tbuckley/cabot-search huggingface dataset:
Extensive Podocyte Loss Triggers a Rapid Parietal Epithelial Cell Response
Authors: Samy Hakroush, Angelika Cebulla, Thomas Schaldecker, Daniel Behr, Peter Mundel, Astrid Weins
Journal: Journal of the American Society of Nephrology (2013)

Damage to podocytes is a central pathomechanism of proteinuric kidney disease. However, it is not fully understood how podocyte injury evolves to progressive glomerulopathies such as FSGS or collapsing glomerulopathy. In particular, the role of parietal epithelial cells remains controversial. Here, we show that adriamycin induces DNA damage and podocyte lysis in mice without evidence of autophagy, endoplasmic reticulum stress, or necroptosis. After extensive podocyte loss, activated parietal cells mediated tuft re-epithelialization by two distinct mechanisms. In the majority of glomeruli, vacuolized parietal epithelial cells attached to denuded glomerular basement membrane and, occasionally, disengaged from the parietal basement membrane. Less frequently, parietal epithelial cells covered the denuded visceral basement membrane via formation of proliferative pseudocrescents. Notably, "visceralized" parietal epithelial cells did not express vascular endothelial growth factor but upregulated hypoxia-inducible factor 1 expression. The presence of visceralized parietal epithelial cells in sclerosing and collapsing lesions in a kidney biopsy from a patient with diabetes underscores the human relevance of our findings. In conclusion, repopulation of the glomerular tuft by parietal cells may represent a compensatory response to extensive podocyte loss. Our results suggest, however, that visceralized parietal epithelial cells cannot induce revascularization of the hyalinized tuft, resulting in hypoxic cell death and irreversible destruction of the glomerulus.
Development and validation of a prognostic nomogram for recurrence-free survival after complete surgical resection of localised primary gastrointestinal stromal tumour: a retrospective analysis
Authors: Jason S Gold, Mithat Gönen, Antonio Gutiérrez, Javier Martín Broto, Xavier García-del-Muro, Thomas C Smyrk, Robert G Maki, Samuel Singer, Murray F Brennan, Cristina R Antonescu, John H Donohue, Ronald P DeMatteo
Journal: The Lancet Oncology (2009)
Healthy People 2000 at Mid Decade
Authors: J M McGinnis, P R Lee
Journal: JAMA (1995)

THE nation's health goals for the year 2000 were set forth with the 1990 release of<i>Healthy People 2000</i>,<sup>1</sup>which reviewed the principal health challenges for Americans and identified in measurable terms the opportunities for health gains during the 1990s. The arrival of the decade's midpoint prompts an assessment of progress to date. For editorial comment see p 1149. <i>Healthy People 2000</i>was based on the previous experience with setting national health targets for the year 1990,<sup>2,3</sup>the results for which have been described elsewhere.<sup>4</sup>The targets contained in<i>Healthy People 2000</i>were developed between 1987 and 1990 through an extensive consultative and hearings process conducted and managed by the US Public Health Service (PHS) in partnership with the National Academy of Sciences' Institute of Medicine.<sup>5</sup>To provide guidance to the effort, a national consortium was formed that included the principal health officials of the 50
SIRPα polymorphisms, but not the prion protein, control phagocytosis of apoptotic cells
Authors: Mario Nuvolone, Veronika Kana, Gregor Hutter, Daiji Sakata, Steven M. Mortin-Toth, Giancarlo Russo, Jayne S. Danska, Adriano Aguzzi
Journal: The Journal of Experimental Medicine (2013)

Prnp−/− mice lack the prion protein PrPC and are resistant to prion infections, but variable phenotypes have been reported in Prnp−/− mice and the physiological function of PrPC remains poorly understood. Here we examined a cell-autonomous phenotype, inhibition of macrophage phagocytosis of apoptotic cells, previously reported in Prnp−/− mice. Using formal genetic, genomic, and immunological analyses, we found that the regulation of phagocytosis previously ascribed to PrPC is instead controlled by a linked locus encoding the signal regulatory protein α (Sirpa). These findings indicate that control of phagocytosis was previously misattributed to the prion protein and illustrate the requirement for stringent approaches to eliminate confounding effects of flanking genes in studies modeling human disease in gene-targeted mice. The plethora of seemingly unrelated functions attributed to PrPC suggests that additional phenotypes reported in Prnp−/− mice may actually relate to Sirpa or other genetic confounders.
Activin A and Follistatin-Like 3 Determine the Susceptibility of Heart to Ischemic Injury
Authors: Yuichi Oshima, Noriyuki Ouchi, Masayuki Shimano, David R. Pimentel, Kyriakos N. Papanicolaou, Kalyani D. Panse, Kunihiro Tsuchida, Enrique Lara-Pezzi, Se-Jin Lee, Kenneth Walsh
Journal: Circulation (2009)

Background— Transforming growth factor-β family cytokines have diverse actions in the maintenance of cardiac homeostasis. Activin A is a member of this family whose regulation and function in heart are not well understood at a molecular level. Follistatin-like 3 (Fstl3) is an extracellular regulator of activin A protein, and its function in the heart is also unknown. Methods and Results— We analyzed the expression of various transforming growth factor-β superfamily cytokines and their binding partners in mouse heart. Activin βA and Fstl3 were upregulated in models of myocardial injury. Overexpression of activin A with an adenoviral vector (Ad-actβA) or treatment with recombinant activin A protein protected cultured myocytes from hypoxia/reoxygenation-induced apoptosis. Systemic overexpression of activin A in mice by intravenous injection of Ad-actβA protected hearts from ischemia/reperfusion injury. Activin A induced the expression of Bcl-2, and ablation of Bcl-2 by small interfering RNA abrogated its protective action in myocytes. The protective effect of activin A on cultured myocytes was abolished by treatment with Fstl3 or by a pharmacological activin receptor-like kinase inhibitor. Cardiac-specific Fstl3 knockout mice showed significantly smaller infarcts after ischemia/reperfusion injury that was accompanied by reduced apoptosis. Conclusions— Activin A and Fstl3 are induced in heart by myocardial stress. Activin A protects myocytes from death, and this activity is antagonized by Fstl3. Thus, the relative expression levels of these factors after injury is a determinant of cell survival in the heart.
Correlation of Laboratory Data for Renal Function in Newly Diagnosed Multiple Myeloma
Authors: Kazuhito Suzuki, Shingo Yano, Takaki Shimada, Shinobu Takahara, Kinuyo Kasama, Tomohito Machishima, Yumiko Inui, Masaharu Kawashima, Noriko Usui, Keisuke Aiba
Journal: Annals of Oncology (2014)
Clinical Expression of Plakophilin-2 Mutations in Familial Arrhythmogenic Right Ventricular Cardiomyopathy
Authors: Petros Syrris, Deirdre Ward, Angeliki Asimaki, Srijita Sen-Chowdhry, Hatim Y. Ebrahim, Alison Evans, Nobuhiko Hitomi, Mark Norman, Antonios Pantazis, Anthony L. Shaw, Perry M. Elliott, William J. McKenna
Journal: Circulation (2006)

Background— Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disorder characterized by loss of cardiomyocytes and their replacement by adipose and fibrous tissue. It is considered a disease of cell adhesion because mutations in desmosomal genes, desmoplakin and plakoglobin, have been implicated in the pathogenesis of ARVC. In a recent report, mutations in plakophilin-2, a gene highly expressed in cardiac desmosomes, have been shown to cause ARVC. Methods and Results— We investigated 100 white patients with ARVC for mutations in plakophilin-2. Nine different mutations were identified by direct sequencing in 11 cases. Five of these mutations are novel (A733fsX740, L586fsX658, V570fsX576, R413X, and P533fsX561) and predicted to cause a premature truncation of the plakophilin-2 protein. Family studies showed incomplete disease expression in mutation carriers and identified a number of individuals who would be misdiagnosed with the existing International Task Force and modified diagnostic criteria for ARVC. Conclusions— In this study, we provide new evidence that mutations in the desmosomal plakophilin-2 gene can cause ARVC. A systematic clinical evaluation of mutation carriers within families demonstrated variable phenotypic expression, even among individuals with the same mutation, and highlighted the need for a more accurate set of diagnostic criteria for ARVC.
Classification criteria for Sjogren's syndrome: nothing ever stands still!
Authors: Simon J Bowman, Robert I Fox
Journal: Annals of the Rheumatic Diseases (2013)

Primary Sjogren's syndrome (SS) probably has the dubious distinction of having more proposed criteria than any other rheumatic condition—certainly this was the case in the 1980s and 1990s (eg, Copenhagen,1 Californian,2 Greek3 and Japanese4 criteria). In 2002, Vitali et al 5 published the revised American European Consensus Group (AECG) criteria, which have now served as the gold standard for over 10 years. In 2012, Shiboski et al 6 published an alternative set of criteria, provisionally adopted by the American College of Rheumatology (ACR). These latter criteria (Sjogren's International Collaborative Clinical Alliance (SICCA-ACR)) are based on objective criteria and do not necessarily require patients to have symptoms of dry eyes or dry mouth. The study by Rasmussen et al 7 examines patients with primary SS in a large cohort who fulfil either the existing AECG criteria and/or the newly proposed SICCA–ACR criteria, and discusses the similarities and differences between them with some important lessons for the field.

The AECG criteria were developed to screen patients with a specific set of questions regarding dryness and then validate the diagnosis with a series of objective tests that indicated immune factors in the pathogenesis. The questionnaires were developed by an expert consensus panel for sensitivity and specificity as an initial screening tool. The AECG criteria require the presence of four out of six components (one of which is symptomatic dry eyes and a second is symptomatic dry mouth), or three out of the four other objective components, although in either case one of the components has to be positive antibodies and/or a positive biopsy. The four objective components are: (1) positive anti-Ro and/or anti-La antibodies; (2) a positive labial gland biopsy defined as at least one periductal focus of 50 or more lymphocytes per 4 mm2 high powered field; (3) reduced …
Human cardiomyocyte hypertrophy induced in vitro by gp130 stimulation
Authors: Cécile Ancey, Emmanuelle Menet, Pierre Corbi, Sandra Fredj, Martine Garcia-Tamisier, Catherine Rucker-Martin, Jocelyn Bescond, Franck Morel, John Wijdenes, Jean-Claude Lecron, Daniel Potreau
Journal: Cardiovascular Research (2003)

Objectives: Recent in vivo and in vitro studies in animals have demonstrated that cytokines of the IL-6 family are involved in cardiac hypertrophy and in protection of cardiomyocytes against apoptosis. The present study aims to analyse the capacity of human atrial cardiac cells (i.e., cardiomyocytes and fibroblasts) to display the gp130 receptor subunit, and to evaluate its functionality. Methods: Twenty human atrial biopsies were used for immunohistochemistry, in situ hybridisation, and western blot analysis or dissociated for isolation and primary culture of cardiac cells. Results: Fibroblasts present in tissue or maintained in primary culture clearly express gp130 whereas the signal in cardiomyocytes is weaker. Culture of cardiac cells with a gp130 agonist antibody enhances atrial natriuretic peptide (ANP), β myosin heavy chain (β-MHC) expression in cardiomyocytes, and significantly increases the cell surface area (μm2). This process could involve STAT3 (signal transducer and activator of transcription 3) phosphorylation. Conclusions: These results demonstrate that gp130 activation in human cardiac cells leads to cardiomyocyte hypertrophy. We discuss several hypotheses on the role of IL-6-type cytokines on cardiomyocyte functions.
C1-Esterase Inhibitor: An Anti-Inflammatory Agent and Its Potential Use in the Treatment of Diseases Other Than Hereditary Angioedema
Authors: C. Caliezi, W. A. Wuillemin, S. Zeerleder, M. Redondo, B. Eisele, C. E. Hack
Journal: Pharmacological Reviews (2000)

C1-esterase inhibitor (C1-Inh) therapy was introduced in clinical medicine about 25 years ago as a replacement therapy for patients with hereditary angioedema caused by a deficiency of C1-Inh. There is now accumulating evidence, obtained from studies in animals and observations in patients, that administration of C1-Inh may have a beneficial effect as well in other clinical conditions such as sepsis, cytokine-induced vascular leak syndrome, acute myocardial infarction, or other diseases. Activation of the complement system, the contact activation system, and the coagulation system has been observed in these diseases. A typical feature of the contact and complement system is that on activation they give rise to vasoactive peptides such as bradykinin or the anaphylatoxins, which in part explains the proinflammatory effects of either system. C1-Inh, belonging to the superfamily of serine proteinase inhibitors (serpins), is a major inhibitor of the classical complement pathway, the contact activation system, and the intrinsic pathway of coagulation, respectively. It is, therefore, endowed with anti-inflammatory properties. However, inactivation of C1-Inh occurs locally in inflamed tissues by proteolytic enzymes (e.g., elastase) released from activated neutrophils or bacteria thereby leading to increased local activation of the various host defense systems. Here we will give an overview on the biochemistry and biology of C1-Inh. We will discuss studies addressing therapeutic administration of C1-Inh in experimental and clinical conditions. Finally, we will provide an explanation for the therapeutic benefit of C1-Inh in so many different diseases.
Fluorouracil, epirubicin, and cyclophosphamide (FEC-75) followed by paclitaxel plus trastuzumab versus paclitaxel plus trastuzumab followed by FEC-75 plus trastuzumab as neoadjuvant treatment for patients with HER2-positive breast cancer (Z1041): a randomised, controlled, phase 3 trial
Authors: Aman U Buzdar, Vera J Suman, Funda Meric-Bernstam, A Marilyn Leitch, Matthew J Ellis, Judy C Boughey, Gary Unzeitig, Melanie Royce, Linda M McCall, Michael S Ewer, Kelly K Hunt
Journal: The Lancet Oncology (2013)
Anatomy of the coronary arteries in transposition of the great arteries and methods for their transfer in anatomical correction.
Authors: M H Yacoub, R Radley-Smith
Journal: Thorax (1978)

For the success of anatomical correction of transposition of the great arteries (TGA) it is essential to transfer the coronary ostia to the posterior vessel without undue tension, torsion, or kinking of the proximal coronary arteries or their early branches. This requires thorough understanding of the different modes of origin and early branching of the coronary arteries in TGA. Based on observations made during anatomical correction, a classification of the coronary arteries in TGA is suggested. In type A the right and left coronary ostia arise from the middle of the right and left posterior aortic sinuses and curve forwards to reach the right atrioventricular groove or anterior interventricular groove respectively. In type B both coronary arteries arise by a single ostium, while in type C the two coronary ostia are situated posteriorly, very close to each other, in a position similar to that in type B. The origin of the coronary arteries in type D is similar to that of type A. However, the right coronary artery gives origin to the circumflex coronary artery that curves round the posterior (pulmonary) vessel to reach the atrioventricular groove. In type E the right coronary artery arises in common with the left anterior descending artery from the left posterior sinus, while the circumflex artery arises separately from the right posterior sinus. Three techniques for the transfer of the different types of coronary arteries during anatomical correction are described.
Acute appendicitis is characterised by local invasion with Fusobacterium nucleatum/necrophorum
Authors: A. Swidsinski, Y. Dorffel, V. Loening-Baucke, F. Theissig, J. C. Ruckert, M. Ismail, W. A. Rau, D. Gaschler, M. Weizenegger, S. Kuhn, J. Schilling, W. V. Dorffel
Journal: Gut (2009)

Acute appendicitis is a local intestinal inflammation with unclear origin. The aim was to test whether bacteria in appendicitis differ in composition to bacteria found in caecal biopsies from healthy and disease controls.We investigated sections of 70 appendices using rRNA-based fluorescence in situ hybridisation. Four hundred caecal biopsies and 400 faecal samples from patients with inflammatory bowel disease and other conditions were used as controls. A set of 73 group-specific bacterial probes was applied for the study.The mucosal surface in catarrhal appendicitis showed characteristic lesions of single epithelial cells filled with a mixed bacterial population ('pinned cells') without ulceration of the surroundings. Bacteria deeply infiltrated the tissue in suppurative appendicitis. Fusobacteria (mainly Fusobacterium nucleatum and necrophorum) were a specific component of these epithelial and submucosal infiltrates in 62% of patients with proven appendicitis. The presence of Fusobacteria in mucosal lesions correlated positively with the severity of the appendicitis and was completely absent in caecal biopsies from healthy and disease controls. Main faecal microbiota represented by Bacteroides, Eubacterium rectale (Clostridium group XIVa), Faecalibacterium prausnitzii groups and Akkermansia muciniphila were inversely related to the severity of the disease. The occurrence of other bacterial groups within mucosal lesions of acute appendicitis was not related to the severity of the appendicitis. No Fusobacteria were found in rectal swabs of patients with acute appendicitis.Local infection with Fusobacterium nucleatum/necrophorum is responsible for the majority of cases of acute appendicitis.
Decline in Genetic Influence on the Co-Occurrence of Alcohol, Marijuana, and Nicotine Dependence Symptoms From Age 14 to 29
Authors: Scott I. Vrieze, Brian M. Hicks, William G. Iacono, Matt McGue
Journal: American Journal of Psychiatry (2012)

Objective Cross-sectional studies have demonstrated high rates of comorbidity among substance use disorders. However, few studies have examined the developmental course of incident comorbidity and how it changes from adolescence to adulthood. The authors examine patterns of comorbidity among substance use disorders to gain insight into the effect of shared versus specific etiological influences on measures of substance abuse and dependence. Method The authors evaluated the pattern of correlations among nicotine, alcohol, and marijuana abuse and dependence symptom counts as well as their underlying genetic and environmental influences in a community-representative twin sample (N=3,762). Symptoms were assessed at ages 11, 14, 17, 20, 24, and 29 years. A single common factor was used to model the correlations among symptom counts at each age. The authors examined age-related changes in the influence of this general factor by testing for differences in the mean factor loading across time. Results Mean levels of abuse or dependence symptoms increased throughout adolescence, peaked around age 20, and declined from age 24 to age 29. The influence of the general factor was highest at ages 14 and 17, but decreased from age 17 to age 24. Genetic influences of the general factor declined considerably with age alongside an increase in nonshared environmental influences. Conclusions Adolescent substance abuse or dependence is largely a function of shared etiology. As young people age, their symptoms are increasingly influenced by substance-specific etiological factors. Heritability analyses revealed that the generalized risk is primarily influenced by genetic factors in adolescence, but nonshared environmental influences increase in importance as substance dependence becomes more specialized in adulthood.
Reversible and irreversible elongation of ischemic, infarcted, and healed myocardium in response to increases in preload and afterload.
Authors: C M Connelly, R J McLaughlin, W M Vogel, C S Apstein
Journal: Circulation (1991)

BACKGROUND Left ventricular aneurysm formation after myocardial infarction (MI) has been associated with elongation of infarcted tissue in response to wall stress. Such elongation most commonly occurs in acutely infarcted or partially healed regions during the early post-MI period; however, recent reports have indicated that mature (15-week-old) healed infarct regions also undergo elongation after stress. METHODS AND RESULTS To assess factors contributing to post-MI left ventricular aneurysm formation, we subjected isolated strips (n = 50) of rabbit myocardial tissue from acutely ischemic (noninfarcted left ventricular), acutely infarcted (24 hours after MI), and healed infarct (3 and 15 weeks after MI) regions to a range of loading conditions and measured the reversible and irreversible length changes that occurred. The isolated strips were repetitively stretched for 1 hour at 4 Hz to impose cyclical physiological peak and resting stresses of 2.0 and 0.2 g/mm2. During a second hour, either peak stress ("afterload") or resting stress ("preload") was tripled, and the increase in strip length (strain) was measured. During a third hour, peak and resting stresses were returned to the initial values to assess the reversibility of length changes occurring during increased load. Elongation was expressed as the increase in natural strain from the first hour. Increasing afterload caused similar irreversible length increases of 4-5%/hr in acutely infarcted and 3- and 15-week-old healed infarct strips; acutely ischemic tissue length increased by 7.4%/hr (p less than 0.05 versus acutely infarcted tissue and scars). Increasing preload in acutely ischemic and acutely infarcted tissue caused a reversible length increase of less than 1%/hr. (Scar strips were not tested for the effect of preload.) CONCLUSIONS Since an irreversible length increase may represent an early event in aneurysm formation, our results suggest that 1) afterload increases are more likely to lead to aneurysm development than preload increases, 2) acutely ischemic tissue is the most vulnerable to increased afterload, and 3) for a given wall stress level, healing scar tissue is as susceptible to irreversible length changes as is acutely infarcted tissue. The observation that even mature post-MI scar elongated in response to increases in afterload implies that long-term pharmacological management of afterload in post-MI patients may be beneficial in preventing tissue elongation and aneurysm formation and that factors that increase wall stress (e.g., hypertension and exercise stress) have the potential to promote aneurysm formation in healed infarct scars.