tbuckley/cabot-search huggingface dataset:
Changes in Ventricular Size and Function in Patients Treated With Valsartan, Captopril, or Both After Myocardial Infarction
Authors: Scott D. Solomon, Hicham Skali, Nagesh S. Anavekar, Mikhail Bourgoun, Stale Barvik, Jalal K. Ghali, J. Wayne Warnica, Margarita Khrakovskaya, J. Malcolm O. Arnold, Yuri Schwartz, Eric J. Velazquez, Robert M. Califf, John V. McMurray, Marc A. Pfeffer
Journal: Circulation (2005)

Angiotensin-converting enzyme (ACE) inhibitors have been shown to attenuate left ventricular (LV) enlargement in association with reducing mortality after myocardial infarction (MI). Preclinical data suggest that angiotensin receptor blockers (ARBs) may have similar structural and functional effects after MI. The Valsartan in Acute Myocardial Infarction (VALIANT) Echo study was designed to test the hypothesis that the ARB valsartan, either alone or in combination with captopril, could attenuate progressive LV enlargement or improve LV ejection fraction to a greater extent than captopril alone.Six hundred ten patients enrolled in the main VALIANT study who experienced MI and evidence of LV dysfunction, heart failure, or both were enrolled in the VALIANT Echo study. Patients were randomized to receive valsartan 160 mg PO BID, captopril 50 mg PO TID, or valsartan 80 mg PO BID plus captopril 50 mg PO TID between 1 and 10 days after MI. Six hundred three patients had echocardiograms of sufficient quality for quantitative analysis. Echocardiograms were digitized, and endocardial borders were traced manually from 2 short-axis and 2 apical views. Ventricular volumes, ejection fractions, combined areas, and infarct segment length were measured, and changes in echocardiographic measures from baseline to 20 months were compared between treatment groups. Baseline clinical and echocardiographic characteristics were similar in the 3 treatment arms. The changes from baseline to 20 months in all echocardiographic parameters were similar in all 3 treatment arms. Baseline echocardiographic measures of ejection fraction, end-diastolic volume, and infarct segment length were highly predictive of outcomes including total mortality, death or hospitalization for heart failure, or death or any cardiovascular event (heart failure, MI, stroke, resuscitated sudden death), even after adjustment for known covariates.Treatment with the ACE inhibitor captopril, valsartan, or the combination of captopril plus valsartan resulted in similar changes in cardiac volume, ejection fraction, and infarct segment length between baseline and 20 months after MI. Baseline echocardiographic measures were powerfully and independently predictive of all major outcomes.
CD44 Deficiency Increases Tubular Damage But Reduces Renal Fibrosis in Obstructive Nephropathy
Authors: Kasper M.A. Rouschop, Miguel E. Sewnath, Nike Claessen, Joris J.T.H. Roelofs, Inge Hoedemaeker, Ronald van der Neut, Jan Aten, Steven T. Pals, Jan J. Weening, Sandrine Florquin
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. CD44 is a glycoprotein involved in inflammation and cell-cell/cell-matrix interactions. CD44 is upregulated in the kidney upon injury; however, its role in the pathogenesis of renal damage and fibrosis remains largely unknown. The authors show that mice lacking CD44 developed more tubular damage, associated with decreased proliferation and increased apoptosis of tubular epithelial cells, but less renal fibrosis after unilateral ureteral obstruction. In addition, impaired influx of macrophages and decreased accumulation of myofibroblasts was observed in the obstructed kidney of CD44−/− mice compared with CD44+/+ mice. Hepatocyte growth factor (HGF) and transforming growth factor-β1 (TGF-β1) exert reciprocal functions in the progression of renal diseases and interact with CD44 in vitro. For the first time, the authors establish diminished HGF-signaling, via its high affinity receptor c-Met, in the absence of CD44 in vivo. In parallel, the signaling of TGF-β1 reflected by the relative phosphorylation and nuclear translocation of Smad-2 and Smad-3 was reduced in the obstructed kidney of CD44−/− mice. In conclusion, CD44 exerts protective effects on tubuli but contributes to renal fibrogenesis at least in part through enhancement of HGF and TGF-β1 signaling pathway in obstructive nephropathy.
Cognitive Abilities and 50- and 100-msec Paired-Click Processes in Schizophrenia
Authors: Ashley K. Smith, J. Christopher Edgar, Mingxiong Huang, Brett Y. Lu, Robert J. Thoma, Faith M. Hanlon, Greg McHaffie, Aaron P. Jones, Rodrigo D. Paz, Gregory A. Miller, José M. Cañive
Journal: American Journal of Psychiatry (2010)

Abnormal 50- and 100-msec event-related brain activity derived from paired-click procedures are well established in schizophrenia. There is little agreement on whether group differences in the ratio score, i.e., the ratio of EEG amplitude after the second stimulus (S2) to the amplitude after the first stimulus (S1), reflect an encoding or gating abnormality. In addition, the functional implications remain unclear. In the present study, EEG and magnetoencephalography (MEG) were used to examine paired-click measures and cognitive correlates of paired-click activity.
Global Pharmacovigilance for Antiretroviral Drugs: Overcoming Contrasting Priorities
Authors: Nyasha Bakare, Ivor Ralph Edwards, Andy Stergachis, Shanthi Pal, Charles B. Holmes, Marie Lindquist, Chris Duncombe, Alex Dodoo, Joel Novendstern, Jude Nwokike, Ricardo Kuchenbecker, Judith A. Aberg, Veronica Miller, Jur Strobos
Journal: PLoS Medicine (2011)

Jur Strobos and colleagues describe the deliberations of a recent multi-stakeholder meeting discussing the creation of a sustainable global pharmacovigilance system for antiretroviral drugs that would be applicable in resource limited settings.
The role of the Grb2–p38 MAPK signaling pathway in cardiac hypertrophy and fibrosis
Authors: Shaosong Zhang, Carla Weinheimer, Michael Courtois, Attila Kovacs, Cindy E. Zhang, Alec M. Cheng, Yibin Wang, Anthony J. Muslin
Journal: Journal of Clinical Investigation (2003)

Cardiac hypertrophy is a common response to pressure overload and is associated with increased mortality. Mechanical stress in the heart can result in the integrin-mediated activation of focal adhesion kinase and the subsequent recruitment of the Grb2 adapter molecule. Grb2, in turn, can activate MAPK cascades via an interaction with the Ras guanine nucleotide exchange factor SOS and with other signaling intermediates. We analyzed the role of the Grb2 adapter protein and p38 MAPK in cardiac hypertrophy. Mice with haploinsufficiency of the Grb2 gene (Grb2+/– mice) appear normal at birth but have defective T cell signaling. In response to pressure overload, cardiac p38 MAPK and JNK activation was inhibited and cardiac hypertrophy and fibrosis was blocked in Grb2+/– mice. Next, transgenic mice with cardiac-specific expression of dominant negative forms of p38α (DN-p38α) and p38β (DN-p38β) MAPK were examined. DN-p38α and DN-p38β mice developed cardiac hypertrophy but were resistant to cardiac fibrosis in response to pressure overload. These results establish that Grb2 action is essential for cardiac hypertrophy and fibrosis in response to pressure overload, and that different signaling pathways downstream of Grb2 regulate fibrosis, fetal gene induction, and cardiomyocyte growth.
Activation of the Interventricular Septum
Authors: ALLEN M. SCHER, ALLAN C. YOUNG, ARTHUR L. MALMGREN, ROBERT V. ERICKSON
Journal: Circulation Research (1955)

Multipolar recording techniques have been used to study excitation of the canine interventricular septum. Activity commences in the mid left septal endocardium and slightly later near the right anterior papillary muscle. From these sites depolarization spreads over the endocardial surfaces, probably via the Purkinje tissue, at 1 m./sec. and through the septal thickness at one-third this speed. Near the upper septum, bilaterally and on the posterior right there is a lack of the rapid endocardial conduction. Septal contribution to the QRS is considered.
<i>In vitro</i> Modeling of Human Pancreatic Duct Epithelial Cell Transformation Defines Gene Expression Changes Induced by K-<i>ras</i> Oncogenic Activation in Pancreatic Carcinogenesis
Authors: Jiaying Qian, Jiangong Niu, Ming Li, Paul J. Chiao, Ming-Sound Tsao
Journal: Cancer Research (2005)

Abstract Genetic analysis of pancreatic ductal adenocarcinomas and their putative precursor lesions, pancreatic intraepithelial neoplasias (PanIN), has shown a multistep molecular paradigm for duct cell carcinogenesis. Mutational activation or inactivation of the K-ras, p16INK4A, Smad4, and p53 genes occur at progressive and high frequencies in these lesions. Oncogenic activation of the K-ras gene occurs in &amp;gt;90% of pancreatic ductal carcinoma and is found early in the PanIN-carcinoma sequence, but its functional roles remain poorly understood. We show here that the expression of K-rasG12V oncogene in a near diploid HPV16-E6E7 gene immortalized human pancreatic duct epithelial cell line originally derived from normal pancreas induced the formation of carcinoma in 50% of severe combined immunodeficient mice implanted with these cells. A tumor cell line established from one of these tumors formed ductal cancer when implanted orthotopically. These cells also showed increased activation of the mitogen-activated protein kinase, AKT, and nuclear factor-κB pathways. Microarray expression profiling studies identified 584 genes whose expression seemed specifically up-regulated by the K-ras oncogene expression. Forty-two of these genes have been reported previously as differentially overexpressed in pancreatic cancer cell lines or primary tumors. Real-time PCR confirmed the overexpression of a large number of these genes. Immunohistochemistry done on tissue microarrays constructed from PanIN and pancreatic cancer samples showed laminin β3 overexpression starting in high-grade PanINs and occurring in &amp;gt;90% of pancreatic ductal carcinoma. The in vitro modeling of human pancreatic duct epithelial cell transformation may provide mechanistic insights on gene expression changes that occur during multistage pancreatic duct cell carcinogenesis.
A selective defect of interferon alpha production in human immunodeficiency virus-infected monocytes.
Authors: H E Gendelman, R M Friedman, S Joe, L M Baca, J A Turpin, G Dveksler, M S Meltzer, C Dieffenbach
Journal: The Journal of Experimental Medicine (1990)

Interferon alpha (IFN-alpha) induces significant antiretroviral activities that affect the ability of human immunodeficiency virus (HIV) to infect and replicate in its principal target cells, CD4+ T cells and macrophages. A major endogenous source of IFN-alpha during any infection is the macrophage. Thus, macrophages have the potential to produce both IFN-alpha and HIV. In this study, we examined the production of IFN-alpha and other cytokines by macrophage colony-stimulating factor (M-CSF)-treated cultured monocytes during HIV infection. Tumor necrosis factor alpha (TNF-alpha), interleukin 1 beta (IL-1 beta), IL-6, IFN-omega, or IFN-beta were not detected nor was the mRNA expressed in either uninfected or HIV-infected monocytes. However, both uninfected and HIV-infected monocytes produced high levels of each of these cytokines after treatment with synthetic double-stranded RNA [poly(I).poly(C)]. Uninfected monocytes also produced high levels of IFN-alpha after treatment with poly(I).poly(C), Newcastle disease virus, or herpes simplex virus. In marked contrast to the preceding observations, HIV-infected monocytes produced little or no IFN-alpha before or after treatment with any of these agents. The absence of detectable IFN-alpha activity and mRNA in poly(I).poly(C)-treated HIV-infected monocytes was coincident with high levels of 2',5' oligoadenylate synthetase and complete ablation of HIV gene expression. The antiviral activity induced by poly(I).poly(C) may be a direct effect of this synthetic double-stranded RNA or secondary to the low levels of IFN-beta and IFN-omega produced by infected cells. The markedly diminished capacity of HIV-infected monocytes to produce IFN-alpha may reflect a specific adaptive mechanism of virus to alter basic microbicidal functions of this cell. The inevitable result of this HIV-induced cytokine dysregulation is virus replication and persistence in mononuclear phagocytes.
A Truncated Polycystin-2 Protein Causes Polycystic Kidney Disease and Retinal Degeneration in Transgenic Rats
Authors: Anna Rachel Gallagher, Sigrid Hoffmann, Nelson Brown, Anna Cedzich, Sujatha Meruvu, Dirk Podlich, Yuxi Feng, Vera Könecke, Uwe de Vries, Hans-Peter Hammes, Norbert Gretz, Ralph Witzgall
Journal: Journal of the American Society of Nephrology (2006)

The cloning of the PKD1 and PKD2 genes has led to promising new insight into the mechanisms that are responsible for cyst development in patients with autosomal dominant polycystic kidney disease. Although the dominant pattern of inheritance would argue for haploinsufficiency, a gain of function, or a dominant negative mechanism, there is good evidence that autosomal dominant polycystic kidney disease behaves like a recessive disease on a cellular level (two-hit mechanism of cystogenesis). For testing of whether other pathomechanisms in addition to the two-hit hypothesis can explain cyst formation, two transgenic rat lines that contain a truncated human polycystin-2 cDNA were generated. The protein product lacks almost the entire COOH-terminus and mimics mutations that frequently are found in patients. The transgene-encoded mRNA could be detected in multiple tissues of both transgenic lines, with the highest expression in the kidney. Both lines present with renal cysts that originate predominantly from the proximal tubule; in the tubular epithelial cells, the epitope-tagged mutant protein was detected in the brush border and in primary cilia. Further evidence of the involvement of primary cilia stems from the finding of retinal degeneration in the transgenic rats and from the fact that stably transfected LLC-PK(1) cells that inducibly produced the truncated polycystin-2 protein elaborated shorter cilia. Other experimental approaches, such as a knock-in strategy, will be necessary to validate these results, but this is the first preliminary evidence that cyst formation is due not only to somatic mutations.
DNA Methylation Does Not Stably Lock Gene Expression but Instead Serves as a Molecular Mark for Gene Silencing Memory
Authors: Noël J.-M. Raynal, Jiali Si, Rodolphe F. Taby, Vazganush Gharibyan, Saira Ahmed, Jaroslav Jelinek, Marcos R.H. Estécio, Jean-Pierre J. Issa
Journal: Cancer Research (2012)

DNA methylation is commonly thought of as a "molecular lock" that leads to permanent gene silencing. To investigate this notion, we tested 24 different histone deacetylase inhibitors (HDACi) on colon cancer cells that harbor a GFP locus stably integrated and silenced by a hypermethylated cytomegalovirus (CMV) promoter. We found that HDACi efficiently reactivated expression of GFP and many other endogenous genes silenced by DNA hypermethylation. After treatment, all promoters were marked with active chromatin, yet DNA hypermethylation did not change. Thus, DNA methylation could not prevent gene reactivation by drug-induced resetting of the chromatin state. In evaluating the relative contribution of DNA methylation and histone modifications to stable gene silencing, we followed expression levels of GFP and other genes silenced by DNA hypermethylation over time after treatment with HDACi or DNA-demethylating drugs. Reactivation of methylated loci by HDACi was detectable for only 2 weeks, whereas DNA-demethylating drugs induced permanent epigenetic reprogramming. Therefore, DNA methylation cannot be considered as a lock for gene expression but rather as a memory signal for long-term maintenance of gene silencing. These findings define chromatin as an important druggable target for cancer epigenetic therapy and suggest that removal of DNA methylation signals is required to achieve long-term gene reactivation.
Letter by Taegtmeyer and Khalaf Regarding Article, “Glucose-Insulin-Potassium Reduces the Incidence of Low Cardiac Output Episodes After Aortic Valve Replacement for Aortic Stenosis in Patients With Left Ventricular Hypertrophy: Results From the Hypertrophy, Insulin, Glucose, and Electrolytes (HINGE) Trial”
Authors: Heinrich Taegtmeyer, Khaled I. Khalaf
Journal: Circulation (2011)
Incidence of rheumatoid arthritis in Finland during 1980-1990.
Authors: O Kaipiainen-Seppanen, K Aho, H Isomaki, M Laakso
Journal: Annals of the Rheumatic Diseases (1996)

OBJECTIVE: To obtain information on the incidence of rheumatoid arthritis and on its recent trends in Finland. METHODS: The study covered those subjects entitled to receive specially reimbursed medication for rheumatoid arthritis under the nationwide sickness insurance scheme in five out of 21 central hospital districts in Finland (population basis about one million adults) during three years: 1980, 1985, and 1990. RESULTS: The annual incidence of rheumatoid arthritis in 1980 and 1985, satisfying the American Rheumatism Association 1987 classification criteria, was 39/100,000 of the population &gt; or = 16 years of age. The combined incidence of rheumatoid factor (RF) positive arthritis and RF negative polyarthritis was 46/100,000. A decline of approximately 40% occurred in the number of RF negative rheumatoid arthritis cases in 1990 compared with the earlier years. The declining trend was statistically significant (P = 0.008). CONCLUSION: The decline in incidence of RF negative rheumatoid arthritis in Finland may reflect changes in the environment specifically affecting the risk of RF negative disease.
How much intimacy is compatible with survival for a cardiomyocyte?
Authors: W LAMERS, S KOHLER
Journal: Cardiovascular Research (2005)

See also article by Driesen et al. (pages 37–46) in this issue. 

Most forms of communication between cells occur at the plasma membrane via signal transduction molecules and only indirectly modify the cell's interior. It is easily conceivable that this safeguard is necessary for the cell to maintain the gradient in concentration of biochemical components between its interior and the environment. For similar defensive reasons, extracellular material that is taken up via endocytosis is shuttled to the lysosomes to terminate any inherent biological activity. Most cells, nevertheless, do permit a tightly regulated form of direct communication with other cells, even if they are phenotypically dissimilar, by allowing the formation of gap junctions. Gap junctions have a functional pore size of ∼1.5 nm, which allows the passage of small (<1 kDa) molecules. Macromolecules, therefore, need “second messengers” generated at the cell membrane to affect composition or function of the cell's interior.

Almost at the other extreme of the spectrum, cells within a tissue can fuse to form a syncytium. Examples are the cells that form striated muscles, the placental syncytiotrophoblast, and osteoclasts. A characteristic feature of these examples of cell fusion is that the participating cells are phenotypically identical. This aspect appears to be important, as experimental fusion between cells originating from different tissues (creating so-called heterokaryons) often induces, in addition to genetic instability, reprogramming of the genome in … 

*Corresponding author. Email address: w.h.lamers{at}amc.uva.nl
Regular follow up for patients irradiated for early stage nonsmall cell lung cancer too!
Authors: B. Jeremic, J. Classen, M. Bamberg
Journal: European Respiratory Journal (2002)

To the Editor: 

It was with interest that we read the recent article by Egermann et al. 1 on the outcome of regular follow­up in patients with nonsmall­cell lung cancer (NSCLC) treated with curative resection, including cost­effectiveness analysis. We wholeheartedly agree with the conclusions of the study, but would like to extend this observation to another subset of patients, namely those with technically operable, but medically inoperable early stage NSCLC, usually treated with radiation therapy (RT) alone 2–5. There are a number of similarities and differences between these two patient groups.

First, contrary to surgical series, RT patients developing metachronous second primary lung cancer (mSPLC) are not treated differently from those relapsing …
Isoform-selective phosphoinositide 3′-kinase inhibitors inhibit CXCR4 signaling and overcome stromal cell–mediated drug resistance in chronic lymphocytic leukemia: a novel therapeutic approach
Authors: Matthias Niedermeier, Bryan T. Hennessy, Zachary A. Knight, Marina Henneberg, Jianhua Hu, Antonina V. Kurtova, William G. Wierda, Michael J. Keating, Kevan M. Shokat, Jan A. Burger
Journal: Blood (2009)
The effectiveness of a squash eyewear promotion strategy
Authors: R Eime, C Finch, R Wolfe, N Owen, C McCarty
Journal: British Journal of Sports Medicine (2005)

Objective: To evaluate the protective eyewear promotion (PEP) project, which was a comprehensive educational strategy to increase the use of appropriate protective eyewear by squash players. Methods: An ecological study design was used. Four squash venues in one playing association were randomly chosen to receive PEP and four in another association maintained usual practice and hence formed a control group. The primary evaluation measurements were surveys of cross sectional samples of players carried out before and after the intervention. The surveys investigated players’ knowledge, behaviours, and attitudes associated with the use of protective eyewear. The survey carried out after the intervention also determined players’ exposure to PEP. Univariate and multivariate analyses were undertaken to describe differences at PEP venues from pre- to post-intervention and to compare these with the control venues. Results: The PEP players had 2.4 times the odds (95% confidence interval, 1.3 to 4.2) of wearing appropriate eyewear compared with control group players post-intervention, relative to the groups’ pre-intervention baselines. Components of PEP, such as stickers and posters and the availability and prominent positioning of the project eyewear, were found to contribute to players adopting favourable eyewear behaviours. Conclusions: Components of the PEP intervention were shown to be effective. The true success will be the sustainability and dissemination of the project, favourable eyewear behaviours, and evidence of the prevention of eye injuries long into the future.
Mutant prominin 1 found in patients with macular degeneration disrupts photoreceptor disk morphogenesis in mice
Authors: Zhenglin Yang, Yali Chen, Concepcion Lillo, Jeremy Chien, Zhengya Yu, Michel Michaelides, Martin Klein, Kim A. Howes, Yang Li, Yuuki Kaminoh, Haoyu Chen, Chao Zhao, Yuhong Chen, Youssef Tawfik Al-Sheikh, Goutam Karan, Denis Corbeil, Pascal Escher, Shin Kamaya, Chunmei Li, Samantha Johnson, Jeanne M. Frederick, Yu Zhao, Changguan Wang, D. Joshua Cameron, Wieland B. Huttner, Daniel F. Schorderet, Frances L. Munier, Anthony T. Moore, David G. Birch, Wolfgang Baehr, David M. Hunt, David S. Williams, Kang Zhang
Journal: Journal of Clinical Investigation (2008)

Familial macular degeneration is a clinically and genetically heterogeneous group of disorders characterized by progressive central vision loss. Here we show that an R373C missense mutation in the prominin 1 gene (PROM1) causes 3 forms of autosomal-dominant macular degeneration. In transgenic mice expressing R373C mutant human PROM1, both mutant and endogenous PROM1 were found throughout the layers of the photoreceptors, rather than at the base of the photoreceptor outer segments, where PROM1 is normally localized. Moreover, the outer segment disk membranes were greatly overgrown and misoriented, indicating defective disk morphogenesis. Immunoprecipitation studies showed that PROM1 interacted with protocadherin 21 (PCDH21), a photoreceptor-specific cadherin, and with actin filaments, both of which play critical roles in disk membrane morphogenesis. Collectively, our results identify what we believe to be a novel complex involved in photoreceptor disk morphogenesis and indicate a possible role for PROM1 and PCDH21 in macular degeneration.