tbuckley/cabot-search huggingface dataset:
Pressure-natriuresis and -diuresis in transgenic rats harboring both human renin and human angiotensinogen genes.
Authors: B Dehmel, E Mervaala, A Lippoldt, V Gross, J Bohlender, D Ganten, F C Luft
Journal: Journal of the American Society of Nephrology (1998)

The hypertensive double transgenic rat harboring both the human renin and human angiotensinogen genes (dTGR) offers a unique opportunity to study the human renin-angiotensin system in an experimental animal model. Since nothing is known about the control of sodium and water excretion in these rats, this study was performed to compare pressure-natriuresis relationships in hypertensive dTGR and normotensive control rats harboring only the human renin gene (hREN), in order to determine how the pressure-natriuresis relationship is reset in hypertensive dTGR. To differentiate between extrinsic and intrinsic renal mechanisms, experiments were performed with and without renal denervation, and with and without infusions of vasopressin, norepinephrine, 17-OH-corticosterone, and aldosterone. Human and rat angiotensinogen and renin mRNA expression were also determined. In hREN without controlled renal function, urine flow and sodium excretion increased from 13 to 169 microl/min per g kidney wet weight (kwt) and from 1 to 30 micromol/min per g kwt, respectively, as renal perfusion pressure was increased from 67 to 135 mmHg. Renal blood flow (RBF) and GFR ranged between 3 to 7 and 0.9 to 1.5 ml/min per g kwt. In dTGR, pressure-natriuresis-diuresis relationships were shifted approximately 40 mmHg rightward. RBF was lower in dTGR than in hREN; GFR was not different. In dTGR with neurohormonal factors controlled, RBF was decreased and pressure-natriuresis-diuresis curves were not different compared to dTGR curves without these interventions. By light microscopy, the kidneys of these 6-wk-old dTGR and hREN rats were normal and indistinguishable. Both human and rat renin and angiotensinogen mRNA were expressed in the kidneys of dTGR. The two renin mRNA were decreased in dTGR, indicating a physiologic downregulation of renin gene expression by high BP. It is concluded that the renal pressure-natriuresis mechanism is reset toward higher pressure levels in dTGR and participates in the maintenance of hypertension. The reduced excretory function in dTGR depends on hREN and human angiotensinogen gene expression and is intrinsic to the kidney as opposed to extrarenal regulators.
Delayed Radiation Effects in Survivors of the Atomic Bombings
Authors: J. W. Hollingsworth
Journal: New England Journal of Medicine (1960)

ON the threshold of an era in which atomic energy holds so much potential for good and evil, the world has naturally focused its attention on the biologic effects of irradiation. This focus is primarily on the long-range changes that may occur in man, particularly so far as industrial and medical use of the atom and the danger from fallout are concerned. Information on delayed radiation changes in human beings is necessarily quite limited, and the thousands of Japanese people who survived the atomic bombings of Hiroshima and Nagasaki constitute a unique group of irradiated human beings who received in . . .
Prevalence and Incidence of Systemic Lupus Erythematosus in a Population‐Based Registry of American Indian and Alaska Native People, 2007–2009
Authors: Elizabeth D. Ferucci, Janet M. Johnston, Jasmine R. Gaddy, Lisa Sumner, James O. Posever, Tammy L. Choromanski, Caroline Gordon, S. Sam Lim, Charles G. Helmick
Journal: Arthritis & Rheumatology (2014)

Few studies have investigated the epidemiology of systemic lupus erythematosus (SLE) in American Indian and Alaska Native populations. The objective of this study was to determine the prevalence and incidence of SLE in the Indian Health Service (IHS) active clinical population in 3 regions of the US.For this population-based registry within the IHS, the denominator consisted of individuals in the IHS active clinical population in 2007, 2008, and/or 2009 and residing in a community in 1 of 3 specified regions. Potential SLE cases were identified based on the presence of a diagnostic code for SLE or related disorder in the IHS National Data Warehouse. Detailed medical record abstraction was performed for each potential case. The primary case definition was documentation in the medical record of ≥4 of the revised American College of Rheumatology criteria for the classification of SLE. Prevalence was calculated for 2007, and the mean annual incidence was calculated for the years 2007 through 2009.The age-adjusted prevalence and incidence of SLE according to the primary definition were 178 per 100,000 person-years (95% confidence interval [95% CI] 157-200) and 7.4 per 100,000 person-years (95% CI 5.1-10.4). Among women, the age-adjusted prevalence was 271, and the age-adjusted incidence was 10.4. The prevalence was highest in women ages 50-59 years and in the Phoenix Area IHS.The first population-based lupus registry in the US American Indian and Alaska Native population has demonstrated that the prevalence and incidence of SLE are high. Our estimates are as high as or higher than the rates reported in the US black population.
A New Method for Measuring Sialic Acid Levels in Serum and Its Application to Rheumatic Fever1
Authors: Eugene L. Hess, Alvin F. Coburn, Richard C. Bates, Priscilla Murphy
Journal: Journal of Clinical Investigation (1957)

Previous reports (1-4) have indicated the clini- cal usefulness of a color reaction given by serum with the diphenylamine reagent of Dische.It has been shown that the purple color produced in this reaction is probably due to the presence of a deoxyhexose structure in the sialic acid molecule (5).Sialic acid, or a closely related substance, appears to be a common constituent of mucopro- teins (glycoproteins) including orosomucoid of serum (6, 7).The color produced in the diphenyl- amine reaction reflects the concentration of the mucoproteins in the serum being tested.In our experience, and as reported by Anderson and Maclagan (8), the color developed with diphenyl- amine appears to be a specific reaction of muco- proteins.An elevation in the mucoproteins found in the alpha globulin fraction of serum is characteristic of many diseases (7).As pointed out in a previous report (4) a con- stant feature of the diphenylamine reaction was the concomitant rise in the color index of the "serum blank" associated with the increased color intensity of the serum samples tested.The "serum blank" in this instance was the combination of depro- teinized serum with the sulfuric acetic acid mix- ture which did not contain diphenylamine.This report will consider the chemical and clini- cal aspects of the "serum blank" reaction.It will be shown that the color produced when a mixture of sulfuric and acetic acids is heated with the de- proteinized serum sample is also probably due to sialic acid.The simplicity of the test suggests its usefulness as a new method for measuring the in- tensity of inflammation.
Molecular Pathways: Resistance to Kinase Inhibitors and Implications for Therapeutic Strategies
Authors: Christine M. Lovly, Alice T. Shaw
Journal: Clinical Cancer Research (2014)

The development of targeted therapies has revolutionized the treatment of cancer patients. The identification of "druggable" oncogenic kinases and the creation of small-molecule inhibitors designed to specifically target these mutant kinases have become an important therapeutic paradigm across several different malignancies. Often these inhibitors induce dramatic clinical responses in molecularly defined cohorts. However, resistance to such targeted therapies is an inevitable consequence of this therapeutic approach. Resistance can be either primary (de novo) or acquired. Mechanisms leading to primary resistance may be categorized as tumor intrinsic factors or as patient/drug-specific factors. Acquired resistance may be mediated by target gene modification, activation of "bypass tracks" that serve as compensatory signaling loops, or histologic transformation. This brief review is a snapshot of the complex problem of therapeutic resistance, with a focus on resistance to kinase inhibitors in EGF receptor mutant and ALK rearranged non-small cell lung cancer, BRAF-mutant melanoma, and BCR-ABL-positive chronic myeloid leukemia. We describe specific mechanisms of primary and acquired resistance and then review emerging strategies to delay or overcome drug resistance.
Mitochondrial Function and Nuclear Factor-κB–Mediated Signaling in Radiation-Induced Bystander Effects
Authors: Hongning Zhou, Vladimir N. Ivanov, Yu-Chin Lien, Mercy Davidson, Tom K. Hei
Journal: Cancer Research (2008)

Abstract Although radiation-induced bystander effects have been well described over the past decade, the mechanisms of the signaling processes involved in the bystander phenomenon remain unclear. In the present study, using the Columbia University charged particle microbeam, we found that mitochondrial DNA–depleted human skin fibroblasts (ρo) showed a higher bystander mutagenic response in confluent monolayers when a fraction of the same population were irradiated with lethal doses compared with their parental mitochondrial–functional cells (ρ+). However, using mixed cultures of ρo and ρ+ cells and targeting only one population of cells with a lethal dose of α-particles, a decreased bystander mutagenesis was uniformly found in nonirradiated bystander cells of both cell types, indicating that signals from one cell type can modulate expression of bystander response in another cell type. In addition, we found that Bay 11-7082, a pharmacologic inhibitor of nuclear factor-κB (NF-κB) activation, and 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, a scavenger of nitric oxide (NO), significantly decreased the mutation frequency in both bystander ρo and ρ+ cells. Furthermore, we found that NF-κB activity and its dependent proteins, cyclooxygenase-2 (COX-2) and inducible NO synthase (iNOS), were lower in bystander ρo cells when compared with their ρ+ counterparts. Our results indicated that mitochondria play an important role in the regulation of radiation-induced bystander effects and that mitochondria-dependent NF-κB/iNOS/NO and NF-κB/COX-2/prostaglandin E2 signaling pathways are important to the process. [Cancer Res 2008;68(7):2233–40]
Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans
Authors: Véronique Ouellet, Sébastien M. Labbé, Denis P. Blondin, Serge Phoenix, Brigitte Guérin, François Haman, Eric E. Turcotte, Denis Richard, André C. Carpentier
Journal: Journal of Clinical Investigation (2012)

Brown adipose tissue (BAT) is vital for proper thermogenesis during cold exposure in rodents, but until recently its presence in adult humans and its contribution to human metabolism were thought to be minimal or insignificant. Recent studies using PET with 18F-fluorodeoxyglucose (18FDG) have shown the presence of BAT in adult humans. However, whether BAT contributes to cold-induced nonshivering thermogenesis in humans has not been proven. Using PET with 11C-acetate, 18FDG, and 18F-fluoro-thiaheptadecanoic acid (18FTHA), a fatty acid tracer, we have quantified BAT oxidative metabolism and glucose and nonesterified fatty acid (NEFA) turnover in 6 healthy men under controlled cold exposure conditions. All subjects displayed substantial NEFA and glucose uptake upon cold exposure. Furthermore, we demonstrated cold-induced activation of oxidative metabolism in BAT, but not in adjoining skeletal muscles and subcutaneous adipose tissue. This activation was associated with an increase in total energy expenditure. We found an inverse relationship between BAT activity and shivering. We also observed an increase in BAT radio density upon cold exposure, indicating reduced BAT triglyceride content. In sum, our study provides evidence that BAT acts as a nonshivering thermogenesis effector in humans.
Circulating CD34-Positive Cells Provide an Index of Cerebrovascular Function
Authors: Akihiko Taguchi, Tomohiro Matsuyama, Hiroshi Moriwaki, Takuya Hayashi, Kohei Hayashida, Kazuyuki Nagatsuka, Kenichi Todo, Katsushi Mori, David M. Stern, Toshihiro Soma, Hiroaki Naritomi
Journal: Circulation (2004)

Increasing evidence points to a role for circulating endothelial progenitor cells, including populations of CD34- and CD133-positive cells present in peripheral blood, in maintenance of the vasculature and neovascularization. Immature populations, including CD34-positive cells, have been shown to contribute to vascular homeostasis, not only as a pool of endothelial progenitor cells but also as a source of growth/angiogenesis factors at ischemic loci. We hypothesized that diminished numbers of circulating immature cells might impair such physiological and reparative processes, potentially contributing to cerebrovascular dysfunction.The level of circulating immature cells, CD34-, CD133-, CD117-, and CD135-positive cells, in patients with a history of atherothrombotic cerebral ischemic events was analyzed to assess possible correlations with the degree of carotid atherosclerosis and number of cerebral infarctions. There was a strong inverse correlation between numbers of circulating CD34- and CD133-positive cells and cerebral infarction. In contrast, there was no correlation between the degree of atherosclerosis and populations of circulating immature cells. Analysis of patients with cerebral artery occlusion revealed a significant positive correlation between circulating CD34- and CD133-positive cells and regional blood flow in areas of chronic hypoperfusion.These results suggest a possible contribution of circulating CD34- and CD133-positive cells in maintenance of the cerebral circulation in settings of ischemic stress. Our data demonstrate the utility of a simple and precise method to quantify circulating CD34-positive cells, the latter providing a marker of cerebrovascular function.
Characterization of Alisertib (MLN8237), an Investigational Small-Molecule Inhibitor of Aurora A Kinase Using Novel <i>In Vivo</i> Pharmacodynamic Assays
Authors: Mark G. Manfredi, Jeffrey A. Ecsedy, Arijit Chakravarty, Lee Silverman, Mengkun Zhang, Kara M. Hoar, Stephen G. Stroud, Wei Chen, Vaishali Shinde, Jessica J. Huck, Deborah R. Wysong, David A. Janowick, Marc L. Hyer, Patrick J. LeRoy, Rachel E. Gershman, Matthew D. Silva, Melissa S. Germanos, Joseph B. Bolen, Christopher F. Claiborne, Todd B. Sells
Journal: Clinical Cancer Research (2011)

Small-molecule inhibitors of Aurora A (AAK) and B (ABK) kinases, which play important roles in mitosis, are currently being pursued in oncology clinical trials. We developed three novel assays to quantitatively measure biomarkers of AAK inhibition in vivo. Here, we describe preclinical characterization of alisertib (MLN8237), a selective AAK inhibitor, incorporating these novel pharmacodynamic assays.We investigated the selectivity of alisertib for AAK and ABK and studied the antitumor and antiproliferative activity of alisertib in vitro and in vivo. Novel assays were used to assess chromosome alignment and mitotic spindle bipolarity in human tumor xenografts using immunofluorescent detection of DNA and alpha-tubulin, respectively. In addition, 18F-3'-fluoro-3'-deoxy-l-thymidine positron emission tomography (FLT-PET) was used to noninvasively measure effects of alisertib on in vivo tumor cell proliferation.Alisertib inhibited AAK over ABK with a selectivity of more than 200-fold in cells and produced a dose-dependent decrease in bipolar and aligned chromosomes in the HCT-116 xenograft model, a phenotype consistent with AAK inhibition. Alisertib inhibited proliferation of human tumor cell lines in vitro and produced tumor growth inhibition in solid tumor xenograft models and regressions in in vivo lymphoma models. In addition, a dose of alisertib that caused tumor stasis, as measured by volume, resulted in a decrease in FLT uptake, suggesting that noninvasive imaging could provide value over traditional measurements of response.Alisertib is a selective and potent inhibitor of AAK. The novel methods of measuring Aurora A pathway inhibition and application of tumor imaging described here may be valuable for clinical evaluation of small-molecule inhibitors.
Switching between anti-tumour necrosis factors: trying to get a handle on a complex issue
Authors: R. F van Vollenhoven
Journal: Annals of the Rheumatic Diseases (2007)

The question of switching is not only a question of clinical practice, but has an important scientific dimension as well See linked article, 893

    Make sense who may. I switch off. Samuel Beckett (1984) 

The registration, almost simultaneously, of etanercept and infliximab, followed some years later by that of adalimumab, presented rheumatologists with outstanding therapeutic options to the benefit of many patients. Nevertheless, it also became clear that none of these drugs are effective in all cases, and the question about switching from one anti-tumour necrosis factor (TNF) to another became an important clinical issue. As we wrote 4 years ago in the Annals of the Rheumatic Diseases : “in these situations, [is] there a rationale for prescribing the other TNFα blocker, or [is this] simply a waste of time and money?”.1 Since that publication, a sizeable number of research articles have investigated this question, and the answers have generally been in the affirmative, implying that, yes, a switch of this type can benefit some patients.2,3,4,5,6,7,8,9,10,11,12,13,14,15,16 However, some reports reached less favourable conclusions,17,18 and it can rightfully be asserted that none of those published studies, nor any of the many abstracts presented at international meetings on the topic, were controlled, prospective, randomised or blinded.

Perhaps the importance and depth of the issue of switching between anti-TNFs has not been sufficiently appreciated. For one thing, the question of switching is not only a question of clinical practice, but has an important scientific dimension as well: a true demonstration that one anti-TNF agent has efficacy in the same patient who failed to respond to another suggests something potentially important about the pathophysiological process in that individual, leading to interesting possibilities for “bedside-to-bench” research. A …
Manchester authority is set to take control of 6bn worth of health and social care spending
Authors: G. Iacobucci
Journal: BMJ (2015)

Greater Manchester local authority is set to become the first in England to take control of the area’s entire £6bn (€8.2bn; $9.3bn) budget for health and social care, under a radical new plan backed by the chancellor of the exchequer, George Osborne.

The plan, expected to be confirmed by Osborne on Friday 27 February, will hand NHS spending powers to a larger region-wide health and wellbeing board from April 2016. The move follows the government’s devolution deal in 2014, which pledged to hand greater power to cities in the north of England.

It will mark the first time a local council in England has been handed direct control of health budgets in addition to the social care budgets they already hold.

The plan was developed after discussions involving 10 …
Analysis of the Relationship between Norepinephrine and Asymmetric Dimethyl Arginine Levels among Patients with End-Stage Renal Disease
Authors: Francesca Mallamaci, Giovanni Tripepi, Renke Maas, Lorenzo Malatino, Rainer Bo[Combining Diaeresis]ger, Carmine Zoccali
Journal: Journal of the American Society of Nephrology (2004)

High sympathetic activity and alterations in nitric oxide synthesis attributable to accumulation of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) have recently been identified as potential causal mechanisms for the high cardiovascular mortality rates among patients with ESRD. The link between these risk factors has not been studied. Therefore, the relationship between plasma norepinephrine (NE) and ADMA levels was examined in a large cohort of hemodialysis patients (n = 224), and whether these factors interacted in predicting all-cause mortality and new cardiovascular event rates among those patients was investigated. Plasma ADMA levels were strongly associated with plasma NE levels (P < 0.001) and to a lesser extent with heart rate (P < 0.01). In multivariate analyses, the ADMA-NE correlation was observed to be independent of age, gender, serum albumin levels, arterial pressure and antihypertensive treatment, duration of dialysis treatment, diabetes mellitus, and other risk factors. NE was an independent significant predictor of both death and cardiovascular events in Cox models not including ADMA. However, when ADMA was introduced into those models, NE became a largely nonsignificant predictor of those outcomes, whereas plasma ADMA levels emerged as a highly significant predictor of both death (P < 0.001) and cardiovascular events (P < 0.001). These findings suggest that ADMA is an intervening factor in the causal pathway leading to those outcomes. Plasma NE and ADMA concentrations are strongly related among patients with ESRD. These two factors are likely to be involved in the same causal pathway leading to death and cardiovascular events among those patients.
Identifying Predictors of Interferon-γ Release Assay Results in Pediatric Latent Tuberculosis: A Protective Role of Bacillus Calmette-Guérin?
Authors: Robindra Basu Roy, Giovanni Sotgiu, Neus Altet-Gómez, Maria Tsolia, Ezia Ruga, Svetlana Velizarova, Beate Kampmann
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

Interferon-γ (IFN-γ) release assays are widely used to diagnose latent infection with Mycobacterium tuberculosis in adults, but their performance in children remains incompletely evaluated to date.
Role of medical history and medication use in the aetiology of upper aerodigestive tract cancers in Europe: the ARCAGE study
Authors: T.V. Macfarlane, G.J. Macfarlane, N.S. Thakker, S. Benhamou, C. Bouchardy, W. Ahrens, H. Pohlabeln, P. Lagiou, A. Lagiou, X. Castellsague, A. Agudo, A. Slamova, J. Plzak, F. Merletti, L. Richiardi, R. Talamini, L. Barzan, K. Kjaerheim, C. Canova, L. Simonato, D.I. Conway, P.A. McKinney, P. Thomson, P. Sloan, A. Znaor, C.M. Healy, B.E. McCartan, M. Marron, P. Brennan
Journal: Annals of Oncology (2011)
The presence of spirochetes in late seronegative syphilis
Authors: J. L. Smith
Journal: JAMA (1967)

Late seronegative syphilis refers to clinical signs of ocular or neurosyphilis in a patient whose routine blood (reagin) test is nonreactive, but in whom a specific treponemal test is reactive. This report documents the presence of spirochetes in aqueous humor, cerebrospinal fluid, and at liver biopsy in such patients. Spirochetes have been found in the aqueous humor with no biomicroscopic abnormality and in cerebrospinal fluids which had normal cell counts, protein levels, and reagin and colloidal gold test results. Identification of the organisms depends on use of the fluorescein antibody technique, in that spirochetes stain with fluorescein-tagged anti- Treponema pallidum globulin on ultraviolet microscopy.
Body dysmorphic disorder among dermatologic patients: Prevalence and clinical features
Authors: Luciana Archetti Conrado, Ana Gabriela Hounie, Juliana Belo Diniz, Victor Fossaluza, Albina Rodrigues Torres, Euripedes Constantino Miguel, Evandro Ararigboia Rivitti
Journal: Journal of the American Academy of Dermatology (2010)