tbuckley/cabot-search huggingface dataset:
Urinary Liver-Type Fatty Acid-Binding Protein Predicts Progression to Nephropathy in Type 1 Diabetic Patients
Authors: Stine Elkjaer Nielsen, Takeshi Sugaya, Peter Hovind, Tsuneharu Baba, Hans-Henrik Parving, Peter Rossing
Journal: Diabetes Care (2010)

OBJECTIVE Urinary liver-type fatty acid-binding protein (u-LFABP) is a marker of tubulointerstitial inflammation and has been shown to be increased in patients with type 1 diabetes and is further increased in patients who progress to micro- and macroalbuminuria. Our aim was to evaluate u-LFABP as a predictor of progression to micro- and macroalbuminuria in type 1 diabetes. RESEARCH DESIGN AND METHODS From an inception cohort of 277 patients, u-LFABP, adjusted for urinary creatinine (enzyme-linked immunosorbent assay), was measured in 24-h urine samples from 165 normoalbuminuric patients 9.6 ± 3.5 (mean ±SD) years after onset of type 1 diabetes. The outcome measured was development of persistent micro- or macroalbuminuria or death. RESULTS Patients were followed for a median of 18 (range 1–19) years; 39 progressed to microalbuminuria, 8 of those progressed further to macroalbuminuria, and 24 died. In a Cox regression model, baseline log u-LFABP levels predicted the development of microalbuminuria, adjusted for known risk factors (sex, age, A1C, systolic and diastolic blood pressure, albumin excretion rate, serum creatinine, and smoking) (hazard ratio [HR] 2.3 [95% CI 1.1–4.6]) and log u-LFABP predicted mortality (adjusted HR 3.0 [1.3–7.0]). u-LFABP (above versus below the median) predicted the development of macroalbuminuria (adjusted HR 2.6 [1.2–5.4]). As a continuous variable, u-LFABP tended to predict macroalbuminuria (HR 1.9, P = 0.2), but numbers were small. CONCLUSIONS High levels of the tubular inflammation marker u-LFABP predict the initiation and progression to diabetic nephropathy and all-cause mortality, independent of urinary albumin excretion rate and other established risk factors.
Survival of DNA HLA-DR typed and matched cadaver kidney transplants
Authors: G. Opelz, J. Mytilineos, S. Scherer, H. Dunckley, J. Trejaut, J. Chapman, D. Middleton, D. Savage, G.F. Fischer, J.D. Bignon, J.C. Bensa, E. Albert, H. Noreen
Journal: The Lancet (1991)
Recurrent spontaneous bacterial peritonitis in a patient with polycythemia vera
Authors: Arnon Nagler, Tony Hayek, Benjamin Brenner, Shmoel Eidelman
Journal: American Journal of Hematology (1988)

Abstract Spontaneous bacterial peritonitis (SBP) is an infectious process that usually occurs in patients with cirrhosis. There are few reports of SBP in patients with other pathologies such as nephrotic syndrome, acute and chronic hepatitis, cardiac ascites, and ascites secondary to neoplastic disease. We report a patient with polycythemia vera in whom recurrent episodes of SBP occurred 8 months following a portacaval shunt operation for Budd‐Chiari syndrome. Conceivably, the polycythemia vera (PV) complicated by hepatic vein thrombosis and portacaval shunt resulted in significant loss of hepatic reticuloen‐dothelial system function and predisposed the patient to bacterial peritonitis.
Effect of reducing ambulance response times on deaths from out of hospital cardiac arrest: cohort study
Authors: J. P Pell
Journal: BMJ (2001)

<h3>Abstract</h3> <b>Objectives:</b> To determine the association between ambulance response time and survival from out of hospital cardiopulmonary arrest and to estimate the effect of reducing response times. <b>Design:</b> Cohort study. <b>Setting:</b> Scottish Ambulance Service. <b>Subjects:</b> All out of hospital cardiopulmonary arrests due to cardiac disease attended by the Scottish Ambulance Service during May 1991 to March 1998. <b>Main outcome measures:</b> Survival rate to hospital discharge and potential improvement from reducing response times. <b>Results:</b> Of 13 822 arrests not witnessed by ambulance crews but attended by them within 15 minutes, complete data were available for 10 554 (76%). Of these patients, 653 (6%) survived to hospital discharge. After other significant covariates were adjusted for, shorter response time was significantly associated with increased probability of receiving defibrillation and survival to discharge among those defibrillated. Reducing the 90th centile for response time to 8 minutes increased the predicted survival to 8%, and reducing it to 5 minutes increased survival to 10-11% (depending on the model used). <b>Conclusions:</b> Reducing ambulance response times to 5 minutes could almost double the survival rate for cardiac arrests not witnessed by ambulance crews. <h3>What is already known on this topic</h3> Three quarters of all deaths from myocardial infarction occur after cardiac arrest in the community Survival after out of hospital arrest is much lower in the United Kingdom than the United States <h3>What this study adds</h3> Ambulance response times are independently associated with defibrillation and survival Decreasing the target for response to 90% of calls from 14 minutes to 8 minutes would increase survival from 6% to 8% A response time of 5 minutes would increase survival to 10-11%
The Cutaneous Lymphocyte Antigen Is an Essential Component of the L-selectin Ligand Induced on Human Vascular Endothelial Cells
Authors: LiLi Tu, Martha D. Delahunty, Han Ding, Francis W. Luscinskas, Thomas F. Tedder
Journal: The Journal of Experimental Medicine (1999)

L-selectin mediates leukocyte rolling on vascular endothelium during inflammation. Although vascular endothelium can be activated with inflammatory cytokines to express functional L-selectin ligands, these ligands have not been well characterized. In this study, fucosyltransferase VII cDNA (Fuc-TVII) transfection of the EA.hy926 human vascular endothelial cell line (926-FtVII) induced functional L-selectin ligand expression and expression of sialyl Lewisx (sLex), as defined by HECA-452 (cutaneous lymphocyte antigen; CLA) and CSLEX-1 mAbs. Cytokine activation of human umbilical vein endothelial cells (HUVEC) also induced functional L-selectin ligand expression, with increased CLA expression and Fuc-TVII transcription. The majority of L-selectin–dependent lymphocyte attachment to activated HUVEC and 926-FtVII cells was blocked specifically by treating the endothelial cells with the HECA-452 mAb, but not the CSLEX-1 mAb. CLA-bearing ligands on vascular endothelium also required sulfation and appropriate molecular scaffolds for functional activity, but were distinct from the L-selectin ligands previously identified by the MECA-79 mAb. These findings demonstrate that the HECA-452– defined antigen, CLA, is an essential carbohydrate component of vascular L-selectin ligands.
Megalin (gp330) possesses an antigenic epitope capable of inducing passive Heymann nephritis independent of the nephritogenic epitope in receptor-associated protein.
Authors: R A Orlando, D Kerjaschki, M G Farquhar
Journal: Journal of the American Society of Nephrology (1995)

The Heymann nephritis antigenic complex (HNAC) consists of two glycoproteins, megalin (gp330), and the receptor-associated protein (RAP). HNAC is expressed on the surface of the glomerular epithelium where it plays a primary role in the pathogenesis of Heymann nephritis (HN). Several models were previously proposed describing how antibody binding epitopes in HNAC may contribute to the initiation and progression of HN. Although these models suggest that nephritogenic epitopes capable of initiating HN are present in both megalin and RAP, the structural relationship between these epitopes has not been established. Previously a nephritogenic epitope was identified and characterized in RAP that initiates immune complex formation in HN. In this report, the immunologic relationship between nephritogenic epitopes in megalin and RAP were examined to determine whether these epitopes are immunologically distinct or antigenically related. To this end, a polyclonal antibody to megalin was generated that does not recognize RAP by immunoblotting or immunoprecipitation and whether this antibody is capable of inducing passive HN was determined. It was found that antimegalin antibodies devoid of RAP cross-reactivity induced the formation of subepithelial immune deposits (passive HN) when injected into rats. Antibodies eluted from glomeruli of the injected rats recognized only megalin by immunoblotting a cortical extract and did not recognize a RAP fusion protein or any other renal protein. In addition, the eluted antibodies immunoprecipitated two proteolytic fragments of megalin (140 and 75 kd) identifying a pathogenic epitope within a smaller fragment of megalin.(ABSTRACT TRUNCATED AT 250 WORDS)
Protein Kinase C β Controls Nuclear Factor κB Activation in B Cells Through Selective Regulation of the IκB Kinase α
Authors: Kaoru Saijo, Ingrid Mecklenbräuker, Angela Santana, Michael Leitger, Christian Schmedt, Alexander Tarakhovsky
Journal: The Journal of Experimental Medicine (2002)

Activation of the nuclear factor (NF)-κB transcription complex by signals derived from the surface expressed B cell antigen receptor controls B cell development, survival, and antigenic responses. Activation of NF-κB is critically dependent on serine phosphorylation of the IκB protein by the multi-component IκB kinase (IKK) containing two catalytic subunits (IKKα and IKKβ) and one regulatory subunit (IKKγ). Using mice deficient for protein kinase C β (PKCβ) we show an essential role of PKCβ in the phosphorylation of IKKα and the subsequent activation of NF-κB in B cells. Defective IKKα phosphorylation correlates with impaired B cell antigen receptor–mediated induction of the pro-survival protein Bcl-xL. Lack of IKKα phosphorylation and defective NF-κB induction in the absence of PKCβ explains the similarity in immunodeficiencies caused by PKCβ or IKKα ablation in B cells. Furthermore, the well established functional cooperation between the protein tyrosine kinase Bruton's tyrosine kinase (Btk), which regulates the activity of NF-κB and PKCβ, suggests PKCβ as a likely serine/threonine kinase component of the Btk-dependent NF-κB activating signal transduction chain downstream of the BCR.
An insertional mutagenesis screen identifies genes that cooperate with Mll-AF9 in a murine leukemogenesis model
Authors: Rachel J. Bergerson, Lara S. Collier, Aaron L. Sarver, Raha A. Been, Sanne Lugthart, Miechaleen D. Diers, Johannes Zuber, Amy R. Rappaport, Molly J. Nixon, Kevin A. T. Silverstein, Danhua Fan, Anne-Francoise J. Lamblin, Linda Wolff, John H. Kersey, Ruud Delwel, Scott W. Lowe, M. Gerard O'Sullivan, Scott C. Kogan, David J. Adams, David A. Largaespada
Journal: Blood (2012)
Altered Expression of <i>Raet1e</i> , a Major Histocompatibility Complex Class 1–Like Molecule, Underlies the Atherosclerosis Modifier Locus <i>Ath11</i> 10b
Authors: José M. Rodríguez, Susanne Wolfrum, Megan Robblee, Kwan Y. Chen, Zachary N. Gilbert, Jae-Hoon Choi, Daniel Teupser, Jan L. Breslow
Journal: Circulation Research (2013)

Rationale : Quantitative trait locus mapping of an intercross between C57. Apoe −/− and FVB. Apoe −/− mice revealed an atherosclerosis locus controlling aortic root lesion area on proximal chromosome 10, Ath11 . In a previous work, subcongenic analysis showed Ath11 to be complex with proximal (10a) and distal (10b) regions. Objective : To identify the causative genetic variation underlying the atherosclerosis modifier locus Ath11 10b. Methods and Results: We now report subcongenic J, which narrows the 10b region to 5 genes, Myb , Hbs1L , Aldh8a1 , Sgk1 , and Raet1e. Sequence analysis of these genes revealed no amino acid coding differences between the parental strains. However, comparing aortic expression of these genes between F1. Apoe −/− Chr10SubJ (B/F) and F1. Apoe −/− Chr10SubJ (F/F) uncovered a consistent difference only for Raet1e , with decreased, virtually background, expression associated with increased atherosclerosis in the latter. The key role of Raet1e was confirmed by showing that transgene-induced aortic overexpression of Raet1e in F1. Apoe −/− Chr10SubJ (F/F) mice decreased atherosclerosis. Promoter reporter constructs comparing C57 and FVB sequences identified an FVB mutation in the core of the major aortic transcription start site abrogating activity. Conclusions : This nonbiased approach has revealed Raet1e , a major histocompatibility complex class 1–like molecule expressed in lesional aortic endothelial cells and macrophage-rich regions, as a novel atherosclerosis gene and represents one of the few successes of the quantitative trait locus strategy in complex diseases.
Evidence for involvement of oxygen free radicals in bile acid toxicity to isolated rat hepatocytes
Authors: Ronald J. Sokol, Michael Devereaux, Rhashmi Khandwala, Kevin O'Brien
Journal: Hepatology (1993)

The mechanisms by which hydrophobic bile acids are toxic to the liver are unknown. To determine whether the generation of free radicals is involved in the hepatotoxicity of bile acids, freshly isolated rat hepatocytes were incubated with individual bile acids (100 to 200 μmol/L) for 4 hr. Hepatocyte viability (trypan blue exclusion) declined to 40% to 50% in incubations with taurochenodeoxycholic acid and taurolithocholic acid, whereas taurocholic acid and tauroursodeoxycholic acid were not toxic. Lipid peroxidation was significantly associated with the loss of cell viability. Preincubation with different antioxidants - D-α-tocopheryl succinate, D-α-tocopherol, diphenyl-p-phenylenediamine, superoxide dismutase, catalase, superoxide dismutase + catalase, deferoxamine or apotransferrin - protected against the loss of viability and inhibited lipid peroxidation in cells incubated with 200 μmol/L taurolithocholic acid. α-Tocopheryl succinate added after 90 min of incubation with taurolithocholic acid ameliorated further hepatocyte toxicity and lipid peroxidation. Incubation of hepatocytes with 500 μmol/L of taurochenodeoxycholic acid or taurolithocholic acid under a low oxygen tension (9% O 2 ) similarly caused lipid peroxidation and cell injury that was reversed by preincubation with D-α-tocopherol. These data suggest that oxygen free radicals may be involved in the pathogenesis of bile acid hepatotoxicity. (Hepatology 1993;17:869-881.)
Nutrition, Genetics, and Risks of Cancer
Authors: Cheryl L. Rock, Johanna W. Lampe, Ruth E. Patterson
Journal: Annual Review of Public Health (2000)

▪ Abstract Dietary patterns, nutrients, and other constituents of food are major components of the environmental influences that contribute to risk for cancer, and the study of interactions between nutritional and genetic factors is a new and important area of research. This review describes the concepts and principles underlying this area of study and types of relationships between nutritional and genetic factors, and it provides examples of specific diet-gene interactions that are of current interest, with an emphasis on implications for cancer prevention and public health. Polymorphisms exist in the genes for the activating and conjugating metabolizing enzymes, and the induction of metabolizing enzyme activity by nutritional factors may result in either the activation of a carcinogen or the detoxification of a reactive intermediate metabolite. The relationship between the methylenetetrahydrofolate reductase gene and dietary folate is an example of a diet-gene interaction that involves a polymorphism in a vitamin metabolism gene, and the presence of the variant appears to influence both risk for cancer and folate requirements. Diet-gene interactions likely contribute considerably to the observed inter-individual variations in cancer risk in response to exposures to the nutritional factors that have the potential to promote or protect against cancer. Insights into mechanisms by which nutritional factors affect the process of carcinogenesis are provided by knowledge of the targeted gene function and enzyme activity. Increased knowledge in this area will allow a more refined approach to reducing risk for cancer, with diet interventions targeted toward individuals and subgroups that are genetically susceptible and responsive to the effects of nutritional factors. Investigating the cellular and molecular pathogenesis of cancer is an established and important area of basic science research. Within the past several years, the capability of examining biomarkers of various genetic factors in the development and progression of chronic diseases, such as cancers, has enabled researchers to study these factors in clinical and community-based populations, in which environmental factors can also be measured or even manipulated. Dietary patterns and the nutrients and other co nstituents of food are a major component of the environmental influen ces that appear to contribute to disease risk, and the study of interactions between nutritional and genetic factors is a new and important area of research. This review describes the concepts and principles underlying this area of study, describes types of relationships between nutritional and genetic factors, provides examples of specific diet-gene interactions that are of current interest, and comments on implications for cancer prevention and public health.
Upregulation of Endothelial Nitric Oxide Synthase by HMG CoA Reductase Inhibitors
Authors: Ulrich Laufs, Vito La Fata, Jorge Plutzky, James K. Liao
Journal: Circulation (1998)

Oxidized low-density lipoprotein (ox-LDL) causes endothelial dysfunction in part by decreasing the availability of endothelial nitric oxide (NO). Although HMG CoA reductase inhibitors restore endothelial function by reducing serum cholesterol levels, it is not known whether they can also directly upregulate endothelial NO synthase (ecNOS) activity.Human saphenous vein endothelial cells were treated with ox-LDL (50 microg/mL thiobarbituric acid reactive substances 12 to 16 nmol/mg) in the presence of HMG CoA reductase inhibitors simvastatin and lovastatin. In a time-dependent manner, ox-LDL decreased ecNOS mRNA and protein levels (91+/-4% and 67+/-8% reduction after 72 hours, respectively). Both simvastatin (1 micromol/L) and lovastatin (10 micromol/L) upregulated ecNOS expression by 3.8-fold and 3.6-fold, respectively, and completely prevented its downregulation by ox-LDL. These effects of simvastatin on ecNOS expression correlated with changes in ecNOS activity. Although L-mevalonate alone did not affect ecNOS expression, cotreatment with L-mevalonate completely reversed ecNOS upregulation by simvastatin. Actinomycin D studies revealed that simvastatin stabilized ecNOS mRNA (tau1/2, 43 versus 35 hours). Nuclear run-on assays and transient transfection studies with a -1.6 kb ecNOS promoter construct showed that simvastatin did not affect ecNOS gene transcription.Inhibition of endothelial HMG CoA reductase upregulates ecNOS expression predominantly by posttranscriptional mechanisms. These findings suggest that HMG CoA reductase inhibitors may have beneficial effects in atherosclerosis beyond that attributed to the lowering of serum cholesterol by increasing ecNOS activity.
Immune Suppression by Recombinant Interleukin (rIL)-12 Involves Interferon γ Induction of Nitric Oxide Synthase 2 (iNOS) Activity: Inhibitors of NO Generation Reveal the Extent of rIL-12 Vaccine Adjuvant Effect
Authors: Holly Kurzawa Koblish, Christopher A. Hunter, Maria Wysocka, Giorgio Trinchieri, William M.F. Lee
Journal: The Journal of Experimental Medicine (1998)

Recombinant interleukin 12 (IL-12) can profoundly suppress cellular immune responses in mice. To define the underlying mechanism, recombinant murine (rm)IL-12 was given to C57BL/6 mice undergoing alloimmunization and found to transiently but profoundly suppress in vivo and in vitro allogeneic responses and in vitro splenocyte mitogenic responses. Use of neutralizing antibodies and genetically deficient mice showed that IFN-γ (but not TNF-α) mediated rmIL-12–induced immune suppression. Splenocyte fractionation studies revealed that adherent cells from rmIL-12–treated mice suppressed the mitogenic response of normal nonadherent cells to concanavalin A and IL-2. Addition of an inhibitor of nitric oxide synthase (NOS) restored mitogenic responses, and inducible (i)NOS−/− mice were not immunosuppressed by rmIL-12. These results support the view that suppression of T cell responses is due to NO produced by macrophages responding to the high levels of IFN-γ induced by rmIL-12. When a NOS inhibitor was given with rmIL-12 during vaccination of A/J mice with irradiated SCK tumor cells, immunosuppression was averted and the extent of rmIL-12's ability to enhance induction of protective antitumor immunity was revealed. This demonstrates that rmIL-12 is an effective vaccine adjuvant whose efficacy may be masked by its transient immunosuppressive effect.
Managing demand: Managing demand in general practice
Authors: S. Gillam, D. Pencheon
Journal: BMJ (1998)

This is the third of five articles on ways of managing demand for health care.

Increasing patient expectations are placing strains on general medical services. While empirical evidence for increasing demand is difficult to establish, the population's use of primary care services has changed and will continue to change in response to demographic and technological pressures. Consultation rates have increased slightly over the past 10 years but out of hours calls have escalated more dramatically.

Most chronic diseases can be managed with little recourse to specialist support, but patients are increasingly aware of diagnostic and therapeutic advances. The information revolution has fuelled demands for user friendly services of constantly improving quality across the public sector. Users seek appropriate information skilfully communicated by the health professional of their choice. Increasingly, people want to be involved in decisions about their management. The sense of a growing gap between what their patients want and what the service can afford provides a stressful undercurrent in the working lives of general practitioners.

The advent of fundholding heralded a major shift of control over the allocation of health service resources to general practitioners. These powers are set to increase and with them new budgetary responsibilities. This paper analyses approaches to demand management which reflect both the changing relationship between general practitioners and their patients and the changing interface between primary and secondary care. With the development of more graduated pathways of access through the health system, these interfaces are blurring. How general practitioners manage needs expressed at first contact can influence patients' future self care; how they manage the interface with secondary care adds to pressure in this sector.

#### Summary points

The advent of primary care groups will involve all general practitioners in resource management

Multifaceted approaches are required that affect demand at all points along the path …