tbuckley/cabot-search huggingface dataset:
Induction of Glomerular Heparanase Expression in Rats with Adriamycin Nephropathy Is Regulated by Reactive Oxygen Species and the Renin-Angiotensin System
Authors: Andrea Kramer, Mabel van den Hoven, Angelique Rops, Tessa Wijnhoven, Lambert van den Heuvel, Joost Lensen, Toin van Kuppevelt, Harry van Goor, Johan van der Vlag, Gerjan Navis, Jo H.M. Berden
Journal: Journal of the American Society of Nephrology (2006)

Heparan sulfate (HS) in the glomerular basement membrane (GBM) is important for regulation of the charge-dependent permeability. Heparanase has been implicated in HS degradation in several proteinuric diseases. This study analyzed the role of heparanase in HS degradation in Adriamycin nephropathy (AN), a model of chronic proteinuria-induced renal damage. Expression of heparanase, HS, and the core protein of agrin (to which HS is attached) was determined on kidney sections from rats with AN in different experiments. First, expression was examined in a model of unilateral AN in a time-course study at 6-wk intervals until week 30. Second, rats were treated with the hydroxyl radical scavenger dimethylthiourea (DMTU) during bilateral AN induction. Finally, 6 wk after AN induction, rats were treated with angiotensin II receptor type 1 antagonist (AT1A) or vehicle for 2 wk. Heparanase expression was increased in glomeruli of rats with AN, which correlated with HS reduction at all time points and in all experiments. Treatment with DMTU prevented the increased heparanase expression, the loss of GBM HS, and reduced albuminuria. Finally, treatment of established proteinuria with AT1A significantly reduced heparanase expression and restored glomerular HS. In conclusion, an association between heparanase expression and reduction of glomerular HS in AN was observed. The effects of DMTU suggest a role for reactive oxygen species in upregulation of heparanase. Antiproteinuric treatment by AT1A decreased heparanase expression and restored HS expression. These results suggest involvement of radicals and angiotensin II in the modulation of GBM permeability through HS and heparanase expression.
Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia
Authors: Jeffrey A. Lieberman, T. Scott Stroup, Joseph P. McEvoy, Marvin S. Swartz, Robert A. Rosenheck, Diana O. Perkins, Richard S.E. Keefe, Sonia M. Davis, Clarence E. Davis, Barry D. Lebowitz, Joanne Severe, John K. Hsiao
Journal: New England Journal of Medicine (2005)

The relative effectiveness of second-generation (atypical) antipsychotic drugs as compared with that of older agents has been incompletely addressed, though newer agents are currently used far more commonly. We compared a first-generation antipsychotic, perphenazine, with several newer drugs in a double-blind study.
Dermatofibrosarcoma Protuberans Treated at a Single Institution: A Surgical Disease With a High Cure Rate
Authors: Marco Fiore, Rosalba Miceli, Chiara Mussi, Salvatore Lo Vullo, Luigi Mariani, Laura Lozza, Paola Collini, Patrizia Olmi, Paolo G. Casali, Alessandro Gronchi
Journal: Journal of Clinical Oncology (2005)

Dermatofibrosarcoma protuberans (DFSP) is a rare, low-grade, cutaneous sarcoma with autocrine overproduction of the platelet-derived growth factor (PDGF) beta-chain from gene rearrangement as a key pathogenetic factor, now susceptible of molecular-targeted therapy. The aim of this retrospective analysis was to explore the outcome of patients with primary or recurrent DFSP.Two hundred eighteen patients surgically treated at the Istituto Nazionale per lo studio e la cura dei Tumori (Milan, Italy) over 20 years were reviewed. Local relapse, distant metastasis, and survival were studied.One hundred thirty-six patients (62.4%) presented with a primary DFSP, while 82 patients (37.6%) had a recurrent disease. In the primary group, margins were microscopically positive in 11.8%, while in the recurrent group they were positive in 14.6% (P =.613). In the primary group, patients undergoing re-excision after inadequate previous surgery had residual disease in 62% of cases. Reconstructive surgery was needed in 30%, significantly more frequently in patients with a recurrence or a head and neck tumor. The crude cumulative incidence of local relapses was 4% at 10 years, and 2% at 10 years for distant metastases. No significant difference was found between primary and recurrent patients, as well as between positive and negative margins.This being one of the largest mono-institutional series of DFSP, we confirm that long-term outcome is excellent, in terms of both local and distant control, after a wide excision with negative margins. Reconstructive surgery is often needed. Novel medical therapies will be of use in a limited subgroup of patients.
Re: Is Patient Travel Distance Associated With Survival on Phase II Clinical Trials in Oncology?
Authors: A. Munoz, J. Samet
Journal: JNCI Journal of the National Cancer Institute (2004)

Background: Prior research has suggested that patients who travel out of their neighborhood for elective care from specialized medical centers may have better outcomes than local patients with the same illnesses who are treated at the same centers. We hypothesized that this phenomenon, often called “referral bias” or “distance bias,” may also be evident in curative-intent cancer trials at specialized cancer centers. Methods: We evaluated associations between overall survival and progression-free survival and the distance from the patient residence to the treating institution for 110 patients treated on one of four phase II curative-intent chemoradiotherapy protocols for locoregionally advanced squamous cell cancer of the head and neck conducted at the University of Chicago over 7 years. Results: Using Cox regression that adjusted for standard patient-level disease and demographic factors and neighborhood-level economic factors, we found a positive association between the distance patients traveled from their residence to the treatment center and survival. Patients who lived more than 15 miles from the treating institution had only one-third the hazard of death of those living closer (hazard ratio [HR] = 0.32, 95% confidence interval [CI] = 0.12 to 0.84). Moreover, with every 10 miles that a patient traveled for care, the hazard of death decreased by 3.2% (HR = 0.97, 95% CI = 0.94 to 0.99). Similar results were obtained for progression-free survival. Conclusion: Results of phase II curative-intent clinical trials in oncology that are conducted at specialized cancer centers may be confounded by patient travel distance, which captures prognostic significance beyond cancer stage, performance status, and wealth. More work is needed to determine what unmeasured factors travel distance is mediating. [J Natl Cancer Inst 2003;95:1370–5]
Classroom-based cognitive behaviour therapy (FRIENDS): a cluster randomised controlled trial to Prevent Anxiety in Children through Education in Schools (PACES)
Authors: Paul Stallard, Elena Skryabina, Gordon Taylor, Rhiannon Phillips, Harry Daniels, Rob Anderson, Neil Simpson
Journal: The Lancet Psychiatry (2014)

Anxiety in children is common, impairs everyday functioning, and increases the risk of severe mental health disorders in adulthood. We investigated the effect of a classroom-based cognitive behaviour therapy prevention programme (FRIENDS) on anxiety symptoms in children.Preventing Anxiety in Children though Education in Schools (PACES) is a three-group parallel cluster randomised controlled trial. Interventions were given between September, 2011, and July, 2012, with schools as the unit of allocation and individual participants as the unit of analysis. We enrolled state-funded junior schools in southwest England. We sent information to all eligible schools (state-funded junior schools in southwest England) inviting them to enrol in the study. School year groups were assigned by computer-generated randomisation (1:1:1) to receive either school-led FRIENDS (led by teacher or school staff member), health-led FRIENDS (led by two trained health facilitators), or usual school provision. Children were not masked to treatment allocation. The allocated programme was given to all students (aged 9-10 years) in the school year (ie, universal delivery) as part of the school curriculum as nine, 60 min weekly sessions. Outcomes were collected by self-completed questionnaire administered by researchers masked to allocation. Primary outcome was symptoms of anxiety and low mood at 12 months assessed by the Revised Child Anxiety and Depression Scale (RCADS 30). Analyses were intention to treat and accounted for the clustered nature of the design. The study is registered, number ISRCTN23563048.45 schools were enrolled: 14 (n=497 children) were randomly assigned to school-led FRIENDS, 14 (n=509) to health-led FRIENDS, and 12 (n=442) to usual school provision. 1257 (92%) children completed 12 month assessments (449 in health-led FRIENDS, 436 in school-led FRIENDS, and 372 in usual school provision). We recorded a difference at 12 months in adjusted mean child-reported RCADS scores for health-led versus school-led FRIENDS (19·49 [SD 14·81] vs 22·86 [15·24]; adjusted difference -3·91, 95% CI -6·48 to -1·35; p=0·0004) and health-led FRIENDS versus usual school provision (19·49 [14·81] vs 22·48 [15·74]; -2·66, -5·22 to -0·09; p=0·043). We noted no differences in parent or teacher ratings. Training teachers to deliver mental health programmes was not as effective as delivery by health professionals.Universally delivered anxiety prevention programmes can be effective when used in schools. However, programme effectiveness varies depending on who delivers them.National Institute for Health Research Public Health Research Programme.
FHL2 inhibits the activated osteoclast in a TRAF6-dependent manner
Authors: S. Bai
Journal: Journal of Clinical Investigation (2005)

TNF receptor-associated factor 6 (TRAF6) associates with the cytoplasmic domain of receptor activator of NF-kappaB (RANK). This event is central to normal osteoclastogenesis. We discovered that TRAF6 also interacts with FHL2 (four and a half LIM domain 2), a LIM domain--only protein that functions as a transcriptional coactivator or corepressor in a cell-type--specific manner. FHL2 mRNA and protein are undetectable in marrow macrophages and increase pari passu with osteoclast differentiation in vitro. FHL2 inhibits TRAF6-induced NF-kappaB activity in wild-type osteoclast precursors and, in keeping with its role as a suppressor of TRAF6-mediated RANK signaling, TRAF6/RANK association is enhanced in FHL2-/- osteoclasts. FHL2 overexpression delays RANK ligand-induced (RANKL-induced) osteoclast formation and cytoskeletal organization. Interestingly, osteoclast-residing FHL2 is not detectable in naive wild-type mice, in vivo, but is abundant in those treated with RANKL and following induction of inflammatory arthritis. Reflecting increased RANKL sensitivity, osteoclasts generated from FHL2-/- mice reach maturation and optimally organize their cytoskeleton earlier than their wild-type counterparts. As a consequence, FHL2-/- osteoclasts are hyperresorptive, and mice lacking the protein undergo enhanced RANKL and inflammatory arthritis-stimulated bone loss. FHL2 is, therefore, an antiosteoclastogenic molecule exerting its effect by attenuating TRAF6-mediated RANK signaling.
Activation of NADPH Oxidase 4 in the Endoplasmic Reticulum Promotes Cardiomyocyte Autophagy and Survival During Energy Stress Through the Protein Kinase RNA-Activated-Like Endoplasmic Reticulum Kinase/Eukaryotic Initiation Factor 2α/Activating Transcription Factor 4 Pathway
Authors: Sebastiano Sciarretta, Peiyong Zhai, Dan Shao, Daniela Zablocki, Narayani Nagarajan, Lance S. Terada, Massimo Volpe, Junichi Sadoshima
Journal: Circulation Research (2013)

Rationale: Autophagy is an essential survival mechanism during energy stress in the heart. Oxidative stress is activated by energy stress, but its role in mediating autophagy is poorly understood. NADPH oxidase (Nox) 4 is an enzyme that generates reactive oxygen species (ROS) at intracellular membranes. Whether Nox4 acts as a sensor of energy stress to mediate activation of autophagy is unknown. Objective: We investigated whether Nox4 is involved in the regulation of autophagy and cell survival during energy stress in cardiomyocytes. Methods and Results: Production of ROS in cardiomyocytes was increased during glucose deprivation (GD) in a Nox4-dependent manner. Protein levels and the ROS-producing activity of Nox4 were increased in the endoplasmic reticulum (ER), but not in mitochondria, in response to GD. Selective knockdown of Nox4, but not Nox2, or selective reduction of ROS in the ER with ER-targeted catalase, but not mitochondria-targeted perioxiredoxin 3, abrogated GD-induced autophagy. Nox4 promoted autophagy during GD through activation of the protein kinase RNA-activated-like ER kinase pathway by suppression of prolyl hydroxylase 4. The decrease in cell survival during GD in the presence of Nox4 knockdown was rescued by reactivation of autophagy by Atg7 overexpression, indicating that the effect of Nox4 on cell survival is critically mediated through regulation of autophagy. Nox4 was activated during fasting and prolonged ischemia in the mouse heart, where Nox4 is also required for autophagy activation and cardioprotection. Conclusions: Nox4 critically mediates autophagy in response to energy stress in cardiomyocytes by eliciting ROS in the ER and stimulating the protein kinase RNA-activated-like ER kinase signaling pathway.
Bacterial control of host gene expression through RNA polymerase II
Authors: Nataliya Lutay, Ines Ambite, Jenny Grönberg Hernandez, Gustav Rydström, Bryndís Ragnarsdóttir, Manoj Puthia, Aftab Nadeem, Jingyao Zhang, Petter Storm, Ulrich Dobrindt, Björn Wullt, Catharina Svanborg
Journal: Journal of Clinical Investigation (2013)

The normal flora furnishes the host with ecological barriers that prevent pathogen attack while maintaining tissue homeostasis. Urinary tract infections (UTIs) constitute a highly relevant model of microbial adaptation in which some patients infected with Escherichia coli develop acute pyelonephritis, while other patients with bacteriuria exhibit an asymptomatic carrier state similar to bacterial commensalism. It remains unclear if the lack of destructive inflammation merely reflects low virulence or if carrier strains actively inhibit disease-associated responses in the host. Here, we identify a new mechanism of bacterial adaptation through broad suppression of RNA polymerase II–dependent (Pol II–dependent) host gene expression. Over 60% of all genes were suppressed 24 hours after human inoculation with the prototype asymptomatic bacteriuria (ABU) strain E. coli 83972, and inhibition was verified by infection of human cells. Specific repressors and activators of Pol II–dependent transcription were modified, Pol II phosphorylation was inhibited, and pathogen-specific signaling was suppressed in cell lines and inoculated patients. An increased frequency of strains inhibiting Pol II was epidemiologically verified in ABU and fecal strains compared with acute pyelonephritis, and a Pol II antagonist suppressed the disease-associated host response. These results suggest that by manipulating host gene expression, ABU strains promote tissue integrity while inhibiting pathology. Such bacterial modulation of host gene expression may be essential to sustain asymptomatic bacterial carriage by ensuring that potentially destructive immune activation will not occur.
The Clinical Pharmacology of L-Arginine
Authors: Rainer H Böger, Stefanie M Bode-Böger
Journal: The Annual Review of Pharmacology and Toxicology (2001)

L-Arginine (2-amino-5-guanidinovaleric acid) is the precursor of nitric oxide, an endogenous messenger molecule involved in a variety of endothelium-mediated physiological effects in the vascular system. Acute and chronic administration of L-arginine has been shown to improve endothelial function in animal models of hypercholesterolemia and atherosclerosis. L-Arginine also improves endothelium-dependent vasodilation in humans with hypercholesterolemia and atherosclerosis. The responsiveness to L-arginine depends on the specific cardiovascular disease studied, the vessel segment, and morphology of the artery. The pharmacokinetics of L-arginine have recently been investigated. Side effects are rare and mostly mild and dose dependent. The mechanism of action of L-arginine may involve nitric oxide synthase substrate provision, especially in patients with elevated levels of the endogenous NO synthase inhibitor asymmetric dimethylarginine. Endocrine effects and unspecific reactions may contribute to L-arginine-induced vasodilation after higher doses. Several long-term studies have been performed that show that chronic oral administration of L-arginine or intermittent infusion therapy with L-arginine can improve clinical symptoms of cardiovascular disease in man.
Common VWF exon 28 polymorphisms in African Americans affecting the VWF activity assay by ristocetin cofactor
Authors: Veronica H. Flood, Joan Cox Gill, Patricia A. Morateck, Pamela A. Christopherson, Kenneth D. Friedman, Sandra L. Haberichter, Brian R. Branchford, Raymond G. Hoffmann, Thomas C. Abshire, Jorge A. Di Paola, W. Keith Hoots, Cindy Leissinger, Jeanne M. Lusher, Margaret V. Ragni, Amy D. Shapiro, Robert R. Montgomery
Journal: Blood (2010)
Retinoids, Retinoic Acid Receptors, and Cancer
Authors: Xiao-Han Tang, Lorraine J. Gudas
Journal: Annual Review of Pathology Mechanisms of Disease (2011)

Retinoids (i.e., vitamin A, all-trans retinoic acid, and related signaling molecules) induce the differentiation of various types of stem cells. Nuclear retinoic acid receptors mediate most but not all of the effects of retinoids. Retinoid signaling is often compromised early in carcinogenesis, which suggests that a reduction in retinoid signaling may be required for tumor development. Retinoids interact with other signaling pathways, including estrogen signaling in breast cancer. Retinoids are used to treat cancer, in part because of their ability to induce differentiation and arrest proliferation. Delivery of retinoids to patients is challenging because of the rapid metabolism of some retinoids and because epigenetic changes can render cells retinoid resistant. Successful cancer therapy with retinoids is likely to require combination therapy with drugs that regulate the epigenome, such as DNA methyltransferase and histone deacetylase inhibitors, as well as classical chemotherapeutic agents. Thus, retinoid research benefits both cancer prevention and cancer treatment.
STUDIES ON THE TOXICITY OF INFLUENZA VIRUSES
Authors: Werner Henle, Gertrude Henle
Journal: The Journal of Experimental Medicine (1946)

Upon intra-abdominal or intravenous injection of allantoic fluids infected with influenza viruses, mice frequently died within 8 to 96 hours. Similar results were observed upon injection of rabbits, rats, and guinea pigs. Autopsy of the mice revealed widespread necrosis of liver and spleen, hemorrhages into the intestines, pleural exudation, and other occasional findings. Survivors frequently developed pulmonary consolidation or jaundice. The dominant type of lesion depended on the strain of virus used. All attempts to demonstrate propagation of the influenza viruses outside of the respiratory tract failed. It was concluded that the early lesions were the result of toxic activities of the virus and not of virus multiplication in the affected tissues. Injection into chick embryos of highly diluted inocula produced higher titers of virus, hemagglutmin, and toxicity in the allantoic fluids than the use of more concentrated seed culture. Serial passage of various strains in high dilution frequently increased the toxic activity. The infectivity often reached its peak in 24 hours when tests for toxicity were still negative. Maximal toxicity was usually not attained before 48 hours. The toxic activity could not be separated from the infective property by such means as differential centrifugation and adsorption onto and elution from chicken red cells. However, upon heating, formalinization, and irradiation with ultraviolet light, the ability of the agents to propagate was lost at a faster rate than the toxic property. The toxic property remained stable for 2 to 3 months at 4 degrees C. This stability was comparable to that of the infectivity for chick embryos. Specific immune sera neutralized in high dilution the toxic activity of the homologous virus. Non-specific neutralization occurred in low dilutions of normal and heterologous immune sera. Strain differences were indicated by this method of testing. Vaccination of mice by the subcutaneous or intra-abdominal routes protected mice specifically against the toxic effects of intra-abdominally or intravenously injected preparations of virus.
Relationship Between Serum Levels of Methylguanidine and Glycemic Control in IDDM Children
Authors: Kanji Nagashima, Hideki Yagi, Shigenori Yutani, Hiroshi Miyake, Kazumichi Onigata, Takayoshi Kuroume
Journal: Diabetes Care (1993)

OBJECTIVE To examine the serum levels of methylguanidine in IDDM children and compare them with markers for glycemic control. Reports have indicated that active oxygen, which damages various tissues, increases in diabetes mellitus. The increase of active oxygen is one of the risk factors for diabetic complications. The synthesis of methylguanidine, a metabolic product of guanidine, is mainly regulated by active oxygen. RESEARCH DESIGN AND METHODS Forty-eight children with IDDM (mean age 13.3 yr) and 17 age-matched nondiabetic control subjects were studied. Diabetic children were divided into a well-controlled group (HbA1c &amp;lt; 8%, n = 24) and a poorly controlled group (HbA1c &amp;gt; 8%, n = 24). Serum concentrations of methylguanidine were measured by enzymatic assay. RESULTS Levels of methylguanidine in the poorly controlled group (1.31 ± 0.08 μM) were significantly higher than those in both the well-controlled group (0.85 ± 0.08 μM) and the control group (0.59 ± 0.11 μM), respectively (P &amp;lt; 0.01). Methylguanidine levels showed a positive correlation with the levels of HbA1c (P &amp;lt; 0.01) or fructosamine (P &amp;lt; 0.01). No significant correlations were noted between methylguanidine levels and age, sex, duration of diabetes, or insulin dose. CONCLUSIONS Our data indicate that the levels of methylguanidine in IDDM children might be affected by glycemic control and that the determination of serum methylguanidine levels could be a useful test for evaluating the state of diabetic control.
Survival and Cardiac Remodeling Benefits in Patients Undergoing Late Percutaneous Coronary Intervention of the Infarct-Related Artery
Authors: Antonio Abbate, Giuseppe G.L. Biondi-Zoccai, Darryn L. Appleton, Paul Erne, Andreas W. Schoenenberger, Michael J. Lipinski, Pierfrancesco Agostoni, Imad Sheiban, George W. Vetrovec
Journal: Journal of the American College of Cardiology (2008)