal tubule in early glomerular hyperfiltration, (2) the role of sodium-glucose cotransport and tubular growth under these conditions, and (3) the primary role of reabsorption by the proximal tubule for the paradoxical relationship between dietary salt and glomerular filtration rate. Finally, an outline is presented of potential therapeutic implications for the prevention of diabetic kidney disease. E-mail: [email protected]
Ventilator-associated pneumonia
Authors: E. Bouza, C. Brun-Buisson, J. Chastre, S. Ewig, J-Y. Fagon, C.H. Marquette, P. Muñoz, M.S. Niederman, L. Papazian, J. Rello, J-J. Rouby, H. Van Saene, T. Welte
Journal: European Respiratory Journal (2001)

This Task Force was supported and endorsed by the following Societies: European Respiratory Society, European Society of Intensive Care Medicine, European Society of Clinical Microbiology and Infectious Diseases and European Society of Anaesthesiology.

⇓In the last decade, considerable investigational efforts have been made in the field of the management of ventilator-associated pneumonia (VAP). Several studies have provided important insights into the relationship of histology and bacteriology of VAP, which remain fundamental for all future research. Moreover, epidemiological research has allowed establishment of concepts for empiric initial antimicrobial treatment that are expected to improve clinical outcomes. Important contributions have also been made regarding prevention of VAP.



Fig. 1.— 

However, despite these advances, the majority of issues related to the management of VAP remain unresolved and are subject to controversy. This is particularly true for the diagnostic evaluation of the patient with suspected VAP. The lack of consensus regarding the best way to diagnose VAP explains in part why incidence rates vary widely from one study to another, from 5 to >50% of mechanically ventilated intensive care unit (ICU) patients.

In this review, a panel of experts in the field of VAP from four European societies has tried to provide an overview of the most important aspects under debate. In order to stimulate further research and discussion, presentation of the main topics was focussed on the breaking current knowledge. The issue of attributable mortality, which is also a matter of controversy, will not be addressed in this review. Each section of the review has been written in an attempt to answer three main questions: 1) what is not controversial, 2) what is still controversial and 3) what should be investigated? The following topics were reviewed: clinical diagnosis, bacteriological and histological aspects, aetiology, diagnostic techniques, antimicrobial treatment and prevention.

#### What is not controversial?

Clinical criteria for the diagnosis …
S124 Macrophage deletion of vHL results in alternative activation and enhanced lung fibrosis independent of HIF-1
Authors: M. A. Gibbons, P. M. Fitch, A. MacDuff, A. C. Mackinnon, S. J. Forbes, V. Aidinis, R. S. Johnson, T. Sethi, C. Haslett, A. G. Rossi, A. J. Simpson, S. E. M. Howie, N. Hirani
Journal: Thorax (2010)

<h3>Background</h3> Hypoxia-inducible factor (HIF-1) is a master regulator of the cellular hypoxic response and has been implicated in the pathogenesis of inflammatory and fibrotic disease including IPF. <h3>Aims</h3> To study the role of hypoxia and HIF-1 activation in macrophages in the i.t. bleomycin-induced lung fibrosis model. <h3>Methods</h3> The i.t. bleomycin model was used to study the effect of HIF-1 manipulation in mice. The primary end-point was lung collagen content at day 24 post i.t. bleomycin instillation. The HIF-1α inducer dimethyloxallyl glycine (DMOG) was administered i.p. on days 14, 17 and 21. The role of myeloid-HIF-1 activity in lung fibrosis was determined using mice in which either HIF-1α or vHL (the dominant negative-regulator of HIF-1α) was selectively knocked out of lysosyme M expressing cells (LysM-Cre-Hif-1 and Cre-LysM-vHL). Lung tissue hypoxia was determined using Hypoxyprobe-1TM administered on day 24. Alternative activation status of HIF-1 null and vHL null macrophages was studied in bone-marrow derived cells from LysM-Cre-Hif-1 and Cre-LysM-vHL mice. <h3>Results</h3> Pharmacological induction of HIF-1 in the late period of the bleomycin model with i.p. dimethyloxallyl glycine (DMOG) resulted in significantly enhanced lung collagen (mean±s.e.mμg/lung) on day 24 compared to controls (193±15 vs 152±8, p&lt;0.05, n&gt;7 per gp). Hypoxyprobe-1 staining in the bleomycin-injured lung revealed hypoxic alveolar macrophages even in areas of lung distant to patches if severe fibrosis, implying a role for hypoxic/HIF-1 expressing alveolar macrophages in lung fibrosis. However, lung collagen content was identical in myeloid-cell Hif-1 null mice and wild-type litter-mate controls (276±23 vs 277±22, n=8 per gp). In contrast, myeloid-cell vHL-null mice exhibited significantly enhanced lung collagen deposition versus controls (373±36 vs 282±54, p&lt;0.05, n&gt;9 per gp). Isolated vHL-null macrophages exhibited enhanced expression of the alternative activation markers YM-1, mannose receptor, arginase-1 and FIZZ-1. <h3>Conclusions</h3> vHL deletion in macrophages enhances alternative activation and promotes lung fibrosis independent of HIF-1.
Mineralocorticoid Hypertensive Cardiovascular Disease Induced in Hypophysectomized Rats
Authors: C. E. HALL, O. HALL, E. G. RENNELS
Journal: Circulation Research (1960)

Reports in the literature to the contrary, hypertensive cardiovascular disease proved to be readily induced by desoxycorticosterone in hypophysectomized rats sensitized to steroid action by partial nephreetomy and high NaCl intake. In the absence of the pituitary, however, hypertension was somewhat slower in onset and progress. Although hypophysectomized animals were able to develop hypertension as severely as did intact animals, they were not, as judged by their better survival and less evident cardiorenal vascular lesions, as severely injured thereby. Contrasted with their exuberant development in hypertensive intact animals, renal lesions in hypertensive hypophysectomized animals were rare. Necrotizing arteritis in the heart was seen in about half of the hypox animals, and periarteritis nodosa of pancreatic and mesenteric arteries was more widespread and severe than in similarly treated intact animals which had, however, died earlier. Steroid treated animals bearing pituitary autotransplants beneath the renal capsule, developed more severe and widespread cardio-renal lesions than did similarly treated hypophysectomized animals, but incidence and severity of periarteritis nodosa in splanchnic arteries was about the same in each. The ingestion of sodium chloride caused "salt hypertension" in some of the pituitary-bearing controls, but not in either hypophysectomized or autotransplant-bearing controls.