tbuckley/cabot-search huggingface dataset:
Cardiomyocyte Apoptosis Induced by Gαq Signaling Is Mediated by Permeability Transition Pore Formation and Activation of the Mitochondrial Death Pathway
Authors: John W. Adams, Amy L. Pagel, Christopher K. Means, Donna Oksenberg, Robert C. Armstrong, Joan Heller Brown
Journal: Circulation Research (2000)

Abstract —Expression of the wild-type α subunit of Gq stimulates phospholipase C and induces hypertrophy in cardiomyocytes. Addition of Gq-coupled receptor agonists additionally activates phospholipase C, as does expression of a constitutively active mutant form of Gαq. Under these conditions, hypertrophy is rapidly succeeded by apoptotic cellular and molecular changes, including myofilament disorganization, loss of mitochondrial membrane potential, alterations in Bcl-2 family protein levels, DNA fragmentation, increased caspase activity (≈4-fold), cytochrome c redistribution, and nuclear chromatin condensation in ≈12% of the cells. We used various interventions to define the molecular relationships between these events and identify potential sites at which these features of apoptosis could be rescued. Treatment with caspase inhibitors prevented DNA fragmentation and promoted myocyte survival; however, cytochrome c release and loss of mitochondrial membrane potential still occurred. In contrast, treatment with bongkrekic acid, an inhibitor of the mitochondrial permeability transition pore, not only prevented DNA fragmentation and reduced nuclear chromatin condensation but also preserved mitochondrial membrane potential and limited cytochrome c redistribution to only ≈2% of cells. These data demonstrate the central role of mitochondrial membrane potential in initiation of caspase activation and downstream apoptotic events and suggest that preservation of mitochondrial integrity is crucial for prolonging the life and function of cardiomyocytes exposed to pathological levels of stress.
Randomized, Open-Label, Phase III Study of a 28-Day Oral Regimen of Eniluracil Plus Fluorouracil Versus Intravenous Fluorouracil Plus Leucovorin as First-Line Therapy in Patients With Metastatic/Advanced Colorectal Cancer
Authors: R. L. Schilsky
Journal: Journal of Clinical Oncology (2002)

PURPOSE: To compare the efficacy and tolerability of eniluracil (EU)/fluorouracil (5-FU) with that of 5-FU/leucovorin (LV) as first-line therapy for patients with metastatic/advanced colorectal cancer. PATIENTS AND METHODS: This multicenter, randomized, open-label, phase III study (FUMA3008) conducted in the United States and Canada compared the safety and efficacy of EU/5-FU (11.5 mg/m2/1.15 mg/m2 twice daily for 28 days every 35 days) with that of intravenous 5-FU/LV (425 mg/m2/20 mg/m2 once daily for 5 days every 28 days) in patients with previously untreated metastatic colorectal cancer. Overall survival (OS) was the primary end point. RESULTS: A total of 981 patients were randomized and 964 patients received treatment (485 EU/5FU, 479 5FU/LV). Survival for EU/5-FU was not statistically equivalent (but not statistically inferior) to that for 5-FU/LV (hazard ratio, 0.880; 95% confidence interval [CI], 0.75 to 1.03). Median duration of survival was 13.3 months in the EU/5-FU group and 14.5 months in the 5-FU/LV group. Median duration of progression-free survival for EU/5-FU was statistically inferior to that of the control group (20.0 weeks [95% CI, 19.1 to 20.9 weeks] v 22.7 weeks [95% CI, 18.3 to 24.6 weeks]; P = .01). Both treatments were well tolerated. Diarrhea was the most common nonhematologic toxicity in both groups; treatment-related grade 3 or 4 diarrhea occurred in 19% of patients treated with EU/5-FU and 16% of patients receiving 5-FU/LV (P = .354). Grade 3 or 4 granulocytopenia occurred in 5% of EU/5-FU patients and 47% of 5-FU/LV patients. CONCLUSION: Safety profiles of both treatments were acceptable. Although antitumor activity was observed, EU/5-FU did not meet the protocol-specified statistical criteria for equivalence to 5-FU/LV in terms of OS.
Use of nontraditional anticoagulants in portal vein thrombosis: A note of caution
Authors: Douglas A. Simonetto, Waldemar E. Wysokinski, Patrick S. Kamath
Journal: Hepatology (2014)

Potential conflict of interest: Dr. Wysokinski consults for Daiichi Sankyo. To the Editor: We read with great interest the articles by Martinez et al.1 and Intagliata et al.2 in Hepatology describing the use of nontraditional anticoagulants for treatment of portal and mesenteric vein thrombosis. We agree that newer anticoagulants for portal and mesenteric vein thrombosis are probably effective in some patients. In addition, routine laboratory monitoring is not required; drug dosage is fixed, and there are no major drug or food interactions. However, before recommending widespread use in patients with liver disease, several concerns need addressing. Patients with cirrhosis are at increased risk for gastrointestinal (GI) bleeding. The lack of reliable reversal agents for newer anticoagulants could be disastrous during variceal bleeding.3 Direct oral factor inhibitors (DOFI(s); other than edoxaban [not approved in the United States]) are not safer than warfarin. Apixaban has similar risk, whereas dabigatran and rivaroxaban have significantly higher GI bleeding than warfarin. Interestingly, dabigatran showed a similar proportion of upper and lower GI bleeding, whereas with rivaroxaban and apixaban use, bleeding was upper GI in two thirds.4 Reliable reversal of anticoagulation is essential in the patient awaiting liver transplantation to decrease bleeding risk at surgery. Warfarin can be readily reversed; not so with DOFIs. Prothrombin complex concentrate (PCC), a highly purified concentrate of clotting factors, is a potential reversal agent for patients taking oral factor Xa inhibitors. Because plasma levels of DOFIs cannot be measured, determination of PCC dose is difficult. Excessive PCC use leads to a higher thrombotic risk. Therefore, monitoring anticoagulation intensity, and its reversal, is vastly superior with warfarin, compared to DOFIs. The safety of DOFIs in liver disease is unknown. Recently, several cases of probable rivaroxaban‐induced liver injury have been reported with elevation of serum transaminases and bilirubin concentration; the majority recovered after rivaroxaban discontinuation.5 Theoretically, there is an increased risk of bleeding in patients with impaired hepatic synthetic function. Finally, self‐testing of international normalized ratio is feasible, well accepted, and cost‐effective.6 Therefore, we are slow to recommend these newer, more expensive anticoagulant agents.
Responses to inflation of vagal afferents with endings in the lung of dogs.
Authors: M P Kaufman, G A Iwamoto, J H Ashton, S S Cassidy
Journal: Circulation Research (1982)

In dogs, inflating the lungs to pressures of 9 cm H2O or less reflexly increases heart rate, whereas inflating the lungs to pressures of 10-30 cm H2O reflexly decreases heart rate. The afferent fibers responsible for the cardioacceleration travel in the vagus nerves and are believed to be pulmonary stretch receptors, whereas the afferent responsible for the deceleration also travel in the vagus nerves, but are believed to be lung C-fibers. To identify the afferents responsible for these effects, we recorded the impulse activity of vagal afferents with endings in the left lung, while we slowly inflated that lung to 30-45 cm H2O. We found that 12 slowly adapting receptors fired at significantly lower inflation pressures than did 10 rapidly adapting receptors (5.8 +/- 1.5 vs. 13.5 +/- 2.2 cm H2O, respectively). We also found that 13 pulmonary C-fibers fired at significantly lower inflation pressures than did 10 bronchial C-fibers (16.4 +/- 1.8 vs 26.5 %/- 2.9 cm H2O, respectively). We conclude that slowly adapting receptors are likely to be responsible for the cardioacceleration evoked by low levels of inflation, and that both pulmonary and bronchial C-fibers are likely to be responsible for the cardiodeceleration evoked by high levels of inflation.
Agalsidase Alfa and Kidney Dysfunction in Fabry Disease
Authors: Michael West, Kathy Nicholls, Atul Mehta, Joe T.R. Clarke, Robert Steiner, Michael Beck, Bruce A. Barshop, William Rhead, Robert Mensah, Markus Ries, Raphael Schiffmann
Journal: Journal of the American Society of Nephrology (2009)

In male patients with Fabry disease, an X-linked disorder of glycosphingolipid metabolism caused by deficient activity of the lysosomal enzyme alpha-galactosidase A, kidney dysfunction becomes apparent by the third decade of life and invariably progresses to ESRD without treatment. Here, we summarize the effects of agalsidase alfa on kidney function from three prospective, randomized, placebo-controlled trials and their open-label extension studies involving 108 adult male patients. The mean baseline GFR among 54 nonhyperfiltrating patients (measured GFR <135 ml/min per 1.73 m(2)) treated with placebo was 85.4 +/- 29.6 ml/min per 1.73 m(2); during 6 mo of placebo, the mean annualized rate of change in GFR was -7.0 +/- 32.9 ml/min per 1.73 m(2). Among 85 nonhyperfiltrating patients treated with agalsidase alfa, the annualized rate of change was -2.9 +/- 8.7 ml/min per 1.73 m(2). Treatment with agalsidase alfa did not affect proteinuria. Multivariate analysis revealed that GFR and proteinuria category (< 1 or > or = 1 g/d) at baseline significantly predicted the rate of decline of GFR during treatment. This summary represents the largest group of male patients who had Fabry disease and for whom the effects of enzyme replacement therapy on kidney function have been studied. These data suggest that agalsidase alfa may stabilize kidney function in these patients.
Comparative genomic analysis of European and Middle Eastern community-associated methicillin-resistant Staphylococcus aureus (CC80:ST80-IV) isolates by high-density microarray
Authors: R.V. Goering, A.R. Larsen, R. Skov, F.C. Tenover, K.L. Anderson, P.M. Dunman
Journal: Clinical Microbiology and Infection (2009)
Hepatic and splanchnic nitric oxide activity in patients with cirrhosis
Authors: A I Sarela, F M A Mihaimeed, J J Batten, B R Davidson, R T Mathie
Journal: Gut (1999)

BACKGROUND In animal models of cirrhosis, altered activity of nitric oxide (NO) has been implicated in the pathogenesis of increased intrahepatic portal vascular resistance and abnormal mesenteric vasodilatation. AIMS To investigate NO activity in the liver and splanchnic vascular bed of patients with cirrhosis. METHODS Activity of the calcium dependent constitutive and calcium independent inducible isoforms of NO synthase (cNOS and iNOS, respectively) was assayed biochemically in biopsy specimens of liver and a vascular portion of the greater omentum (representative of mesenteric vasculature) obtained from patients with cirrhosis undergoing liver transplantation (n=14) and non-cirrhotic control patients undergoing liver resection for metastases (n=9). The concentration of NO metabolites (NO 2 + NO 3 ) in portal and peripheral venous plasma was measured. RESULTS The activity of cNOS was lower in cirrhotic compared with non-cirrhotic subjects for both liver and omentum. Hepatic and omental iNOS activities did not differ significantly between the two groups. Portal (NO 2 + NO 3 ) was threefold higher in cirrhotic than non-cirrhotic patients, but no differences were observed in systemic venous samples from the two groups. CONCLUSIONS The activity of cNOS is diminished in the cirrhotic human liver. The resultant decrease in constitutive NO release may promote an increase in the intrahepatic portal vascular resistance. Elevated portal venous (NO 2 + NO 3 ) indicates enhanced splanchnic vascular release of NO in cirrhotic patients, but the absence of increased NOS activity in the mesenteric vasculature suggests differential regulation of NO synthesis within the splanchnic vascular bed.
Restoration of β-Adrenergic Receptor Signaling and Contractile Function in Heart Failure by Disruption of the βARK1/Phosphoinositide 3-Kinase Complex
Authors: Cinzia Perrino, Sathyamangla V. Naga Prasad, Jacob N. Schroder, Jonathan A. Hata, Carmelo Milano, Howard A. Rockman
Journal: Circulation (2005)

Background— Desensitization and downregulation of myocardial β-adrenergic receptors (βARs) are initiated by the increase in βAR kinase 1 (βARK1) levels. By interacting with βARK1 through the phosphoinositide kinase (PIK) domain, phosphoinositide 3-kinase (PI3K) is targeted to agonist-stimulated βARs, where it regulates endocytosis. We tested the hypothesis that inhibition of receptor-targeted PI3K activity would alter receptor trafficking and ameliorate βAR signaling, ultimately improving contractility of failing cardiomyocytes. Methods and Results— To competitively displace PI3K from βARK1, we generated mice with cardiac-specific overexpression of the PIK domain. Seven-day isoproterenol administration in wild-type mice induced desensitization of βARs and their redistribution from the plasma membrane to early and late endosomes. In contrast, transgenic PIK overexpression prevented the redistribution of βARs away from the plasma membrane and preserved their responsiveness to agonist. We further tested whether PIK overexpression could normalize already established βAR abnormalities and ameliorate contractile dysfunction in a large animal model of heart failure induced by rapid ventricular pacing in pigs. Failing porcine hearts showed increased βARK1-associated PI3K activity and marked desensitization and redistribution of βARs to endosomal compartments. Importantly, adenoviral gene transfer of the PIK domain in failing pig myocytes resulted in reduced receptor-localized PI3K activity and restored to nearly normal agonist-stimulated cardiomyocyte contractility. Conclusions— These data indicate that the heart failure state is associated with a maladaptive redistribution of βARs away from the plasma membrane that can be counteracted through a strategy that targets the βARK1/PI3K complex.
ATTEMPTS TO TRANSMIT RHEUMATIC FEVER TO RABBITS AND GUINEA PIGS
Authors: C. Philip Miller
Journal: The Journal of Experimental Medicine (1924)

In a series of attempts to transmit a virus from patients in the acute stages of rheumatic fever, twenty-seven rabbits and fourteen guinea pigs were inoculated with one of the following materials: whole blood, serum, joint fluid, pleural fluid, throat washings, suspensions of tonsil tissue. Subsequent transfer inoculations from animal to animal brought the total number of animals employed in the experiments to 67 rabbits and 40 guinea pigs. Only two animals developed an acute non-bacterial arthritis. No other evidence of successful transmission of the disease was obtained. In about one-half of the rabbits and two-thirds of the guinea pigs myocardial lesions were encountered which consisted of interstitial accumulations of lymphocytes and endothelial cells. Similar lesions were found in control animals.
S region sequence, RNA polymerase II, and histone modifications create chromatin accessibility during class switch recombination
Authors: Lili Wang, Robert Wuerffel, Scott Feldman, Ahmed Amine Khamlichi, Amy L. Kenter
Journal: The Journal of Experimental Medicine (2009)

Immunoglobulin class switch recombination is governed by long-range interactions between enhancers and germline transcript promoters to activate transcription and modulate chromatin accessibility to activation-induced cytidine deaminase (AID). However, mechanisms leading to the differential targeting of AID to switch (S) regions but not to constant (C(H)) regions remain unclear. We show that S and C(H) regions are dynamically modified with histone marks that are associated with active and repressed chromatin states, respectively. Chromatin accessibility is superimposable with the activating histone modifications, which extend throughout S regions irrespective of length. High density elongating RNA polymerase II (RNAP II) is detected in S regions, suggesting that the transcription machinery has paused and stalling is abolished by deletion of the S region. We propose that RNAP II enrichment facilitates recruitment of histone modifiers to generate accessibility. Thus, the histone methylation pattern produced by transcription localizes accessible chromatin to S regions, thereby focusing AID attack.
Regulation of cardiac β-adrenergic response by nitric oxide
Authors: J Balligand
Journal: Cardiovascular Research (1999)

Time for primary review 12 days. 

The force and frequency of myocardial contraction are physiologically regulated by neurotransmitters and hormones. Norepinephrine released by the sympathetic nerves in the heart and epinephrine released into the circulation by adrenal glands increase myocardial contractility by acting on both α- and β-adrenergic receptors on heart muscle. Opposed to that is the action of acetylcholine released from parasympathetic nerves which reduces contractility by binding to muscarinic cholinergic receptors. The first demonstration that these two autonomic pathways are regulated by nitric oxide (NO) produced endogenously within cardiac muscle cells [1] both completes the understanding of the molecular mechanism of action of neurotransmitters in the heart and offers potential new therapeutic approaches for the correction of the altered responsiveness of cardiac muscle to autonomic regulation in circumstances such as heart failure.

We will briefly review the molecular pathways leading to the intracellular actions of β-adrenergic and muscarinic cholinergic agonists in the cardiac myocyte, integrating the more recent evidence implicating the NO pathway from the single myocyte to clinical situations.

### 1.1 β-Adrenergic pathway

β-Adrenergic agonists are well known to increase the force and frequency of contraction and increase the rate of relaxation of cardiac muscle. Despite some differences between regions of the heart, in general, the early increase in force of contraction is related directly to an increase in transmembrane flux of calcium, through phosphorylation of the L-type Ca channel, and the subsequent calcium-induced calcium release from the sarcoplasmic reticulum, whereas the sustained inotropic effect during the subsequent beats results from both increased influx and increased mobilization of internal calcium resulting from an increased replenishing of the reservoir of calcium in the sarcoplasmic reticulum [2,3].

A hallmark of the β-adrenergic effect on the heart is to increase the rate of relaxation which has been related to more rapid termination of … 

* Corresponding author. Tel.: +32-2-764-5349; fax: +32-2-764-9322 balligand{at}mint.ucl.ac.be
Cytokine blockade attenuates sympathoexcitation in heart failure: Cross‐talk between nNOS, AT‐1R and cytokines in the hypothalamic paraventricular nucleus
Authors: Anuradha Guggilam, Kaushik P. Patel, Masudul Haque, Philip J. Ebenezer, Daniel R. Kapusta, Joseph Francis
Journal: European Journal of Heart Failure (2008)
Origin of Cardiac Fibroblasts and the Role of Periostin
Authors: Paige Snider, Kara N. Standley, Jian Wang, Mohamad Azhar, Thomas Doetschman, Simon J. Conway
Journal: Circulation Research (2009)

Cardiac fibroblasts are the most populous nonmyocyte cell type within the mature heart and are required for extracellular matrix synthesis and deposition, generation of the cardiac skeleton, and to electrically insulate the atria from the ventricles. Significantly, cardiac fibroblasts have also been shown to play an important role in cardiomyocyte growth and expansion of the ventricular chambers during heart development. Although there are currently no cardiac fibroblast-restricted molecular markers, it is generally envisaged that the majority of the cardiac fibroblasts are derived from the proepicardium via epithelial-to-mesenchymal transformation. However, still relatively little is known about when and where the cardiac fibroblasts cells are generated, the lineage of each cell, and how cardiac fibroblasts move to reside in their final position throughout all four cardiac chambers. In this review, we summarize the present understanding regarding the function of Periostin, a useful marker of the noncardiomyocyte lineages, and its role during cardiac morphogenesis. Characterization of the cardiac fibroblast lineage and identification of the signals that maintain, expand and regulate their differentiation will be required to improve our understanding of cardiac function in both normal and pathophysiological states.
The Na+/I− Symporter (NIS): Mechanism and Medical Impact
Authors: Carla Portulano, Monika Paroder-Belenitsky, Nancy Carrasco
Journal: Endocrine Reviews (2013)

The Na(+)/I(-) symporter (NIS) is the plasma membrane glycoprotein that mediates active I(-) transport in the thyroid and other tissues, such as salivary glands, stomach, lactating breast, and small intestine. In the thyroid, NIS-mediated I(-) uptake plays a key role as the first step in the biosynthesis of the thyroid hormones, of which iodine is an essential constituent. These hormones are crucial for the development of the central nervous system and the lungs in the fetus and the newborn and for intermediary metabolism at all ages. Since the cloning of NIS in 1996, NIS research has become a major field of inquiry, with considerable impact on many basic and translational areas. In this article, we review the most recent findings on NIS, I(-) homeostasis, and related topics and place them in historical context. Among many other issues, we discuss the current outlook on iodide deficiency disorders, the present stage of understanding of the structure/function properties of NIS, information gleaned from the characterization of I(-) transport deficiency-causing NIS mutations, insights derived from the newly reported crystal structures of prokaryotic transporters and 3-dimensional homology modeling, and the novel discovery that NIS transports different substrates with different stoichiometries. A review of NIS regulatory mechanisms is provided, including a newly discovered one involving a K(+) channel that is required for NIS function in the thyroid. We also cover current and potential clinical applications of NIS, such as its central role in the treatment of thyroid cancer, its promising use as a reporter gene in imaging and diagnostic procedures, and the latest studies on NIS gene transfer aimed at extending radioiodide treatment to extrathyroidal cancers, including those involving specially engineered NIS molecules.