tbuckley/cabot-search huggingface dataset:
Human Endothelial Cell Storage Granules
Authors: Fraser D. Russell, Jeremy N. Skepper, Anthony P. Davenport
Journal: Circulation Research (1998)

Abstract —We have previously shown endothelin (ET)-like immunoreactive staining in Weibel-Palade bodies, storage granules that are an integral component of the regulated secretory pathway in endothelial cells. These structures degranulate after chemical or mechanical stimuli that result in cytosolic calcium influx. We therefore investigated whether the regulated pathway might be an intracellular site involved in the cleavage of big ET-1 to the biologically active peptide ET-1 by determining the ultrastructural localization of endothelin-converting enzyme (ECE)-1. A low level of ECE-like immunoreactivity was detected on the cell surface of human umbilical vein and coronary artery endothelial cells by scanning electron microscopy. Exogenous big ET-1 was added to permeabilized and nonpermeabilized cultured human umbilical vein endothelial cells, and ECE activity was measured by the detection of ET-like immunoreactivity in the culture supernatant. A marked increase in ECE activity was observed in permeabilized cells, indicating that ECE may also be expressed in intracellular compartments. Confocal microscopy revealed intense immunofluorescence staining for big ET-1 and the 2 isoforms of ECE-1 (ECE-1α and ECE-1β) in the perinuclear region and in Weibel-Palade bodies of the human umbilical vein endothelial cells. Stimulated degranulation of storage granules by the calcium ionophore A23187 caused release of ET into the culture supernatants. The findings of this study indicate that big ET-1 is processed to the mature vasoactive peptide by ECEs located within endothelial storage granules. We hypothesize that this activity may be important in the regulated mobilization of ET in human endothelial cells.
The Natural History of Chronic Allograft Nephropathy
Authors: Brian J. Nankivell, Richard J. Borrows, Caroline L.-S. Fung, Philip J. O'Connell, Richard D.M. Allen, Jeremy R. Chapman
Journal: New England Journal of Medicine (2003)

With improved immunosuppression and early allograft survival, chronic allograft nephropathy has become the dominant cause of kidney-transplant failure.
Increased Na+ concentration and altered Na/K pump activity in hypertrophied canine ventricular cells
Authors: Fons Verdonck, Paul G A Volders, Marc A Vos, Karin R Sipido
Journal: Cardiovascular Research (2003)

Objective: To investigate whether hypertrophy in the dog with chronic atrioventricular block (CAVB) alters [Na+]i and Na/K-pump function of ventricular myocytes. Methods: We measured the [Na+]i dependence of the Na/K pump current, Ip. This relation was used as a calibration curve for [Na+]i based on Ip. We measured Ip at the time of access and extrapolated [Na+] at the pump sites, i.e. subsarcolemmal [Na+], [Na+]subs, from the calibration curve. Results: The extrapolated [Na+]subs was significantly higher in CAVB (7.9 vs. 3.2 mM in control). The [Na+]i dependence of Ip in CAVB myocytes was shifted to the right (range of [Na+]i: 0–20 mM). In resting cells, the Ip, i.e. steady state Na+ efflux, which matches Na+ influx, was higher in CAVB (0.25±0.02 vs. 0.47±0.06 pA/pF, P<0.05). Maximal Ip density was not different, and DHO sensitivity was not altered. Conclusions: Hypertrophy in CAVB cells is associated with increased [Na+]subs. This results from an increase in Na+ influx, and a decreased sensitivity of Ip for Na+ in the range of [Na+]i studied. There is no evidence for a decrease in total pump capacity or for a functional Na/K-ATPase isoform shift. The rise in Na+ contributes to the contractile adaptation and preservation of sarcoplasmic reticulum Ca2+ content at the low heart rates of the dog with CAVB.
Synthetic Biology of Phenotypic Adaptation in Vertebrates: The Next Frontier
Authors: S. Yokoyama
Journal: Molecular Biology and Evolution (2013)

For over the last 2 decades, positively selected amino acid sites have been inferred almost exclusively by showing that the number of nonsynonymous substitutions per nonsynonymous site (dn) is greater than that of synonymous substitutions per synonymous site (ds). However, virtually none of these statistical results have been experimentally tested and remain as hypotheses. To perform such experimental tests, we must connect genotype and phenotype and relate the phenotypic changes to the environmental and behavioral changes of the organism. The genotype–phenotype relationship can be established only by synthesizing and manipulating "proper" ancestral phenotypes, whereas the actual functions of adaptive mutations can be learned by studying their chemical roles in phenotypic changes.
Surgical Specialties in the Medical Curriculum
Authors: C. Rollins Hanlon
Journal: JAMA (1967)

It is a custom of speakers afflicted with a difficult topic to spend considerable time in analyzing the title of their troublesome assignment and follow this with a disclaimer of responsibility for the title. In adopting this custom, I might characterize my assigned title as illegitimate and immediately and steadfastly deny paternity. Alternatively, I could have diminished its tendentious character by changing it to some pleasant banality, such as, "Surgical Specialties in the Significant Sixties." Ultimately, I recognized that I must face up to the challenge. The title states quite baldly that there<i>are</i>impertinent purposes in the relation of the surgical specialties to the medical curriculum. I am charged with determining what these presumed impertinences are, stating them here publicly, and thereafter rendering judgment on those responsible for their inclusion in the curriculum—flogging them, forgiving them, or congratulating them as fancy dictates. Let me say at once that I
Treating activated CD4+ T cells with either of two distinct DNA methyltransferase inhibitors, 5-azacytidine or procainamide, is sufficient to cause a lupus-like disease in syngeneic mice.
Authors: J Quddus, K J Johnson, J Gavalchin, E P Amento, C E Chrisp, R L Yung, B C Richardson
Journal: Journal of Clinical Investigation (1993)

Human antigen-specific CD4+ T cells become autoreactive after treatment with various DNA methylation inhibitors, including 5-azacytidine, procainamide, and hydralazine. This suggests a mechanism that could contribute to the development of some forms of autoimmunity. In this report we have asked whether T cells treated with DNA methylation inhibitors can induce autoimmunity. Murine CD4+ T cells were treated with 5-azacytidine or procainamide and were shown to respond to syngeneic antigen-presenting cells, similar to CD4+ human T cell clones treated with these drugs. Functional characterization demonstrated that cells treated with either drug spontaneously lysed syngeneic macrophages and secreted IL-4, IL-6, and IFN-gamma. Adoptive transfer of 5-azacytidine- or procainamide-treated cells into unirradiated syngeneic recipients induced an immune complex glomerulonephritis and IgG anti-DNA and antihistone antibodies. These experiments demonstrate that T cells treated with either of two distinct DNA methyltransferase inhibitors are sufficient to induce a lupus-like disease. It is possible that the lysis of macrophages, together with the release of cytokines promoting B cell differentiation, contributes to the autoantibody production and immune complex deposition. These results suggest that environmental agents that inhibit DNA methylation could interact with T cells in vivo to produce a lupus-like illness, a mechanism that could have relevance to drug-induced and idiopathic lupus.
Survival of Patients With Implantable Cardioverter Defibrillators in the Era of Remote-Monitoring: The 5000-Foot, High-Altitude View
Authors: Rachel Lampert
Journal: Circulation (2010)

L arge randomized trials have demonstrated unequivocally that implantable cardioverter defibrillators (ICDs) improve outcome for individuals with defined clinical characteristics known to be associated with a high risk of ventricular arrhythmias.However, less is known about outcomes of patients receiving ICDs in the "real world."The National Cardiovascular Data Registry provides extensive and detailed clinical information about patients receiving ICDs at the time of implant, but does not include longitudinal data on mortality or shocks except in a small subset. 1 Industry databases of ICD patients undergoing remote (transtelephonic) monitoring, which provide extensive information on therapies received, thus present a unique opportunity to fill this gap in knowledge.
Trastuzumab and Metastatic Breast Cancer: Trastuzumab Use in Australia—Monitoring the Effect of an Expensive Medicine Access Program
Authors: Sallie-Anne Pearson, Clare L. Ringland, Robyn L. Ward
Journal: Journal of Clinical Oncology (2007)

Data from clinical trials are used for drug registration; however, many cancer medicines are ultimately used off-label. This study examines the extent to which the clinical practice use of trastuzumab for the treatment of metastatic breast cancer differs from its use under trial conditions.This study involved all women (N = 1,469) with metastatic breast cancer who received trastuzumab in Australia between December 2001 and March 2005. Given that Australia operates a universal health care system, administrative databases could be examined to determine the duration of therapy, rate of off-label use, compliance with cardiac monitoring, and the extent of drug wastage (volume and cost).A total of 433 enrollees (29.5%) received trastuzumab as monotherapy and 1,036 enrollees (70.5%) received the drug in combination with chemotherapy. A total of 321 women (22%) received off-label trastuzumab. The median duration of trastuzumab therapy was longer than that on trial: 5.6 v 3.1 months for enrollees receiving monotherapy and 12.5 v 6.9 months for concomitant chemotherapy. Only 47 (3%) of enrollees received cardiac monitoring before and during trastuzumab therapy. We estimated 24% of trastuzumab dispensed was discarded, at a cost of $21.1 million Australian. Alternative administration schedules and the addition of another vial size potentially reduce wastage to 6% of volume dispensed.Debates about the use of expensive cancer medicines should consider postmarketing assessments as well as trial experience. The longer duration of trastuzumab use in clinical practice and the high rates of off-label use provide incentive for new clinical trials. Strategies to improve cardiac monitoring and to minimize drug wastage are issues that require immediate attention.
Iron uptake from plasma transferrin by a transferrin receptor 2 mutant mouse model of haemochromatosis
Authors: Anita C.G. Chua, Roheeth D. Delima, Evan H. Morgan, Carly E. Herbison, Janina E.E. Tirnitz-Parker, Ross M. Graham, Robert E. Fleming, Robert S. Britton, Bruce R. Bacon, John K. Olynyk, Debbie Trinder
Journal: Journal of Hepatology (2010)
Quantifying Position-Dependent Codon Usage Bias
Authors: Adam J. Hockenberry, M. Irmak Sirer, Luís A. Nunes Amaral, Michael C. Jewett
Journal: Molecular Biology and Evolution (2014)

Although the mapping of codon to amino acid is conserved across nearly all species, the frequency at which synonymous codons are used varies both between organisms and between genes from the same organism. This variation affects diverse cellular processes including protein expression, regulation, and folding. Here, we mathematically model an additional layer of complexity and show that individual codon usage biases follow a position-dependent exponential decay model with unique parameter fits for each codon. We use this methodology to perform an in-depth analysis on codon usage bias in the model organism Escherichia coli. Our methodology shows that lowly and highly expressed genes are more similar in their codon usage patterns in the 5'-gene regions, but that these preferences diverge at distal sites resulting in greater positional dependency (pD, which we mathematically define later) for highly expressed genes. We show that position-dependent codon usage bias is partially explained by the structural requirements of mRNAs that results in increased usage of A/T rich codons shortly after the gene start. However, we also show that the pD of 4- and 6-fold degenerate codons is partially related to the gene copy number of cognate-tRNAs supporting existing hypotheses that posit benefits to a region of slow translation in the beginning of coding sequences. Lastly, we demonstrate that viewing codon usage bias through a position-dependent framework has practical utility by improving accuracy of gene expression prediction when incorporating positional dependencies into the Codon Adaptation Index model.
Cost effectiveness analysis of strategies for tuberculosis control in developing countries
Authors: Rob Baltussen, Katherine Floyd, Christopher Dye
Journal: BMJ (2005)

A 45-year-old woman with long standing surgical hypoparathyroidism presented with right hemichorea of three months9 duration. She had profound hypocalcaemia and hyperphosphataemia and extensive cerebral, cerebellar and basal ganglia calcification. Correction of the chemical abnormalities with 1α-hydroxycholecalciferol, calcium supplements and aluminium hydroxide resulted within 10 weeks in complete disappearance of the abnormal movements.
Relationship between blood pressure of spontaneously hypertensive rats and alterations in membrane properties of mesenteric arteries.
Authors: J W Wei, R A Janis, E E Daniel
Journal: Circulation Research (1977)

Spontaneously hypertensive rats (SHR) and two strains of normotensive rats were compared with respect to enzymatic activities and calcium accumulation of plasma membrane and endoplasmic reticulum enriched fractions from their mesenteric arteries. Increased specific activities of alkaline phosphatase, 5'-nucleotidase and Mg2+-ATPase, and increased ATP-dependent calcium accumulation were found in 5- to 6-month-old SHR as compared to both strains fo age-matched normotensive rats. Alkaline phosphatase was increased in 33-day-old "early hypertensive" and 3- to 4-month-old SHR, but 5'-nucleotidase, Mg2+-ATPase, and calcium accumulation were not. Hydralazine treatment of young SHR partially prevented the increase of both alkaline phosphatase activity and blood pressure that develops with age. The relationship between alkaline phosphatase activity and the alterations in vascular reactivity associated with hypertension remains to be determined.
Population Stratification in Epidemiologic Studies of Common Genetic Variants and Cancer: Quantification of Bias
Authors: S. Wacholder
Journal: JNCI Journal of the National Cancer Institute (2000)

Background: Some critics argue that bias from population stratification (the mixture of individuals from heterogeneous genetic backgrounds) undermines the credibility of epidemiologic studies designed to estimate the association between a genotype and the risk of disease. We investigated the degree of bias likely from population stratification in U.S. studies of cancer among non-Hispanic Caucasians of European origin. Methods: An expression of the confounding risk ratio—the ratio of the effect of the genetic factor on risk of disease with and without adjustment for ethnicity—is used to measure the potential relative bias from population stratification. We first use empirical data on the frequency of the N-acetyltransferase (NAT2) slow acetylation genotype and incidence rates of male bladder cancer and female breast cancer in non-Hispanic U.S. Caucasians with ancestries from eight European countries to assess the bias in a hypothetical population-based U.S. study that does not take ethnicity into consideration. Then, we provide theoretical calculations of the bias over a large range of allele frequencies and disease rates. Results: Ignoring ethnicity leads to a bias of 1% or less in our empirical studies of NAT2. Furthermore, evaluation of a wide range of allele frequencies and representative ranges of cancer rates that exist across European populations shows that the risk ratio is biased by less than 10% in U.S. studies except under extreme conditions. We note that the bias decreases as the number of ethnic strata increases. Conclusions: There will be only a small bias from population stratification in a well-designed case–control study of genetic factors that ignores ethnicity among non-Hispanic U.S. Caucasians of European origin. Further work is needed to estimate the effect of population stratification within other populations.
PKCθ Signals Activation versus Tolerance In Vivo
Authors: Nancy N. Berg-Brown, Matthew A. Gronski, Russell G. Jones, Alisha R. Elford, Elissa K. Deenick, Bernhard Odermatt, Dan R. Littman, Pamela S. Ohashi
Journal: The Journal of Experimental Medicine (2004)

Understanding the pathways that signal T cell tolerance versus activation is key to regulating immunity. Previous studies have linked CD28 and protein kinase C-theta (PKCtheta) as a potential signaling pathway that influences T cell activation. Therefore, we have compared the responses of T cells deficient for CD28 and PKCtheta in vivo and in vitro. Here, we demonstrate that the absence of PKCtheta leads to the induction of T cell anergy, with a phenotype that is comparable to the absence of CD28. Further experiments examined whether PKCtheta triggered other CD28-dependent responses. Our data show that CD4 T cell-B cell cooperation is dependent on CD28 but not PKCtheta, whereas CD28 costimulatory signals that augment proliferation can be uncoupled from signals that regulate anergy. Therefore, PKCtheta relays a defined subset of CD28 signals during T cell activation and is critical for the induction of activation versus tolerance in vivo.
Lung Function Loss, Smoking, Vitamin C Intake, and Polymorphisms of the Glutamate-Cysteine Ligase Genes
Authors: Mateusz Siedlinski, Dirkje S. Postma, Cleo C. van Diemen, Anneke Blokstra, Henriette A. Smit, H. Marike Boezen
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

Rationale: Smoking-induced oxidative stress contributes to chronic obstructive pulmonary disease, a lung disease characterized by low lung function and increasing mortality worldwide. The counterbalance for this effect may be provided by, for example, increased intake of the antioxidant vitamin C or endogenously acting antioxidant enzymes like glutamate-cysteine ligase (GCL), which is responsible for glutathione biosynthesis.Objectives: To investigate associations of functional polymorphisms in GCL subunits (GCLM and GCLC) with lung function level and its longitudinal course, with vitamin C and smoking habits as potential interactive factors.Methods: Two independent general population samples (Doetinchem, n = 1,152, and Vlagtwedde-Vlaardingen, n = 1,390) with multiple lung function (FEV1, VC) measurements were genotyped for three polymorphisms (C[−129]T, C[−588]T, and a trinucleotide GAG repeat [TNR]) in the subunits of GCL. Genetic effects on lung function level and decline were estimated using linear regression and linear mixed effect models adjusted for confounders. Findings were further investigated for interactions with vitamin C intake in the Doetinchem cohort.Measurements and Main Results: GCLC polymorphisms were significantly associated with lower lung function levels in interaction with pack-years smoked in both cohorts. TNR variants in GCLC were associated with accelerated FEV1 decline in both cohorts in interaction with pack-years. All significant effects were specifically present in subjects within the lowest tertile of vitamin C intake.Conclusions: GCLC is a novel susceptibility gene for low level of lung function in two independent populations. We provide suggestive evidence that this occurs due to an interaction between GCLC polymorphisms, smoking, and low vitamin C intake, which all contribute to the oxidative burden.
Effect of lung resection for bronchial carcinoma on pulmonary function in patients with and without chronic obstructive bronchitis.
Authors: J S Legge, K N Palmer
Journal: Thorax (1975)

Pulmonary function was measured before and after lung resection (pneumonectomy or lobectomy) in 58 patients with bronchial carcinoma, 33 of whom also had chronic obstructive bronchitis. Lung resection was well tolerated and caused no greater impairment of lung function postoperatively in the bronchitics than in those without bronchitis.
The significance of a residual mediastinal mass following treatment for aggressive non-Hodgkin's lymphomas
Authors: J Tredaniel, P Brice, E Lepage, C Bris, JP Marolleau, C Ferme, C Hennequin, JP Fermand, J Frija, C Gisselbrecht, al. et
Journal: European Respiratory Journal (1992)

The chest radiographs of 252 patients with aggressive non-Hodgkin's lymphoma, prospectively treated according to one of three protocols of combination chemotherapy, were reviewed to determine the incidence and prognostic significance of mediastinal abnormalities following treatment. Residual mediastinal masses were defined as any abnormality, greater than 2 cm in diameter, that had initially responded to chemotherapy and then remained stable in size for at least three months after its maximal response, together with the disappearance of all other clinical and biological signs of active lymphoma. At the end of treatment, 21 (8%) patients had some residual mediastinal abnormality. The predominant histological pattern was the diffuse large cell subtype (p less than 0.001). Disease free survival and overall survival for these patients were similar to those observed among patients in complete remission without a persisting radiological mass after treatment. We conclude that mediastinal residual masses after completion of treatment for aggressive lymphoma are frequent and do not indicate a poorer prognosis. Such patients can be observed clinically without any need for additional chemotherapy or radiotherapy.
High dose chemotherapy and syngeneic stem cell transplantation in a patient with refractory rheumatoid arthritis: poor response associated with persistence of host autoantibodies and synovial abnormalities
Authors: M van Oosterhout
Journal: Annals of the Rheumatic Diseases (2005)

Immunoablative therapy combined with haematopoietic stem cell transplantation (SCT) is a possible treatment for patients with severe rheumatoid arthritis (RA).A patient with rheumatoid factor positive, progressively erosive RA, refractive to treatment, was treated with high dose cyclophosphamide, followed by reinfusion of an unmanipulated peripheral blood graft derived from her identical twin sister. The clinical response was unsatisfactory, necessitating reinstitution of treatment with disease modifying antirheumatic drugs, which was associated with persistence of host serum autoantibodies and a cellular infiltrate in synovium, notably of plasma cells.The effectiveness of syngeneic SCT may be critically dependent on the degree of immunoablation achieved or on the composition of the graft.
Activin-A: a novel dendritic cell–derived cytokine that potently attenuates CD40 ligand–specific cytokine and chemokine production
Authors: Neil C. Robson, David J. Phillips, Tristan McAlpine, Amanda Shin, Suzanne Svobodova, Tracey Toy, Vinochani Pillay, Naomi Kirkpatrick, Damien Zanker, Kathy Wilson, Imke Helling, Heng Wei, Weisan Chen, Jonathan Cebon, Eugene Maraskovsky
Journal: Blood (2007)