tbuckley/cabot-search huggingface dataset:
Comparison of Pancreatic Human and Biosynthetic Human Insulin with Respect to Their Action on Adipocytes and Chick Embryo Fibroblasts
Authors: J Zapf, E R Froesch
Journal: Diabetes Care (1981)

Biosynthetic human insulin (BHI) was compared to pancreatic human insulin and sperm whale insulin in terms of ability to stimulate incorporation of glucose into isolated rat adipocytes and thymidine into DNA in chick embryo fibroblasts. The human insulins were identical in their effects in both assays. Sperm whale insulin was more potent than the human insulins in stimulating glucose incorporation into rat adipocytes. All three insulins showed identical stimulation of DNA synthesis in the fibroblast assay. That action, however, is mediated via the receptor for insulin-like growth factor (IGF-I). Therefore, both human insulins were evaluated in terms of binding to the IGF-1 receptor in chick embryo fibroblasts. The two human insulins behaved identically (and agreed with previous findings for sperm whale insulin). All insulins, however, were approximately 200-fold less potent than IGF-I itself in this binding assay.
OSU-HDAC42, a Histone Deacetylase Inhibitor, Blocks Prostate Tumor Progression in the Transgenic Adenocarcinoma of the Mouse Prostate Model
Authors: Aaron M. Sargeant, Robert C. Rengel, Samuel K. Kulp, Russell D. Klein, Steven K. Clinton, Yu-Chieh Wang, Ching-Shih Chen
Journal: Cancer Research (2008)

Histone deacetylase (HDAC) inhibitors suppress tumor cell growth via a broad spectrum of mechanisms, which should prove advantageous in the context of cancer prevention. Here, we examined the effect of dietary administration of OSU-HDAC42, a novel HDAC inhibitor, on prostate tumor progression in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Based on a series of pilot studies, an AIN-76A diet was formulated containing 208 ppm OSU-HDAC42, which was estimated to deliver approximately 25 mg/kg of drug per day to each mouse and found to cause a suppression of PC-3 xenograft tumor growth equivalent to that achieved by gavage administration of a similar dose. At 6 weeks of age, TRAMP mice received this drug-containing or control diet for 4 or 18 weeks and were evaluated for prostatic intraepithelial neoplasia (PIN) and carcinoma development, respectively. OSU-HDAC42 not only decreased the severity of PIN and completely prevented its progression to poorly differentiated carcinoma (74% incidence in controls versus none in drug-treated mice), but also shifted tumorigenesis to a more differentiated phenotype, suppressing absolute and relative urogenital tract weights by 86% and 85%, respectively, at 24 weeks of age. This tumor suppression was associated with the modulation of intraprostatic biomarkers, including those indicative of HDAC inhibition, increased apoptosis and differentiation, and decreased proliferation. With the exception of completely reversible hematologic alterations and testicular degeneration, no significant changes in body weight or other indicators of general health were observed in drug-treated mice. These results suggest that OSU-HDAC42 has value in prostate cancer prevention. [Cancer Res 2008;68(10):3999-4009].
The Linkage of Innate to Adaptive Immunity via Maturing Dendritic Cells In Vivo Requires CD40 Ligation in Addition to Antigen Presentation and CD80/86 Costimulation
Authors: Shin-ichiro Fujii, Kang Liu, Caroline Smith, Anthony J. Bonito, Ralph M. Steinman
Journal: The Journal of Experimental Medicine (2004)

Dendritic cell (DC) maturation is an innate response that leads to adaptive immunity to coadministered proteins. To begin to identify underlying mechanisms in intact lymphoid tissues, we studied α-galactosylceramide. This glycolipid activates innate Vα14+ natural killer T cell (NKT) lymphocytes, which drive DC maturation and T cell responses to ovalbumin antigen. Hours after giving glycolipid i.v., tumor necrosis factor (TNF)–α and interferon (IFN)-γ were released primarily by DCs. These cytokines induced rapid surface remodeling of DCs, including increased CD80/86 costimulatory molecules. Surprisingly, DCs from CD40−/− and CD40L−/− mice did not elicit CD4+ and CD8+ T cell immunity, even though the DCs exhibited presented ovalbumin on major histocompatibility complex class I and II products and expressed high levels of CD80/86. Likewise, an injection of TNF-α up-regulated CD80/86 on DCs, but CD40 was required for immunity. CD40 was needed for DC interleukin (IL)-12 production, but IL-12p40−/− mice generated normal ovalbumin-specific responses. Therefore, the link between innate and adaptive immunity via splenic DCs and innate NKT cells has several components under distinct controls: antigen presentation in the steady state, increases in costimulatory molecules dependent on inflammatory cytokines, and a distinct CD40/CD40L signal that functions together with antigen presentation (“signal one”) and costimulation (“signal two”) to generate functioning CD4+ T helper cell 1 and CD8+ cytolytic T lymphocytes.
Role of Tet1 and 5-hydroxymethylcytosine in cocaine action
Authors: Jian Feng, Ningyi Shao, Keith E Szulwach, Vincent Vialou, Jimmy Huynh, Chun Zhong, Thuc Le, Deveroux Ferguson, Michael E Cahill, Yujing Li, Ja Wook Koo, Efrain Ribeiro, Benoit Labonte, Benjamin M Laitman, David Estey, Victoria Stockman, Pamela Kennedy, Thomas Couroussé, Isaac Mensah, Gustavo Turecki, Kym F Faull, Guo-li Ming, Hongjun Song, Guoping Fan, Patrizia Casaccia, Li Shen, Peng Jin, Eric J Nestler
Journal: Nature Neuroscience (2015)
Drug/polymer nanoparticles prepared using unique spray nozzles and recent progress of inhaled formulation
Authors: Tetsuya Ozeki, Tatsuaki Tagami
Journal: Asian Journal of Pharmaceutical Sciences (2014)

Inhaled formulations are promising for pulmonary and systemic non-pulmonary diseases. Functional engineered particles including drugs and drug-loaded nanocarriers have been anticipated because they can improve drug delivery efficacy against target sites in the lungs or blood. In this review, unique spray nozzles (e.g., four-fluid spray nozzle and two-solution mixing type nozzle) for the preparation of nanocomposite particles which mean microparticles containing drug nanoparticles are described. These nozzles can produce nanocomposite particles in one-step and their spray drying system is suitable for scaling-up. Nanocomposite particles are useful in improving drug absorption and delivery efficacy against alveolar macrophages. In addition, recent studies on several pulmonary diseases (tuberculosis, lung cancer, cystic fibrosis, pneumonia, vaccine and others) and related inhaled formulations were also reviewed.
Conditional Mineralocorticoid Receptor Expression in the Heart Leads to Life-Threatening Arrhythmias
Authors: Antoine Ouvrard-Pascaud, Yannis Sainte-Marie, Jean-Pierre Bénitah, Romain Perrier, Christelle Soukaseum, Aurelie Nguyen Dinh Cat, Anne Royer, Khai Le Quang, Flavien Charpentier, Sophie Demolombe, Fatima Mechta-Grigoriou, Ahmed T. Beggah, Pierre Maison-Blanche, Marie-Edith Oblin, Claude Delcayre, Glenn I. Fishman, Nicolette Farman, Brigitte Escoubet, Frederic Jaisser
Journal: Circulation (2005)

Background— Life-threatening cardiac arrhythmia is a major source of mortality worldwide. Besides rare inherited monogenic diseases such as long-QT or Brugada syndromes, which reflect abnormalities in ion fluxes across cardiac ion channels as a final common pathway, arrhythmias are most frequently acquired and associated with heart disease. The mineralocorticoid hormone aldosterone is an important contributor to morbidity and mortality in heart failure, but its mechanisms of action are incompletely understood. Methods and Results— To specifically assess the role of the mineralocorticoid receptor (MR) in the heart, in the absence of changes in aldosteronemia, we generated a transgenic mouse model with conditional cardiac-specific overexpression of the human MR. Mice exhibit a high rate of death prevented by spironolactone, an MR antagonist used in human therapy. Cardiac MR overexpression led to ion channel remodeling, resulting in prolonged ventricular repolarization at both the cellular and integrated levels and in severe ventricular arrhythmias. Conclusions— Our results indicate that cardiac MR triggers cardiac arrhythmias, suggesting novel opportunities for prevention of arrhythmia-related sudden death.
Geographical Variations in Use of Surgery for Glue Ear
Authors: Nick Black
Journal: Journal of the Royal Society of Medicine (1985)

Study of geographical variations in the rate of surgery for glue ear reveals striking differences both between English health regions and between health districts. There are two-fold differences between regions and up to seven-fold differences between districts. Analysis of these differences at different levels of population aggregation reveals that professional uncertainty about the indications and value of surgery for this condition is the major factor responsible. In addition, the availability of otolaryngologists influences the surgical rate at district though not at regional level. The method used in this study is unable to determine the part played by geographical variation in patient expectation and morbidity rate. In contrast to the lack of consensus among otolaryngologists regarding the use of surgery for glue ear, there appears to be a high degree of agreement as regards tonsillectomy. The latter has coincided with the end of the decline in the tonsillectomy rate in the late 1970s.
A novel missense mutation in the amino-terminal domain of the human androgen receptor gene in a family with partial androgen insensitivity syndrome causes reduced efficiency of protein translation.
Authors: C S Choong, C A Quigley, F S French, E M Wilson
Journal: Journal of Clinical Investigation (1996)

The role of the androgen receptor (AR) in male sexual differentiation is revealed in part by the analysis of naturally occurring mutations in families with androgen insensitivity syndrome (AIS). We have investigated a family with partial AIS affecting three generations and have identified a G to A substitution in the AR gene at the fourth position 3' from the A of the ATG initiation codon changing the second amino acid residue from glutamic acid to lysine (EK2). Transient expression of the mutant EK2-pCMVhAR expression vector in COS cells revealed decreased translation with a 20-50% reduction in mutant protein relative to wild type AR by immunoblot analysis. The rate of dissociation of [3H]methyltrienolone from the EK2 mutant (half-time [t1/2] = 1.7 +/- 0.08 SE h) was increased compared with wild type AR (t1/2 = 2.4 +/- 0.11 h). Cotransfection studies using an androgen responsive luciferase reporter vector demonstrated a 50% reduction in transcriptional activation by EK2. These functional alterations are consistent with the partial AIS phenotype in affected males, corroborate the AR amino-terminal domain effect on kinetics of androgen binding, and provide physiological evidence for earlier translation experiments identifying the nucleotide sequence for optimal translation initiation.
Dietary Salt Intake and Mortality in Patients With Type 2 Diabetes
Authors: Elif I. Ekinci, Sophie Clarke, Merlin C. Thomas, John L. Moran, Karey Cheong, Richard J. MacIsaac, George Jerums
Journal: Diabetes Care (2011)

OBJECTIVE Many guidelines recommend that patients with type 2 diabetes should aim to reduce their intake of salt. However, the precise relationship between dietary salt intake and mortality in patients with type 2 diabetes has not been previously explored. RESEARCH DESIGN AND METHODS Six hundred and thirty-eight patients attending a single diabetes clinic were followed in a prospective cohort study. Baseline sodium excretion was estimated from 24-h urinary collections (24hUNa). The predictors of all-cause and cardiovascular mortality were determined by Cox regression and competing risk modeling, respectively. RESULTS The mean baseline 24hUNa was 184 ± 73 mmol/24 h, which remained consistent throughout the follow-up (intraindividual coefficient of variation [CV] 23 ± 11%). Over a median of 9.9 years, there were 175 deaths, 75 (43%) of which were secondary to cardiovascular events. All-cause mortality was inversely associated with 24hUNa, after adjusting for other baseline risk factors (P &amp;lt; 0.001). For every 100 mmol rise in 24hUNa, all-cause mortality was 28% lower (95% CI 6–45%, P = 0.02). After adjusting for the competing risk of noncardiovascular death and other predictors, 24hUNa was also significantly associated with cardiovascular mortality (sub-hazard ratio 0.65 [95% CI 0.44–0.95]; P = 0.03). CONCLUSIONS In patients with type 2 diabetes, lower 24-h urinary sodium excretion was paradoxically associated with increased all-cause and cardiovascular mortality. Interventional studies are necessary to determine if dietary salt has a causative role in determining adverse outcomes in patients with type 2 diabetes and the appropriateness of guidelines advocating salt restriction in this setting.
Analysis of gut microbial regulation of host gene expression along the length of the gut and regulation of gut microbial ecology through MyD88
Authors: Erik Larsson, Valentina Tremaroli, Ying Shiuan Lee, Omry Koren, Intawat Nookaew, Ashwana Fricker, Jens Nielsen, Ruth E Ley, Fredrik Bäckhed
Journal: Gut (2011)

<h3>Background</h3> The gut microbiota has profound effects on host physiology but local host–microbial interactions in the gut are only poorly characterised and are likely to vary from the sparsely colonised duodenum to the densely colonised colon. Microorganisms are recognised by pattern recognition receptors such as Toll-like receptors, which signal through the adaptor molecule MyD88. <h3>Methods</h3> To identify host responses induced by gut microbiota along the length of the gut and whether these required MyD88, transcriptional profiles of duodenum, jejunum, ileum and colon were compared from germ-free and conventionally raised wild-type and <i>Myd88−/−</i> mice. The gut microbial ecology was assessed by 454-based pyrosequencing and viruses were analysed by PCR. <h3>Results</h3> The gut microbiota modulated the expression of a large set of genes in the small intestine and fewer genes in the colon but surprisingly few microbiota-regulated genes required MyD88 signalling. However, MyD88 was essential for microbiota-induced colonic expression of the antimicrobial genes <i>Reg3β</i> and <i>Reg3γ</i> in the epithelium, and <i>Myd88</i> deficiency was associated with both a shift in bacterial diversity and a greater proportion of segmented filamentous bacteria in the small intestine. In addition, conventionally raised <i>Myd88−/−</i> mice had increased expression of antiviral genes in the colon, which correlated with norovirus infection in the colonic epithelium. <h3>Conclusion</h3> This study provides a detailed description of tissue-specific host transcriptional responses to the normal gut microbiota along the length of the gut and demonstrates that the absence of MyD88 alters gut microbial ecology.
CC Chemokine Receptor-1 Activates Intimal Smooth Muscle–Like Cells in Graft Arterial Disease
Authors: Koichi Shimizu, Manabu Minami, Rica Shubiki, Marco Lopez-Ilasaca, Lindsey MacFarlane, Yukiko Asami, Yuxin Li, Richard N. Mitchell, Peter Libby
Journal: Circulation (2009)

Graft arterial disease (GAD) limits long-term solid-organ allograft survival. The thickened intima in GAD contains smooth muscle-like cells (SMLCs), leukocytes, and extracellular matrix. The intimal SMLCs in mouse GAD lesions differ from medial smooth muscle cells in their function and phenotype. Although intimal SMLCs may originate by migration and modulation of donor medial cells or by recruitment of host-derived precursors, the mechanisms that underlie their localization within grafts and the factors that drive these processes remain unclear.This study of aortic transplantation in mice demonstrated an important function for chemokines beyond their traditional role in leukocyte recruitment and activation. Intimal SMLCs, but not medial smooth muscle cells, express functional CC chemokine receptor-1 (CCR1) and respond to RANTES by increased migration and proliferation. Although RANTES infusion in vivo promoted inflammatory cell accumulation in the adventitia of aortic allografts of wild-type and CCR1-deficient recipients, it increased GAD intimal thickening with SMLC proliferation in only the wild-type hosts. Aortic allografts transplanted into CCR1-deficient mice after wild-type bone marrow transplantation did not develop intimal lesions, which indicates that CCR1-bearing inflammatory cells do not contribute to intimal lesion formation. Moreover, RANTES induced SMLC proliferation in vitro but did not promote medial smooth muscle cell growth. Blockade of CCR5 attenuated RANTES-induced T-cell and monocyte/macrophage proliferation but did not affect RANTES-induced SMLC proliferation, consistent with a larger role of CCR1-binding chemokines in SMLC migration and proliferation and GAD development.These studies provide a novel mechanistic insight into the formation of vascular intimal hyperplasia and suggest a novel therapeutic strategy for preventing allograft arteriopathy.
Blood methanethiol in alcoholic liver disease with and without hepatic encephalopathy.
Authors: C J McClain, L Zieve, W M Doizaki, S Gilberstadt, G R Onstad
Journal: Gut (1980)

<h3>Abstract</h3> In the human neocortex, coherent theta oscillations between superficial and deep cortical layers are driven by deep layer neurons, suggesting distinct intrinsic electrophysiological properties of neurons across cortical layers. Here, we used in vitro whole-cell recordings to characterize pyramidal cells in layer 2/3 (L2/3) and layer 5 (L5) of the human neocortex. We found that human L5 pyramidal cells were more excitable and were endowed with a more prominent sag voltage and larger <i>I</i><sub>h</sub> currents relative to L2/3 neurons, that were abolished through direct pharmacological blockade. Although no peak in subthreshold resonance was observed for either L2/3 or L5 cells, we found that L5 neurons demonstrated greater spiking gain at low frequencies. Integrating patient-level demographic features revealed larger sag amplitudes in pyramidal cells recorded from older patients. These data suggest that sag is prominently expressed in L5 pyramidal cells and is a dynamic feature of human cortical microcircuits.
Fitness Test Pro: a one-stop application to assess cardiorespiratory fitness
Authors: Aaron T Scanlan, Patrick S Tucker, Robert Stanton, Vincent J Dalbo
Journal: British Journal of Sports Medicine (2015)

Fitness Test Pro

Fitness or health

Apple (iOS 4.3 or later); Android (V.2.2 and up)

US$3.00

Fitness Test Pro permits users to conduct a range of cardiorespiratory fitness assessments outside of laboratory settings. Users can directly record and store performance data related to commonly used cardiorespiratory tests related to running (Cooper test, Bruce treadmill test, 20 m multistage fitness test, Andersen test and a variable Any distance run test), cycling (Watt max bicycle test, Astrand-Rhyming cycle test and Two-stage bicycle test) and step/walking categories (Danish step test and One-mile walk test) (figure 1). The reliability1 ,2 and validity2 ,3 of many of these tests have been published.



Figure 1 
The Fitness Test Pro menu, including the selection of running tests.



Fitness Test Pro uses demographic (age, gender, body mass and height), distance, time and heart rate data to …
Evidence for adenosine mediation of atrioventricular block in the ischemic canine myocardium.
Authors: L Belardinelli, E C Mattos, R M Berne
Journal: Journal of Clinical Investigation (1981)

Adenosine levels in oxygen-deprived myocardium can rise to 10- 100 microM concentrations known to cause atrioventricular (AV) conduction delay and block. We reported that the AV conduction delay and block caused by hypoxia is markedly attenuated by 10 microM aminophylline, and adenosine competitive antagonist. THe purpose of the present study was to investigate adenosine's role in ischemic AV conduction disturbances. Dogs were anesthetized and instrumented for His bundle and surface electrogram recordings. The total AV conduction time was subdivided in to atrial-His bundle (AH) and His bundle-ventricle intervals. The atrioventricular node artery (AVNA) was cannulated for selective injection of drugs in the AV node region. Adenosine (10 to 100 microgram), as a 2-ml bolus injection, rapidly produced a dose-dependent, transient increase in the AH interval; a 1,000-microgram dose caused second degree AV block. The duration of the increase in AH interval was also dose-dependent. Dipyridamole, and inhibitor of nucleoside transport, potentiated the negative dromotropic effects of adenosine, whereas aminophylline attenuated them. In some dogs, after cannulation of the AVNA, first and second degree AV block occurred spontaneously or were induced by rapid atrial pacing. Injection of the aminophylline (5 mg/kg, i.e.) or theophylline (100-1,000 microgram) into the AVNA rapidly reversed the AV blocks. Upon washout of the drugs the AV blocks recurred. We conclude that endogenously released adenosine may account for a major fraction of the AV conduction delay and block associated with impaired blood supply to the AV node, and the theophylline and aminophylline reverse the AV conduction defect by antagonizing the effects of adenosine.
Cancer Vaccine Enhanced, Non–Tumor-Reactive CD8+ T Cells Exhibit a Distinct Molecular Program Associated with “Division Arrest Anergy”
Authors: Marc Beyer, Julia Karbach, Michael R. Mallmann, Thomas Zander, Daniela Eggle, Sabine Classen, Svenja Debey-Pascher, Michael Famulok, Elke Jäger, Joachim L. Schultze
Journal: Cancer Research (2009)

Immune-mediated tumor rejection relies on fully functional T-cell responses and neutralization of an adverse tumor microenvironment. In clinical trials, we detected peptide-specific but non-tumor-reactive and therefore not fully functional CD8(+) T cells post-vaccination against tumor antigens. Understanding the molecular mechanisms behind nontumor reactivity will be a prerequisite to overcome this CD8(+) T-cell deviation. We report that these non-tumor-reactive CD8(+) T cells are characterized by a molecular program associated with hallmarks of "division arrest anergy." Non-tumor-reactive CD8(+) T cells are characterized by coexpression of CD7, CD25, and CD69 as well as elevated levels of lck(p505) and p27(kip1). In vivo quantification revealed high prevalence of non-tumor-reactive CD8(+) T cells with increased levels during cancer vaccination. Furthermore, their presence was associated with a trend toward shorter survival. Dynamics and frequencies of non-target-reactive CD8(+) T cells need to be further addressed in context of therapeutic vaccine development in cancer, chronic infections, and autoimmune diseases.