tbuckley/cabot-search huggingface dataset:
Signal transduction during cardiac hypertrophy: the role of Gαq, PLC βI, and PKC
Authors: Thunder Jalili, Yasuchika Takeishi, Richard A Walsh
Journal: Cardiovascular Research (1999)

Time for primary review 34 days. 

Currently the precise biochemical pathogenesis of cardiac hypertrophy remains unclear. A great deal of investigation has been directed toward the examination of various signal transduction pathways that are thought to be involved in stimulating this process. In particular, the signaling pathways that use heterotrimeric G protein-coupled receptors have been the focus for many investigations. This review will focus on the function of the Gαq family of proteins and its downstream effectors during cardiac hypertrophy. Hypertrophy is the final common pathway for a variety of insults to the normal cardiovascular system. Many mechanical and hormonal stimuli such as hypertension, valve disorders, and ischemic events, can produce a hypertrophic response. These pathologic stimuli cause an increase in the workload placed upon the heart resulting in hypertrophy and remodeling that has been observed at the myocyte [1] and the gross anatomical level. Current thought suggests that the hypertrophic response is a compensatory mechanism that allows normal cardiac function against a gradient of increasing workload. If the pathologic stimulus is sufficiently intense or prolonged, a period of failure characterized by impaired function, dilation of the left ventricle, and pulmonary congestion ensues.

Recently, experiments using cardiac specific transgenesis to investigate G protein-mediated mechanisms of cardiac hypertrophy have yielded novel information that may give us cause to re-evaluate our traditional stratification of hypertrophic states [2]. It is important to evaluate these results along with other conventional and transgenic models so that we can develop a more comprehensive understanding of this complex disease.

Heterotrimeric G protein-coupled receptors serve to convey an extracellular biochemical signal to intracellular effectors. These receptors are heptahelical structures with extracellular, transmembrane, and intracellular domains coupled to specific G proteins which are comprised of three (α, β, γ) subunits. When the G protein complex is in … 

* Corresponding author. Tel.: 1-216-844-3293; fax: 1-216-844-3145 raw19{at}po.cwru.edu
Effects of intravenous amiodarone on electrical dispersion in normal and ischaemic tissues and on arrhythmia inducibility: monophasic action potential studies
Authors: R. D Mayuga, D. H Singer
Journal: Cardiovascular Research (1992)

Objective: The aim was to study the effects of intravenous amiodarone on: (1) repolarisation and other monophasic action potential characteristics of normal and ischaemic tissues, and (2) vulnerability to pacing induced repetitive ventricular firing following acute left anterior descending coronary artery ligation. Methods: Epicardial monophasic action potentials were continuously and simultaneously recorded from ischaemic and non-ischaemic regions of the hearts of 24 pentobarbitone anaesthetised dogs. Monophasic action potential duration, rise time, and amplitude, as well as the degree of dispersion of repolarisation between normal and ischaemic areas and vulnerability to electrical induction of repetitive ventricular firing, were determined using hand held silver-silver chloride "contact pressure" electrodes, before and 15 min after coronary ligation; and 15 min after exposure to low (10 mg·kg−1) doses of amiodarone. Similar determinations were made in drug free controls. Results: Under control conditions, monophasic action potentials from both the (potentially) ischaemic and non-ischaemic regions were comparable, dispersion of repolarisation was minimal, and repetitive ventricular firing could not be induced. Coronary ligation significantly decreased monophasic action potential duration and increased rise time in the ischaemic, but not in the non-ischaemic, regions. Dispersion of repolarisation increased markedly. Repetitive ventricular firing could be induced in all dogs. "Low dose" amiodarone caused a much greater prolongation of repolarisation duration at ischaemic than at non-ischaemic sites. Dispersion of repolarisation decreased virtually to control levels and repetitive firing could no longer be induced in six of seven dogs. "High dose" amiodarone increased ischaemic region repolarisation duration and rise time relative to the non-ischaemic region to an even greater extent than the "low" dose, with the result that dispersion of repolarisation increased rather than decreased and repetitive ventricular firing again became inducible. Conclusions: The data indicate that: (1) intravenous amiodarone prolongs repolarisation of ischaemic tissues to a greater extent than that of normal tissues; (2) "low" dose amiodarone resulted in an overall decrease in dispersion of repolarisation, with little or no change in dispersion of rise time; (3) the "high" dose increased dispersion of both repolarisation and rise time. These changes were paralleled by changes in vulnerability to induction of repetitive ventricular firing by programmed ventricular pacing, the "low" dose being associated with decreases, and the "high" dose with further increases, in vulnerability, respectively.
Abstract A38: T cell costimulation by TNFRSF4, TNFRSF18, and TNFRSF25 in the context of vaccination.
Authors: Taylor H. Schreiber, Louis Gonzalez, Dietlinde Wolf, Maria Bodero, Eckhard R. Podack
Journal: Cancer Research (2013)

Abstract TNFRSF4 (OX40, CD134), TNFRSF18 (GITR) and TNFRSF25 are costimulatory receptors that influence CD4+ and CD8+ T cell responses to cognate-antigen. Independently, these receptors have been described to stimulate overlapping functions including enhanced proliferation and activation for both regulatory (CD4+FoxP3+, Treg) and conventional (CD4+FoxP3- or CD8+FoxP3-) T cells. To determine the relative functionality of TNFRSF4, TNFRSF18 and TNFRSF25 in T cell immunity, the activity of TNFRSF4, TNFRSF18 and TNFRS25 agonistic antibodies was compared in the context of both traditional protein/adjuvant (ovalbumin/alum) and CD8+ specific heat shock protein based (gp96-Ig) vaccine approaches. These studies demonstrate that both TNFRSF4, TNFRSF18 and TNFRSF25 independently and additively costimulate vaccine induced CD8+ T cell proliferation following both primary and secondary antigen challenge. In contrast, the activity of TNFRSF4 and TNFRSF25 were observed to be divergent in the costimulation of CD4+ T cell immunity. TNFRSF4 and TNFRSF18 agonists were potent costimulators of ova/alum induced CD4+ conventional T cell proliferation but only weakly costimulated Treg proliferation and IgG2a production, while TNFRSF25 agonists were strong costimulators of Treg proliferation, production of IgG1, IgG2a and IgG2b and weak costimulators of CD4+ Tconv proliferation. Interestingly, antigen-specific cellular and humoral responses were uncoupled upon secondary immunization, which was dramatically effected by the presence of TNFRSF4, TNFRSF18 or TNFRSF25 costimulation. These studies highlight the overlapping but non-redundant activities of these three TNF receptors in T cell immunity, which may guide the application of receptor agonistic agents as vaccine adjuvants for infectious disease and tumor immunity. Citation Format: Taylor H. Schreiber, Louis Gonzalez, Dietlinde Wolf, Maria Bodero, Eckhard R. Podack. T cell costimulation by TNFRSF4, TNFRSF18, and TNFRSF25 in the context of vaccination. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr A38.
Abstract 5334: Mechanism of cysteine-mcMMAF release from the stably linked antibody-drug conjugate SGN-75
Authors: Xinqun Zhang, Nicole M. Okeley, Jocelyn Setter, Che-Leung Law, Dennis R. Benjamin, Peter D. Senter, Stephen C. Alley
Journal: Cancer Research (2010)

Abstract The antibody-drug conjugate SGN-75 is composed of the humanized monoclonal antibody (mAb) h1F6 and the drug-linker mcMMAF conjugated through interchain disulfide cysteine residues. SGN-75 has been shown to be highly active against tumor cell lines both in vitro and in vivo. The mcMMAF drug-linker was designed to be protected from protease cleavage, and we have shown that cysteine-mcMMAF is the major released drug in vitro. We demonstrate that the cysteine residue in cysteine-mcMMAF comes from the mAb, implying antibody degradation as the mechanism for generation of cysteine-mcMMAF. Two isotope cysteine labeling approaches were utilized in which either total cysteine in tumor cells or the mAb cysteines of h1F6 were labeled with heavy isotope cysteine. Metabolic incorporation of heavy cysteine into CD70-expressing tumor cells or mAb-producing CHO cells using media depleted of cysteine and supplemented with heavy isotope cysteine gave complete labeling by heavy cysteine. Heavy cysteine-labeled cells were treated with unlabeled SGN-75, and unlabeled cells were treated with heavy-cysteine-labeled SGN-75. The results demonstrate that the mAb backbone of SGN-75 is the origin of the cysteine in cysteine-mcMMAF providing evidence that an active drug component can be released from a stably linked ADC through proteolytic degradation of the mAb inside of target cells. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5334.
Relation of Blood Glucose to Blood Ammonia and Urea Cycle Enzymes
Authors: Henry Brown
Journal: JAMA (1967)

It has been known for some time that patients with advanced liver disease frequently exhibit an abnormal oral glucose tolerance test curve resembling that of a mildly diabetic patient. 1 It has also been a matter of concern to clinicians for many years that abnormally high blood ammonia levels may accompany hepatic failure particularly in the presence of portasystemic venous shunting. 2 The appearance of these two biochemical abnormalities together is very probably related. The tricarboxylic acid cycle for glucose utilization and the urea cycle for ammonia metabolism are closely related through use of common intermediates as oxaloacetate and aspartate (Fig 1). To obtain clinical and biochemical evidence that glucose and ammonia metabolism do, in fact, influence one another, a two-phase study was carried out. The first and principal study was to measure effects of glucose and blood ammonia levels in patients with advanced liver disease, particularly following portacaval shunt surgery.
Monitoring Japanese Allergenic Pollen Using Durham's and Burkard Sampler for Asia Pollen Allergy Network
Authors: Reiko Kishikawa, Akemi Saito, Hiroyuki Nanba, Norio Sahashi, Yoshinori Higaki, Eiko Koto, Terufumi Shimoda, Kazuo Akiyama, Tomoaki Iwanaga
Journal: Journal of Allergy and Clinical Immunology (2013)
Heterozygosity for hereditary hemochromatosis is associated with more fibrosis in chronic hepatitis C
Authors: Belinda C. Smith, Jane Grove, Muna A. Guzail, Christopher P. Day, Ann K. Daly, Alastair D. Burt, Margaret F. Bassendine
Journal: Hepatology (1998)

Hepatic iron has been associated with more aggressive liver disease in chronic viral hepatitis. We evaluated whether the recently described C282Y mutation of the hemochromatosis gene, designated HFE (responsible for at least 83% of hereditary hemochromatosis), was associated with more advanced liver disease in chronic hepatitis C. One hundred thirty-seven patients with biopsy-proven chronic hepatitis C were studied and liver biopsies scored for necroinflammation (grade 0-18) and fibrosis (stage 0-6). Genomic DNA was amplified by polymerase chain reaction and the C282Y mutation identified by restriction with RsaI and electrophoretic separation of restriction fragments. Ten (7.3%) patients had the C282Y mutation. No C282Y homozygous patients were identified. Age, sex distribution, and estimated weekly alcohol consumption were not significantly different between those with and without the mutation. Serum ferritin was higher in the heterozygotes (mean, 339 microg/L) compared with homozygous wild types (153 microg/L; P = .0005). In the majority of patients, liver iron was graded 0 out of 4, but hepatocyte iron staining was more commonly present in heterozygotes compared with homozygous normals (30% compared with 4% [P = .02]). Liver disease was more advanced in those with the mutant allele (mean fibrosis stage: 3.6, compared with wild type: 1.5 [P = .01]). Cirrhosis was found more often in those with the mutation (40%) compared with those without (8.7%) (P = .01; odds ratio: 7.6 [1.9-31.2]). There was no significant difference in inflammation scores between heterozygotes and wild type (mean, 5.4 compared with 4.1). Hepatitis C virus (HCV)-RNA titers were measured by branched DNA assay (HCV RNA 2.0-Chiron), and there was no difference between heterozygous and homozygous normal patients. Thus, despite relatively minor increases in iron stores, individuals who are heterozygous for hemochromatosis appear to develop more fibrosis in chronic hepatitis C. Venesection may be useful therapy in this subgroup.
Hereditary Vesicoureteral Reflux
Authors: John A. Hutch
Journal: JAMA (1972)

To the Editor.—  I am fascinated by the articles in the May 8th JAMA  1-3 in which the authors suggest that primary vesicoureteral reflux may be a familial hereditary disease transmitted genetically. It is certainly true that reflux is rare in blacks. However, reflux has some characteristics that make it very difficult to interpret the pedigrees.  An as yet undetermined percentage of babies are born with reflux. Some continue to reflux for their lifetime, but others stop refluxing spontaneously without their reflux ever being discovered. Thus, in studying a family, if the mother and father have no reflux on their cystograms you cannot be certain that they did not have childhood reflux that healed spontaneously, and, therefore, they could be carrying the gene that is transmitting the reflux. Even in studying the children, one cannot be certain that those with normal cystograms did not actually have reflux earlier in life.
Online hemodiafiltration reduces systemic inflammation compared to low-flux hemodialysis
Authors: Claire H. den Hoedt, Michiel L. Bots, Muriel P.C. Grooteman, Neelke C. van der Weerd, Albert H.A. Mazairac, E. Lars Penne, Renée Levesque, Piet M. ter Wee, Menso J. Nubé, Peter J. Blankestijn, Marinus A. van den Dorpel, None for the CONTRAST Investigators
Journal: Kidney International (2014)
MEASLES AND DIPHTHERIA OCCURRING CONCURRENTLY
Authors: J. L. POMEROY
Journal: JAMA (1925)

To the Editor:  —Recently, attention has been called to carelessness on the part of some physicians in not examining patients thoroughly. The following two cases well illustrate need of a thorough examination even though the diagnosis seems absolutely certain from a casual inspection:  A boy, aged 9 years, was taken sick with sneezing, fever, watering of the eyes and a slight sore throat, January 21. The following day an eruption had appeared. A physician was called and diagnosed the case as measles. However, as the physician is a competent pediatrician, he examined farther and found an inflamed throat with a small patch on one tonsil. He diagnosed it as diphtheria and gave antitoxin. Cultures proved the correctness of his diagnosis. With the prompt administration of antitoxin the child made a nice recovery, even if two serious diseases were present at the same time.  A boy, aged 5 years, had an
Risk Factors for HIV-1 Seroconversion May Not Be What They Seem-Reply
Authors: David D. Celentano
Journal: JAMA (1996)

<h3>In Reply.</h3> —Dr Brody raises several issues about our elicitation of HIV-1 infection among young male conscripts in northern Thailand. These concerns reflect common difficulties in conducting HIV research, principally that the reliability of self-reports of stigmatized or socially undesirable behaviors such as anal intercourse and injection drug use may be subject to some doubt. Some reports of unsafe behaviors may be underestimated. However, the inference that the hierarchy of risk factors from developed country settings is relevant to the Thai epidemic is not supported by the situation or the data we presented. Brody suggests that our conclusion that the Thai epidemic is heterosexually spread and is largely attributable to frequent contact with female commercial sex workers is unwarranted and that unreported anal intercourse with men or injection drug use is the purported culprit. The Royal Thai Ministry of Public Health estimates that more than 70% of cases of AIDS
In Vivo Antitumor Activity of 9-[(2-Phosphonylmethoxy)ethyl]-guanine and Related Phosphonate Nucleotide Analogues
Authors: W. C. Rose, A. R. Crosswell, J. J. Bronson, J. C. Martin
Journal: JNCI Journal of the National Cancer Institute (1990)

Phosphonylmethoxyalkylpurine analogues were evaluated for their antitu-mor activity in murine tumor models. Three compounds, (S)-9-[(3-hydroxy-2-phosphonylmethoxy)propyl]adenine (HPMPA), 9-[(2-phosphonylmethoxy) ethyl]adenine (PMEA), and 9-[(2-phosphonylmethoxy)ethyl]guanine (PMEG) were modestly active with treated versus control (T/C) values of 125%–175% versus intraperitoneal P388 leukemia, but were inactive versus intravenously implanted P388. The most active and most potent of the three was PMEG, which was also evaluated against subcu-taneously (SC) implanted B16 melanoma. In confirmatory experiments, optimal therapy with PMEG yielded reproducible increases in life span (T/C values of 164%–170%) and delays in primary tumor growth (7.3- to 13.0-day T-C values). PMEG is representative of a new class of antitumor antimetabo-lites heretofore recognized only for their antiviral properties. [J Natl Cancer Inst 82: 510–512, 1990]
NICE promises on infertility and caesarean section are unmet
Authors: L. Mascarenhas, Z. Nash, B. Nathan
Journal: BMJ (2013)

Current underfunding of the NHS means that some National Institute for Health and Care Excellence (NICE) guidelines are unachievable.1 Updated NICE guidelines recommend that women under 42 years with unexplained infertility should be offered three cycles of in vitro fertilisation funded by the NHS.2 …
Hypercoagulability, Hyperlipidemia, and Serum Antiproteases
Authors: PAUL R. BILLINGS
Journal: Annals of Internal Medicine (1985)

Letters and Corrections1 May 1985Hypercoagulability, Hyperlipidemia, and Serum AntiproteasesPAUL R. BILLINGS, M.D.Ph.D.PAUL R. BILLINGS, M.D.Ph.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-102-5-724_1 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTo the editor: Alpha1antitrypsin and antithrombin III belong to a family of plasma proteins known as the serum antiproteases (or serum protease inhibitors). The antiproteases have distinctly different physiologic functions and are coded for by unlinked genes (alpha1antitrypsin on chromosome 14; antithrombin III on chromosome 1), although they are genetically related via a common ancestral gene from which the genes for angiotensinogen and ovalbumin also have arisen (1). Recently, a mutant alpha1antitrypsin protein (A1AT Pittsburgh) has been shown to affect functions usually regulated by antithrombin III, proving that a de-novo genetic change at the alpha1antitrypsin locus...References1. DOOLITTLE R. Angiotensinogen is related to the antitrypsin-antithrombin-ovalbumin family. Science. 1983;222:417-9. CrossrefMedlineGoogle Scholar2. OWEN M, BRENNAN S, LEWIS J, and CARRELL R. Mutation of antitrypsin to antithrombin: alpha1-antitrypsin Pittsburgh (358 Met Arg), a fatal bleeding disorder. N Engl J Med. 1983;309:694-8. CrossrefMedlineGoogle Scholar3. VICTORINO R, SILVEIRA J, GEADA H, and MOURA M. Familial hypercholesterolaemia with alpha-1-antitrypsin deficiency. Br Med J. 1978;1:413-4. CrossrefMedlineGoogle Scholar4. DILIBERTI J, MCMURRY M, CONNOR W, and ALAUPOVIC P. Hypercholesterolemia associated with alpha-1-antitrypsin deficiency and hepatitis: lipoprotein and apoprotein and apoprotein determinations, sterol balance and treatment. Am J Med Sci. 1984;288:81-8. CrossrefMedlineGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAuthors: PAUL R. BILLINGS, M.D.Ph.D. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 May 1985Volume 102, Issue 5Page: 724-724KeywordsChromosomesGeneticsHyperlipidemiaPlasma proteinsProtease inhibitorsProteins ePublished: 1 December 2008 Issue Published: 1 May 1985 PDF downloadLoading ...
HCV viraemia is more important than genotype as a predictor of response to interferon in sicily (Southern Italy)
Authors: Silvio Magrin, Antonio Craxi, Carmelo Fabiano, Liliana Marino, Germana Fiorentino, Oreste Lo Iacono, Riccardo Volpes, Vito Di Marco, Piero Almasio, Alessandra Vaccaro, Mickey S. Urdea, Judith C. Wilber, Celestino Bonoura, Fabrizio Gianguzza, Vincenza Capursi, Salvatore Filiberti, Lieven Stuyver, Luigi Pagliaro
Journal: Journal of Hepatology (1996)
Infants, Children Test Positive for Cocaine After Exposure to Second-hand Crack Smoke
Authors: Teri Randall
Journal: JAMA (1992)

COCAINE can show up in the most unexpected places. Recently, at Children's Hospital of Michigan in Detroit, the emergency department found cocaine metabolite in the urine of more than 5% of the toddlers and children treated there for routine pediatric complaints (<i>Am J Dis Child</i>. 1991;145:1430-1432). The most likely route of exposure, the researchers suggest, is second-hand smoke inhaled when adult caretakers use freebase or crack cocaine. The physiological and behavioral effects of chronic environmental exposure to cocaine in children are not well established. There have been several cases reported in the scientific literature of cocaine toxicity in children exposed to crack smoke. Two had transient neurological symptoms such as drowsiness and unsteady gait, and three had seizures that laboratory tests could not explain (<i>Am J Dis Child</i>. 1989;143:25-27 and 1990;144:743-744). Some studies in adult animals have suggested a "kindling" phenomenon, in which the central nervous system becomes more sensitive
The “dark side” of overly aggressive multidevice atherectomy
Authors: Gaston R. Dussaillant, Gary S. Mintz, Augusto D. Pichard, Kenneth M. Kent, Lowell F. Satler, Jeffrey J. Popma, Theresa Bucher, Carol Walsh, Paul Mackel, Regina Deible, Bridget Golden, Martin B. Leon
Journal: Journal of the American College of Cardiology (1996)
Ondine's curse after carotid endarterectomy.
Authors: D Beamish, J A Wildsmith
Journal: BMJ (1978)

doctor's awareness about current drug treatment, and is in the overall interests of patient care.We thank all doctors in ward 4, Aberdeen Royal Infirmary, and ward 3, Woodend General Hospital, who participated in this study and gave helpful advice.We also acknowledge the financial support of the DHSS and SHHD to the Medicines Evaluation and Monitoring Group.