tbuckley/cabot-search huggingface dataset:
Use of risk adjustment in setting budgets and measuring performance in primary care I: how it works
Authors: A. Majeed, A. B Bindman, J. P Weiner
Journal: BMJ (2001)

Healthcare systems in countries throughout the developed world are faced with the problem of limiting the growth in spending on health services while ensuring that their populations have access to appropriate care. The United Kingdom is no different in this respect, and the past 20 years have seen the introduction of numerous initiatives aimed at improving the efficiency of the NHS. Approaches adopted by the NHS to help improve efficiency include the introduction of capitation based budgets and increased monitoring of providers' performance. In the United States similar pressures to improve the efficiency of the healthcare system have led to the wide scale adoption of fixed budgets and monitoring of healthcare providers.

Diagnosis based methods for adjusting risk are becoming increasingly common within the US managed healthcare industry. The objective of risk adjustment is to help ensure that budgetary allocations or provider assessments take into account the morbidity of individual patients. In this and a subsequent article, we will describe this still evolving process and discuss its possible implications for the NHS, particularly for the new primary care organisations. There are various methods for carrying out risk adjustment, but we have used the Johns Hopkins adjusted clinical group system to show how risk adjustment works. The system is particularly relevant to primary care and is the most widely used method of measuring population case mix in the United States.

#### Summary points

Primary care groups and general practices will be funded largely through capitation based formulas, and their performance will be monitored more closely

Current methods of funding primary care trusts and general practices, and of monitoring their performance, do not take into account differences in case mix

Risk adjustment methods have been developed in the United States to allow measurement of case mix and morbidity of primary care populations

Risk adjustment methods …
Epimutations mimic genomic mutations of DNMT3A in acute myeloid leukemia
Authors: E Jost, Q Lin, C I Weidner, S Wilop, M Hoffmann, T Walenda, M Schemionek, O Herrmann, M Zenke, T H Brümmendorf, S Koschmieder, W Wagner
Journal: Leukemia (2013)

Mutations in the genetic sequence of the DNA de novo methyltransferase DNMT3A (DNA methyltransferase 3A) are found in many patients with acute myeloid leukemia (AML). They lead to dysfunction of DNMT3A protein and represent a marker for poor prognosis. Effects of genetic mutations can be mimicked by epigenetic modifications in the DNA methylation (DNAm) pattern. Using DNAm profiles of the Cancer Genome Atlas Research Network (TCGA), we identified aberrant hypermethylation at an internal promoter region of DNMT3A, which occurred in about 40% of AML patients. Bisulfite pyrosequencing assays designed for this genomic region validated hypermethylation specifically in a subset of our AML samples. High DNAm levels at this site are particularly observed in samples without genetic mutations in DNMT3A. Epimutations and mutations of DNMT3A were associated with related gene expression changes such as upregulation of the homeobox genes in HOXA and HOXB clusters. Furthermore, epimutations in DNMT3A were enriched in patients with poor or intermediate cytogenetic risk, and in patients with shorter event-free survival and overall survival (OS). Taken together, aberrant DNA hypermethylation within the DNMT3A gene, in analogy to DNMT3A mutations, is frequently observed in AML and both modifications seem to be useful for risk stratification or choice of therapeutic regimen.
CD133+ liver cancer stem cells from methionine adenosyl transferase 1A-deficient mice demonstrate resistance to transforming growth factor (TGF)-β-induced apoptosis
Authors: Wei Ding, Marialena Mouzaki, Hanning You, Joshua C. Laird, Jose Mato, Shelly C. Lu, Bart C. Rountree
Journal: Hepatology (2008)

Abstract Methionine adenosyltransferase (MAT) is an essential enzyme required for S -adenosylmethionine biosynthesis. Hepatic MAT activity falls during chronic liver injury, and mice lacking Mat1a develop spontaneous hepatocellular carcinoma by 18 months. We have previously demonstrated that CD133 + CD45 − oval cells isolated from 16-month-old Mat1a −/− mice represent a liver cancer stem cell population. The transforming growth factor β (TGF-β) pathway constitutes a central signaling network in proliferation, apoptosis, and tumorigenesis. In this study, we tested the response of tumorigenic liver stem cells to TGF-β. CD133 + CD45 − oval cells were isolated from premalignant 16-month-old Mat1a −/− mice by flow cytometry and expanded as five clone lines derived from a single cell. All clone lines demonstrated expression of both hepatocyte and cholangiocyte markers and maintained a small population (0.5% to 2%) of CD133 + cells in vitro, and three of five clone lines produced tumors. Although TGF-β1 inhibited cell growth equally in CD133 − and CD133 + cells from each clone line, the CD133 + population demonstrated significant resistance to TGF-β–induced apoptosis compared with CD133 − cells. Furthermore, CD133 + cells demonstrated a substantial increase in mitogen-activated protein kinase (MAPK) pathway activation, as demonstrated by phosphorylated extracellular signal-regulated kinase levels before and after TGF-β stimulation. MAPK inhibition using mitogen-activated protein kinase kinase 1 (MEK1) inhibitor PD98059 led to a significant increase in TGF-β–induced apoptosis in CD133 + cells. Conversely, a constitutively active form of MEK1 blocked the apoptotic effects of TGF-β in CD133 − cells. Conclusion: CD133 + liver cancer stem cells exhibit relative resistance to TGF-β–induced apoptosis. One mechanism of resistance to TGF-β–induced apoptosis in CD133 + cancer stem cells is an activated mitogen-activated protein kinase/extracellular signal-regulated kinase pathway. (Hepatology 2009.)
Destruction Box–Dependent Degradation of Aurora B Is Mediated by the Anaphase-Promoting Complex/Cyclosome and Cdh1
Authors: Scott Stewart, Guowei Fang
Journal: Cancer Research (2005)

Abstract Aurora B kinase, a subunit of the chromosomal passenger protein complex, plays essential roles in spindle assembly, chromosome bi-orientation, and cytokinesis. The kinase activity of Aurora B, which peaks in mitosis, is tightly controlled in the cell cycle. Modulation of Aurora B protein levels could partly account for the regulation of its kinase activity in the cell cycle. However, little is known on the molecular mechanism of regulation of Aurora B levels. Here, we examined Aurora B protein levels and confirmed that they fluctuate during the cell cycle, peaking in mitosis and dropping drastically in G1. This profile for Aurora B in the cell cycle is reminiscent of those for substrates of the anaphase-promoting complex/cyclosome (APC/C), a ubiquitin ligase essential for mitotic progression. Indeed, Aurora B is a substrate of APC/C both in vitro and in vivo. Aurora B is efficiently ubiquitinated in an in vitro reconstituted system by APC/C that had been activated by Cdh1. The recognition of Aurora B by APC/C-Cdh1 is specific as it requires the presence of a conserved D-box at the COOH terminus of Aurora B. Furthermore, endogenous Aurora B and Cdh1 form a complex exclusively in mitotic cells. Degradation of Aurora B at the end of mitosis requires Cdh1 in vivo as a reduction of the Cdh1 level by RNA interference stabilizes the Aurora B protein. We conclude that, as a key mitotic regulator, Aurora B is regulated both by its activation during early mitosis and by its destruction by APC/C-Cdh1 in late mitosis and in G1.
Common and low-frequency variants associated with genome-wide recombination rate
Authors: Augustine Kong, Gudmar Thorleifsson, Michael L Frigge, Gisli Masson, Daniel F Gudbjartsson, Rasmus Villemoes, Erna Magnusdottir, Stefania B Olafsdottir, Unnur Thorsteinsdottir, Kari Stefansson
Journal: Nature Genetics (2013)
Abstract B57: Regulation of Eag expression by p53 and Rb in tumoral cells
Authors: Maria de Guadalupe Chavez-Lopez, Enrique Garcia-Villa, Patricio Gariglio, E. Garrido, Elizabeth Hernandez-Gallegos, Veronica Ponce, Javier Camacho
Journal: Cancer Research (2009)

Abstract Introduction: Ether à go-go (Eag) potassium channels display oncogenic properties. Their expression in healthy tissues is limited almost exclusively to the brain; however, it is highly expressed in several types of cancer. In addition, the inhibition of its activity or expression remarkably diminishes cellular proliferation and tumor progression. Our group found the expression of Eag in cells having alterations in p53 and Rb including C-33 and HeLa from cervical cancer. On the other hand, we have observed that Eag gene expression is regulated by factors that inhibit Rb or p53, such as, E6 and E7 oncogenes of the human papilloma virus and estradiol. Therefore, we have considered p53 and Rb like possible pathways for Eag regulation. To our knowledge, there are no reports on Eag regulation by tumor suppressor proteins. Thus in this work we evaluated the effect of p53 and Rb overexpression on the expression of Eag in C-33, HeLa (cervix) and A549 (lung cancer) cells. We also analyzed the expression of Eag in tumor samples from patients with retinoblastoma (a malignant tumor characterized by the loss of the gene Rb and alterations in the p53 pathway). Methods: C-33, HeLa and A549 cells were obtained from American Type Culture Collection (ATCC) and the RNA's of patients with retinoblastoma from the Hospital of Pediatrics of the Medical Centre XXI century. In order to evaluate the expression of Eag, retrotranscription was performed and the analysis of gene expression was carried out by real time PCR, the results were analyzed by the method of ΔΔ-CT. In order to evaluate the effect of p53 and Rb overexpression on Eag, HeLa and C-33 cells were grown in DMEM and A549 cells on F12-K medium, supplemented with 10% of bovine fetal serum; later they were transfected with 1 µg of plasmid containing p53 and/or Rb. The RNA was obtained 72 hours later and then subjected to retrotranscription. Eag gene expression was then analyzed by real time PCR. Results: We found that p53 and Rb transfection in C-33 cells does not affect the expression of Eag. However, Eag expression in HeLa cells was clearly down-regulated when transfected with p53 and/or Rb. Transfection of p53 in A549 cells diminished the expression of Eag, in contrast to Rb transfection which increased expression. Interestingly, we observed a very high expression of Eag in samples of retinoblastoma in comparison with the Eag expression in HeLa cells and in normal retina. Conclusions: Our results suggest that tumor suppressor proteins p53 and Rb regulate the expression of Eag. In addition, our results also suggest Eag as a retinoblastoma potential therapeutic target for this type of tumors. This project was partially supported by ICyT DF. Citation Information: Cancer Res 2009;69(23 Suppl):B57.
Section of Physiology and Dietetics.
Authors: Ephraim Cutter
Journal: JAMA (1891)

<h3>To the Editor:</h3> —By order of Chairman C. H. A. Kleinschmidt, those interested in the Section of Physiology and Dietetics are invited to present papers or essays, and send titles to the undersigned, that we may get up the programme as soon as possible. 1730 Broadway, New York.
Getting Into a Residency: A Guide for Medical Students
Authors: Leigh Page
Journal: JAMA (1994)

ABSTRACT Choosing a specialty is one of the biggest decisions a physician ever makes. But is much thought put into it? The answer seems to be, not enough.In his book, Getting Into a Residency, Kenneth V. Iserson, MD, reports that a quarter of all medical students change their specialty choice after graduation— sometimes following unhappy years practicing in an unsuitable field.This how-to book tries to help medical students avoid these agonies by breaking down a fairly overwhelming career decision into digestible parts. Readers are walked through virtually every aspect of picking a specialty and subsequent training program. Advice ranges from big picture, such as a thorough examination of the demands of each major specialty, to prosaica, such as how to pack your bag to interview for a residency position.Besides medical students, the book may be useful to their faculty advisers, program directors, and policymakers interested in specialty choice.
Glucose transport in human skeletal muscle cells in culture. Stimulation by insulin and metformin.
Authors: V Sarabia, L Lam, E Burdett, L A Leiter, A Klip
Journal: Journal of Clinical Investigation (1992)

Primary human muscle cell cultures were established and the regulation of glucose transport was investigated. Primary cultures were allowed to proceed to the stage of myotubes through fusion of myoblasts or were used for clonal selection based on fusion potential. In clonally selected cultures, hexose (2-deoxy-glucose) uptake into myotubes was linear within the time of study and inhibitable by cytochalasin B (IC50 = 400 nM). Cytochalasin B photolabeled a protein(s) of 45,000-50,000 D in a D-glucose-protectable manner, suggesting identity with the glucose transporters. In the myotube stage, the cells expressed both the GLUT1 and GLUT4 glucose transporter protein isoforms at an average molar ratio of 7:1. Preincubation in media of increasing glucose concentrations (range 5-25 mM) progressively decreased the rate of 2-deoxyglucose uptake. Insulin elevated 2-deoxyglucose uptake in a dose-dependent manner, with half maximal stimulation achieved at 3.5 nM. Insulin also stimulated the transport of the nonmetabolizable hexose 3-O-methylglucose, as well as the activity of glycogen synthase, responsible for nonoxidative glucose metabolism. The oral antihyperglycemic drug metformin stimulated the cytochalasin B-sensitive component of both 2-deoxyglucose and 3-O-methylglucose uptake. Maximal stimulation was observed at 8 h of exposure to 50 microM metformin, and this effect was not prevented by incubation with the protein-synthesis inhibitor cycloheximide. The relative effect of metformin was higher in cells incubated in 25 mM glucose than in 5 mM glucose, consistent with its selective action in hyperglycemic conditions in vivo. Metformin (50 microM for 24 h) was more effective than insulin (1 microM for 1 h) in stimulating hexose uptake and the hormone was effective on top of the stimulation caused by the biguanide, suggesting independent mechanisms of action.
Thrombocytopenia associated with chronic liver disease
Authors: Nezam Afdhal, John McHutchison, Robert Brown, Ira Jacobson, Michael Manns, Fred Poordad, Babette Weksler, Rafael Esteban
Journal: Journal of Hepatology (2008)

Thrombocytopenia (platelet count <150,000/μL) is a common complication in patients with chronic liver disease (CLD) that has been observed in up to 76% of patients. Moderate thrombocytopenia (platelet count, 50,000/μL–75,000/μL) occurs in approximately 13% of patients with cirrhosis. Multiple factors can contribute to the development of thrombocytopenia, including splenic platelet sequestration, bone marrow suppression by chronic hepatitis C infection, and antiviral treatment with interferon-based therapy. Reductions in the level or activity of the hematopoietic growth factor thrombopoietin (TPO) may also play a role. Thrombocytopenia can impact routine care of patients with CLD, potentially postponing or interfering with diagnostic and therapeutic procedures including liver biopsy, antiviral therapy, and medically indicated or elective surgery. Therapeutic options to safely and effectively raise platelet levels could have a significant effect on care of these patients. Several promising novel agents that stimulate TPO and increase platelet levels, such as the oral platelet growth factor eltrombopag, are currently in development for the prevention and/or treatment of thrombocytopenia. The ability to increase platelet levels could significantly reduce the need for platelet transfusions and facilitate the use of interferon-based antiviral therapy and other medically indicated treatments in patients with liver disease. Thrombocytopenia (platelet count <150,000/μL) is a common complication in patients with chronic liver disease (CLD) that has been observed in up to 76% of patients. Moderate thrombocytopenia (platelet count, 50,000/μL–75,000/μL) occurs in approximately 13% of patients with cirrhosis. Multiple factors can contribute to the development of thrombocytopenia, including splenic platelet sequestration, bone marrow suppression by chronic hepatitis C infection, and antiviral treatment with interferon-based therapy. Reductions in the level or activity of the hematopoietic growth factor thrombopoietin (TPO) may also play a role. Thrombocytopenia can impact routine care of patients with CLD, potentially postponing or interfering with diagnostic and therapeutic procedures including liver biopsy, antiviral therapy, and medically indicated or elective surgery. Therapeutic options to safely and effectively raise platelet levels could have a significant effect on care of these patients. Several promising novel agents that stimulate TPO and increase platelet levels, such as the oral platelet growth factor eltrombopag, are currently in development for the prevention and/or treatment of thrombocytopenia. The ability to increase platelet levels could significantly reduce the need for platelet transfusions and facilitate the use of interferon-based antiviral therapy and other medically indicated treatments in patients with liver disease.
Myeloid, Erythroid, and Immune System Defects in a Family
Authors: WILLIAM O. DOBBINS
Journal: Annals of Internal Medicine (1975)

Comments and Corrections1 September 1975Myeloid, Erythroid, and Immune System Defects in a FamilyWILLIAM O. DOBBINS III, M.D.WILLIAM O. DOBBINS III, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-83-3-431_2 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTo the editor: I read with considerable interest the paper by Linsk, Khoory, and Meyers (Ann Intern Med82:659-662, 1975). I agree with the authors that the electron microscopic findings of intranuclear and intracytoplasmic linear "crystalloid" structures in the mature neutrophils of the two subjects are unique in that such an observation has not been previously reported. However, this finding may not be characteristic of the disorder that they describe. We observed similar intracytoplasmic and intranuclear filaments in polymorphonuclear leukocytes (Figure 1) found in the colonic specimen of a patient who had total colectomy for treatment of Crohn's disease. There... This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Division of Gastroenterology Department of Medicine The George Washington University Medical Center Washington, D.C. 20037 PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 September 1975Volume 83, Issue 3Page: 431-432KeywordsColectomyCrohn's diseaseElectron microscopyImmune systemNeutrophilsSpecimen preparation and treatment ePublished: 1 December 2008 Issue Published: 1 September 1975 PDF downloadLoading ...
Morphometric quantification of myocyte dimensions validated in normal growing rat hearts and applied to hypertrophic human hearts
Authors: H W VLIEGEN, A v. d. LAARSE, J A N HUYSMAN, E C WIJNVOORD, M MENTAR, C J CORNELISSE, F EULDERINK
Journal: Cardiovascular Research (1987)

To obtain quantitative information on changes in myocyte size in hearts with increased myocardial mass light microscopical morphometry was used in fixed and stained myocardial tissue sections. A modification of the azan staining procedure made longitudinal (sarcolemma) and transverse (intercalated discs) boundaries visible with a contrast that allowed morphometric analysis. The method was validated in left ventricular tissue of rats ranging in age from 4 to 17 weeks. Myocyte width, cut surface area, length, and volume were significantly correlated with left ventricular weight with residual errors of 5%, 5%, 6%, and 8% respectively. The method was applied to 21 human hearts, nine of which had left ventricular hypertrophy. Myocyte width, area, length, and volume both in subepicardial and subendocardial left ventricular tissue were significantly greater in hypertrophic than in normal hearts. Although the mean weight of the hypertrophic hearts exceeded that of normal hearts by 40%, myocyte volumes in subepicardial and subendocardial left ventricular tissue of hypertrophic hearts were higher by 78% and 43% respectively, indicating a transmural difference in the extent of myocyte hypertrophy. The method is accurate and reproducible and gives useful quantitative information on changes in myocyte dimensions during normal cardiac growth as well as in cardiac hypertrophy.
Identification and genotyping of human papillomavirus in a Spanish cohort of penile squamous cell carcinomas: Correlation with pathologic subtypes, p16INK4a expression, and prognosis
Authors: Carla Ferrándiz-Pulido, Emili Masferrer, Ines de Torres, Belen Lloveras, Javier Hernandez-Losa, Sergio Mojal, Carlos Salvador, Juan Morote, Santiago Ramon y Cajal, Ramon M. Pujol, Vicente Garcia-Patos, Agustin Toll
Journal: Journal of the American Academy of Dermatology (2012)
Allergen-induced IgE-dependent gut inflammation in a human PBMC–engrafted murine model of allergy
Authors: Benno Weigmann, Nadja Schughart, Christian Wiebe, Stephan Sudowe, Hans A. Lehr, Helmut Jonuleit, Lothar Vogel, Christoph Becker, Markus F. Neurath, Stephan Grabbe, Joachim Saloga, Iris Bellinghausen
Journal: Journal of Allergy and Clinical Immunology (2012)
Interaction of the legionnaires' disease bacterium (legionella pneumophila) with human phagocytes. I. L. pneumophila resists killing by polymorphonuclearleukocytes, antibody, and complement
Authors: MA Horwitz, SC Silverstein
Journal: The Journal of Experimental Medicine (1981)

We have previously reported that virulent egg yolk-grown Legionella pneumophila, Philadelphia 1 strain, multiplies intracellularly in human blood monocytes. We now report on the interaction between virulent L. pneumophila and human polymorphonuclear leukocytes (PMN), antibody, and complement, in vitro, under antibiotic-free conditions. L. pneumophila in concentrations ranging from 10(3) to 10(6) colony forming units (CFU)/ml are completely resistant to the bactericidal effects of 0-50 percent fresh normal human serum, even in the presence of high concentrations of rabbit or human anti-L. pneumophila antibody. L. pneumophila bacteria fix the third component of complement (C3) to their surfaces, as measured by fluorescence microscopy using rhodamine- conjugated goat anti-human C3 IgG, only when the bacteria are incubated with both specific anti-L. pneumophila antibody and complement. Similarly, L. pneumophila adhere to PMN, as measured by fluorescence microscopy, only in the presence of both specific antibody and complement. Electron microscopy revealed that these opsonized bacteria are phagocytosed by the PMN. PMN require both antibody and complement to kill L. pneumophila; even then, PMN reduced CFU of L. pneumophila by only 0.5 log under conditions in which they reduce CFU of a serum-resistant encapsulated strain of Escherichia coli by 2.5 logs. Separation of PMN-associated and nonassociated CFU of L. pneumophila revealed that the major proportion of the surviving bacteria are PMN associated. Thus, the ineffective killing of opsonized L. pneumophila is a result of a failure of PMN to kill these bacteria after they become PMN- associated. With or without antibody, PMN do not support the growth of L. pneumophila. These findings suggest that PMN, even in conjunction with the humoral immune system, do not play a decisive role in defense against the Legionnaires' disease bacterium.