tbuckley/cabot-search huggingface dataset:
Delayed recovery of homogeneous perfusion distribution in isolated rat heart after vasodilatation induced by 1 adrenoceptor blockade during postischaemic reperfusion
Authors: R W MOHANLAL, I MAUVE, L VAN DER VALK, A V G BRUSCHKE, A VAN DER LAARSE
Journal: Cardiovascular Research (1989)

The purpose of this study was to investigate whether vasodilatation induced by doxazosin, an alpha 1 adrenoceptor blocker, during postischaemic reperfusion was able to accelerate reflow in unperfused myocardium. Isolated isovolumetrically beating rat hearts were exposed to global ischaemia by perfusion at 15 mm Hg for 2 h, resulting in an end ischaemic coronary flow rate of 2.3 (SD 1.7)% of preischaemic value, and an unperfused myocardial volume of 71.8(4.3)% of total myocardial volume. Subsequent reperfusion at 80 mm Hg for 2 h produced a partial recovery of coronary flow rate of 41(6)% in the absence of doxazosin and a complete recovery [97(28)%] in the presence of doxazosin 2 mumol.litre-1. Surprisingly, doxazosin induced vasodilatation retarded the disappearance of "no reflow" during reperfusion: after 3 h of reperfusion the volume of unperfused myocardium was 14.3(5.5)% v 1.5(1.7)% in the control group (p less than 0.005). Assessed histologically the regions of "no-reflow" were localised predominantly in the subendocardium. In the presence of doxazosin, left ventricular end diastolic pressure during reperfusion was twice as high as in the control group, indicating pronounced subendocardial compression. The mechanism underlying prolonged subendocardial "no-reflow" in the presence of doxazosin during postischaemic reperfusion is a compressive action of dilated (sub)epicardial vessels on the vasculature in the unperfused subendocardial regions ("hydraulic" or "erectile" effect of increased vascular volume). Thus coronary vasodilatation induced by alpha 1 adrenergic receptor blockade during postischaemic reperfusion delays the recovery of homogeneous transmural perfusion distribution.
Ventricular Fusion Beats during Electric Stimulation in Man
Authors: ARTHUR J. LINENTHAL, PAUL M. ZOLL
Journal: Circulation (1965)

Quantitative studies of ventricular fusion beats were made in 40 patients with Stokes- Adams disease after implantation of electric pacemakers in the left ventricle. The two fusing complexes came from an electric pacemaker and either a second electric pacemaker or a conducted sinoatrial beat. The limit of fusion, that is the maximal time between two fusing complexes, gives a measure of the conduction time and velocity between the two points of initial ventricular depolarization. Conduction between two electric pacemakers and in retrograde direction from an electric pacemaker to the point of entry of a conducted beat was by way of ordinary myocardium; its velocity was about 1 meter per second. Conduction in antegrade direction, on the other hand, was by way of specialized Purkinje tissue; and its velocity was 4.5 to 9 times faster. Variations in conduction times with bundle-branch block support this interpretation: retrograde conduction time did not change; antegrade conduction time was prolonged in left but was usually unchanged in right bundle-branch block. The morphologic similarities of fusion beats in our patients to the features of anomalous AV excitation add strong evidence in man to the previous analogous experimental observations that the WPW complex is a fusion beat. Furthermore, quantitative comparison of WPW and our fusion beats supports the theory that the anomalous excitation in the WPW phenomenon, like the peripherally located artificial stimulus, enters the ventricle peripherally, by way of an accessory AV pathway.
Quantitative hepatitis B core antibody level may help predict treatment response in chronic hepatitis B patients
Authors: Quan Yuan, Liu-Wei Song, Chun-Jen Liu, Zhuo Li, Ping-Guo Liu, Cheng-Hao Huang, Yan Yan, Sheng-Xiang Ge, Ying-Bin Wang, Cheng-Yuan Peng, Jun Zhang, Jia-Horng Kao, Ding-Shinn Chen, Pei-Jer Chen, Ning-Shao Xia
Journal: Gut (2012)

We read with interest the recent article by Dandri emphasising the use of novel quantitative biomarkers as tools for predicting treatment response and disease progression in chronic hepatitis B infection (CHB).1 The authors carried out a comprehensive review of the clinical implications of quantitative measurement of viral biomarkers both in blood and in liver, such as: serum HBsAg, serum HBeAg and intrahepatic cccDNA, based on current knowledge.1 In addition to these, …
Optimized siRNA-PEG Conjugates for Extended Blood Circulation and Reduced Urine Excretion in Mice
Authors: Frank Iversen, Chuanxu Yang, Frederik Dagnæs-Hansen, David H. Schaffert, Jørgen Kjems, Shan Gao
Journal: Theranostics (2013)

Some of the main concerns with in vivo application of naked small interfering RNA are rapid degradation and urinary excretion resulting in a short plasma half-life.In this study we investigated how conjugation of polyethylene glycol (PEG) with variable chain length affects siRNA pharmacokinetics and biodistribution.The PEG chains were conjugated to chemically stabilized siRNA at the 5' terminal end of the passenger strand using click chemistry.The siRNA conjugate remained functionally active and showed significantly prolonged circulation in the blood stream after intravenous injection.siRNA conjugated with 20kDa PEG (PEG20k-siRNA) was most persistent, approximately 50% PEG20k-siRNA remained 1h post-injection, while the uncoupled siRNA was rapidly removed >90% at 15min.In vivo fluorescent imaging of the living animal showed increased concentration of siRNA in peripheral tissue and delayed urine excretion when coupled to PEG 20k.Biodistribution studies by northern blotting revealed equal distribution of conjugated siRNA in liver, kidney, spleen and lung without significant degradation 24 h post-injection.Our study demonstrates that PEG conjugated siRNA can be applied as a delivery system to improve siRNA bioavailability in vivo and may potentially increase the efficiency of siRNA in therapeutic applications.
Inducible differentiation and morphogenesis of bipotential liver cell lines from wild-type mouse embryos
Authors: Hélène Strick-Marchand, Mary C. Weiss
Journal: Hepatology (2002)

This work shows that hepatic cell lines reproducibly can be derived from E14 embryos of many mouse inbred strains. These bipotential mouse embryonic liver (BMEL) cell lines present a mixed morphology, containing both epithelial and palmate-like cells, and an uncoupled phenotype, expressing hepatocyte transcription factors (HNF1α, HNF4α, GATA4) but not functions (apolipoproteins, albumin). BMEL cells are bipotential: under inducing conditions they express hepatocyte and bile duct functions. In addition, they can undergo morphogenesis in Matrigel culture to form bile duct units. When returned to basal culture conditions, the differentiated cells revert, within a few days, to an undifferentiated state. The ensemble of markers expressed by BMEL cells implies that they originate from hepatoblasts, the endodermal precursors of the liver. In conclusion, the establishment of a simple and reproducible method to isolate from any mouse embryo bipotential hepatic cell lines that exhibit the properties of transit stem cells provides a novel paradigm for investigation of hepatic cell lineage relationships.
Nitrosative Stress–Induced <i>S</i>-Glutathionylation of Protein Disulfide Isomerase Leads to Activation of the Unfolded Protein Response
Authors: Danyelle M. Townsend, Yefim Manevich, Lin He, Ying Xiong, Robert R. Bowers, Steven Hutchens, Kenneth D. Tew
Journal: Cancer Research (2009)

The rapid proliferation of cancer cells mandates a high protein turnover. The endoplasmic reticulum (ER) is intimately involved in protein processing. An accumulation of unfolded or misfolded proteins in the ER leads to a cascade of transcriptional and translational events collectively called the unfolded protein response (UPR). Protein disulfide isomerase (PDI) is one of the most abundant ER proteins and maintains a sentinel function in organizing accurate protein folding. Treatment of cells with O(2)-[2,4-dinitro-5-(N-methyl-N-4-carboxyphenylamino)phenyl]1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate (PABA/NO) resulted in a dose-dependent increase in intracellular nitric oxide that caused S-glutathionylation of various proteins. Within 4 h, PABA/NO activated the UPR and led to translational attenuation as measured by the phosphorylation and activation of the ER transmembrane kinase, pancreatic ER kinase, and its downstream effector eukaryotic initiation factor 2 in human leukemia (HL60) and ovarian cancer cells (SKOV3). Cleavage of the transcription factor X-box protein 1 and transcriptional activation of the ER resident proteins BiP, PDI, GRP94, and ERO1 (5- to 10-fold induction) also occurred. Immunoprecipitation of PDI showed that whereas nitrosylation was undetectable, PABA/NO treatment caused S-glutathionylation of PDI. Mass spectroscopy analysis showed that single cysteine residues within each of the catalytic sites of PDI had a mass increase [+305.3 Da] consistent with S-glutathionylation. Circular dichroism confirmed that S-glutathionylation of PDI results in alterations in the alpha-helix content of PDI and is concurrent with inhibition of its isomerase activity. Thus, it appears that S-glutathionylation of PDI is an upstream signaling event in the UPR and may be linked with the cytotoxic potential of PABA/NO.
Impaired microvascular response to cholinergic stimuli in primary Sjogren's syndrome
Authors: L. Kovacs
Journal: Annals of the Rheumatic Diseases (2000)

Signs of a parasympathetic dysfunction have been revealed in primary Sjögren's syndrome (SS). Its role in the pathogenesis and the clinical picture of the disease is not clear. To investigate the responsiveness of SS patients to a cholinergic agonist, a model was used involving examination of the cutaneous microcirculation. The microvascular response to the administration of carbachol was measured, a muscarinic cholinergic agonist.Twenty two SS patients and 12 controls were examined. Carbachol and 0.9% saline solution were administered intracutaneously into the forearm skin at two distinct places. Skin blood flow (SBF) in the injected areas was measured continuously before and for 10 minutes after the injections by means of a laser Doppler perfusion monitor. The increase in SBF in response to carbachol (dSBF), reflecting vasodilatation, was calculated by a formula including the baseline and the maximum SBF values after the injections of carbachol and saline solution.The vasodilatation was significantly lower in SS patients than in the controls (mean dSBF: 2.1 (range: 1.0-4.5) versus 3.3 (range: 1.7-7.6), p=0.02). With non-responder patients defined as those in whom a smaller response was observed than in any of the controls, 11 of the 22 SS patients proved to be non-responders to carbachol. Comparisons of demographic, clinical and laboratory characteristics and HLA class II genotypes between responder and non-responder SS patients did not show any significant differences.A diminished or absent response to carbachol indicates a cholinergic dysfunction in SS patients. A disturbance in the neurotransmission at a receptorial or postreceptorial level is hypothesised. Unresponsiveness to cholinergic stimuli may contribute to exocrine insufficiency.
Prognostic Significance of Molecular Upstaging of Paraffin-Embedded Sentinel Lymph Nodes in Melanoma Patients
Authors: Hiroya Takeuchi, Donald L. Morton, Christine Kuo, Roderick R. Turner, David Elashoff, Robert Elashoff, Bret Taback, Akihide Fujimoto, Dave S.B. Hoon
Journal: Journal of Clinical Oncology (2004)

Purpose Detection of micrometastases in sentinel lymph nodes (SLNs) is important for accurate staging and prognosis in melanoma patients. However, a significant number of patients with histopathology-negative SLNs subsequently develop recurrent disease. We hypothesized that a quantitative realtime reverse transcriptase polymerase chain reaction (qRT) assay using multiple specific mRNA markers could detect occult metastasis in paraffin-embedded (PE) SLNs to upstage and predict disease outcome. Patients and Methods qRT was performed on retrospectively collected PE SLNs from 215 clinically node-negative patients who underwent lymphatic mapping and sentinel lymphadenectomy for melanoma and were followed up for at least 8 years. PE SLNs (n = 308) from these patients were sectioned and assessed by qRT for mRNA of four melanoma-associated genes: MART-1 (antigen recognized by T cells-1), MAGE-A3 (melanoma antigen gene-A3 family), GalNAc-T (β1→4-N-acetylgalactosaminyl-transferase), and Pax3 (paired-box homeotic gene transcription factor 3). Results Fifty-three (25%) patients had histopathology-positive SLNs by hemotoxylin and eosin and/or immunohistochemistry. Of the 162 patients with histopathology-negative SLNs, 48 (30%) had nodes that expressed at least one of the four qRT markers, and these 48 patients also had a significantly increased risk of disease recurrence by a Cox proportional hazards model analysis (P &lt; .0001; risk ratio, 7.48; 95% CI, 3.70 to 15.15). The presence of ≥ one marker in histopathology-negative SLNs was also a significant independent prognostic factor by multivariate analysis for overall survival (P = .0002; risk ratio, 11.42; 95% CI, 3.17 to 41.1). Conclusion Molecular upstaging of PE histopathology-negative SLNs by multiple-marker qRT assay is a significant independent prognostic factor for long-term disease recurrence and overall survival of patients with early-stage melanoma.
Induced tolerance and chimaerism in human fetuses using coelocentesis: a medical opportunity to avert genetic disease?
Authors: R. Edwards
Journal: Human Reproduction Update (1995)

Coelocentesis offers a new opportunity for gaining access to the coelomic cavity of human embryos from 28 days post-fertilization (42 days menstrual age). With this technique, cells can be extracted from the cavity for the genetic typing of embryos in early pregnancy. Coelocentesis may also offer a unique opportunity of inducing tolerance to foreign grafts and chimaerism in these human embryos by replacing donor cells into the coelomic cavity. This cavity appears to be closely associated with the fetal haemopoietic system. The optimal age to inject stem cells designed to produce chimaerism may be at 5-6 weeks embryonic age, and these grafted cells may induce tolerance later in gestation. Two successive coelocenteses would be needed, the first to extract fetal cells to type the fetus, and a second within a few days to inject the donor cells into the coelomic cavity. Alternatively, non-invasive methods of diagnosis such as lower uterine pole extramembra-nous sampling of fetal trophoblast, or the extraction of fetal cells from maternal blood, could be combined with coelocentesis. If tolerance and chimaerism can be established, repeated tissue grafts could be carried out during fetal life and after birth, so that disorders caused by single or multiple gene defects in the haemopoietic system and other organs may be corrected.
Phase III study comparing oxaliplatin plus S-1 with cisplatin plus S-1 in chemotherapy-naïve patients with advanced gastric cancer
Authors: Y. Yamada, K. Higuchi, K. Nishikawa, M. Gotoh, N. Fuse, N. Sugimoto, T. Nishina, K. Amagai, K. Chin, Y. Niwa, A. Tsuji, H. Imamura, M. Tsuda, H. Yasui, H. Fujii, K. Yamaguchi, H. Yasui, S. Hironaka, K. Shimada, H. Miwa, C. Hamada, I. Hyodo
Journal: Annals of Oncology (2014)
THE FUNGI FOUND IN NORTH AMERICAN BLASTOMYCOSIS: THEIR PLURALITY OF SPECIES
Authors: ALDO CASTELLANI
Journal: British Journal of Dermatology (1930)

Journal Article THE FUNGI FOUND IN NORTH AMERICAN BLASTOMYCOSIS: THEIR PLURALITY OF SPECIES Get access ALDO CASTELLANI, Hon, K.C.M.G., D.S.C., M.D., F.R.C.P. Sir ALDO CASTELLANI, Hon, K.C.M.G., D.S.C., M.D., F.R.C.P. Sir Director of Tropical Medicine and Dermatology, Ross Institute; Physician, Ross Hospital, London; Lecturer on Mycology and Mycotic Diseases, London School of Hygiene and Tropical Medicine; formerly Professor of Tropical Medicine, Tulane University of New Orleans, U.S.A Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology and Syphilis, Volume 42, Issue 8-9, 1 August 1930, Pages 365–374, https://doi.org/10.1111/j.1365-2133.1930.tb09429.x Published: 01 August 1930
Histamine release upon adenosine 5'-monophosphate (AMP) nasal provocation in allergic subjects
Authors: R Polosa, C Pagano, G Prosperini, J L Low, D Dokic, M K Church, N Crimi
Journal: Thorax (1999)

<h3>BACKGROUND</h3> Nasal provocation with adenosine 5′-monophosphate (AMP) elicits nasal symptoms in subjects with rhinitis. Histamine released from mast cells may play a part in AMP induced nasal responses. <h3>METHODS</h3> Symptoms of rhinitis were recorded and histamine release in the fluid obtained by nasal lavage after AMP, guanosine 5′-monophosphate (GMP), and placebo instillations was measured in nine subjects with allergic rhinitis and nine non-allergic controls in a double blind, randomised, placebo controlled study. <h3>RESULTS</h3> No symptoms or significant increases in histamine were observed after GMP and placebo challenge. Significantly higher levels of histamine were seen in the nasal lavage fluids of allergic subjects following AMP challenge than in non-allergic controls, the median (range) histamine concentration increasing from the baseline value of 1.62 (0.44–6.99) ng/ml to 6.45 (0.81–16.17) ng/ml at three minutes. No increase in histamine levels was seen in the non-allergic subjects in whom the median histamine concentration was 1.13 (0.29–4.25) ng/ml at baseline and 0.97 (0.31–5.89) ng/ml three minutes after AMP challenge. <h3>CONCLUSIONS</h3> AMP elicits an immediate rise in histamine levels in the nasal lavage fluid of allergic subjects compared with non-allergic individuals. These findings indicate that the exaggerated nasal response to adenosine may reflect mast cell priming in vivo, thus supporting its application as a potential new marker of allergic inflammation.
Effects of Axonal Ion Channel Dysfunction on Quality of Life in Type 2 Diabetes
Authors: Natalie C.G. Kwai, Ria Arnold, Chathupa Wickremaarachchi, Cindy S.-Y. Lin, Ann M. Poynten, Matthew C. Kiernan, Arun V. Krishnan
Journal: Diabetes Care (2013)

OBJECTIVE Pharmacological agents for diabetic peripheral neuropathy (DN) target a number of mechanisms, including sodium channel function and γ-aminobutyric acid–minergic processes. At present, prescription is undertaken on a trial-and-error basis, leading to prolonged medication trials and greater healthcare costs. Nerve-excitability techniques are a novel method of assessing axonal ion channel function in the clinical setting. The aim of this study was to determine the effects of axonal ion channel dysfunction on neuropathy-specific quality-of-life (QoL) measures in DN. RESEARCH DESIGN AND METHODS Fifty-four patients with type 2 diabetes mellitus underwent comprehensive neurologic assessment, nerve-conduction studies, and nerve-excitability assessment. Neuropathy severity was assessed using the Total Neuropathy Score. Neuropathy-specific QoL was assessed using a DN-specific QoL questionnaire (Neuropathy-Specific Quality of Life Questionnaire [NeuroQoL]). Glycosylated hemoglobin and BMI were recorded in all patients. RESULTS NeuroQoL scores indicated significant QoL impairment (mean 9.08 ± 5.93). Strength-duration time constant (SDTC), an excitability parameter reflecting sodium channel function, was strongly correlated with QoL scores (r = 0.545; P &amp;lt; 0.005). SDTC was prolonged in 48.6% of patients who experienced neuropathic symptoms. A significant correlation was also noted between SDTC and neuropathy severity (r = 0.29; P &amp;lt; 0.05). This relationship was strengthened when looking specifically at patients with clinically graded neuropathy (r = 0.366; P &amp;lt; 0.05). CONCLUSIONS The current study has demonstrated an association between markers of sodium channel function and QoL in DN. The study demonstrates that excitability techniques may identify patients in whom altered sodium channel function may be the dominant abnormality. The findings suggest that excitability techniques may have a role in clinical decision making regarding neuropathic treatment prescription.
Adenylyl Cyclase Increases Survival in Cardiomyopathy
Authors: David M. Roth, Hamed Bayat, Jeffrey D. Drumm, Mei Hua Gao, James S. Swaney, Aziz Ander, H. Kirk Hammond
Journal: Circulation (2002)

Background — To test the hypothesis that increased cardiac adenylyl cyclase type VI (AC VI ) content, which results in increased cAMP generation, would increase survival in cardiomyopathy, we crossbred mice with Gq-associated cardiomyopathy and those with cardiac-directed expression of AC VI . We also assessed myocardial hypertrophy after prolonged cardiac expression of Gq versus coexpression of Gq and AC VI . Methods and Results — Three experimental groups, Gq/AC (double positive), Gq, and control (double negative), were studied. Survival was increased by cardiac-directed expression of AC VI ( P &lt;0.0001), and Gq/AC mice had survival rates indistinguishable from control mice. Myocardial hypertrophy developed in older Gq mice but was abrogated by cardiac expression of AC VI , as documented by the ratio of ventricular weight to tibial length (Gq, 11.93±0.99 mg/mm, n=11; Gq/AC, 8.00±0.73 mg/mm, n=9; P &lt;0.01) and by left ventricular cardiac myocyte size (Gq, 2800±254 μm 2 , n=4; Gq/AC, 1721±166 μm 2 , n=5; P &lt;0.01). Hearts of Gq mice were dilated, and function was impaired. Concurrent expression of AC reduced end-diastolic diameter (Gq, 4.20±0.15 mm, n=12; Gq/AC, 3.68±0.12 mm, n=7; P &lt;0.05) and increased fractional shortening (Gq, 32±1%, n=12; Gq/AC, 41±2%, n=7; P &lt;0.001). Cardiac myocytes from Gq/AC mice showed increased forskolin-stimulated cAMP production (Gq, 3.8±1.3 fmol/cell, n=5; Gq/AC, 10.7±2.6 fmol/cell, n=6; P &lt;0.02), documenting increased AC function. Conclusions — Cardiac-directed expression of AC VI restores myocyte AC function, improves heart function, increases cAMP generation, abrogates myocardial hypertrophy, and increases survival in Gq cardiomyopathy.
Novel Delivery of SN38 Markedly Inhibits Tumor Growth in Xenografts, Including a Camptothecin-11–Refractory Model
Authors: Puja Sapra, Hong Zhao, Mary Mehlig, Jennifer Malaby, Patricia Kraft, Clifford Longley, Lee M. Greenberger, Ivan D. Horak
Journal: Clinical Cancer Research (2008)

Clinical development of SN38, the active metabolite of camptothecin-11 (CPT-11), has been hampered due to its poor solubility. We have developed a novel polymer-drug conjugate, EZN-2208, made by linking SN38 with a multiarm polyethylene glycol via a glycine linker.The in vitro cytotoxicity of EZN-2208 was tested using the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay. The therapeutic efficacy of EZN-2208 was evaluated in various xenografts, including an in vivo-selected CPT-11-refractory model. Tumor and blood concentration of EZN-2208, CPT-11, and SN38 was determined by high-performance liquid chromatography.In vitro, EZN-2208 was 10- to 245-fold more potent than CPT-11 in a panel of human tumor cell lines. In xenograft models of MX-1 breast, MiaPaCa-2 pancreatic, or HT-29 colon carcinoma, treatment with either a single dose or multiple injections of EZN-2208 was more efficacious (and in some cases produced tumor eradication for >16 weeks) compared with CPT-11 at their respective maximum tolerated doses or corresponding dose levels (P < 0.01). Most interestingly, EZN-2208 showed marked antitumor activity in animals that developed resistance to an 8-day course of CPT-11 treatment, as well as outperformed CPT-11 as second-round therapy in mice initially sensitive to CPT-11. EZN-2208 had prolonged circulation in the blood compared with CPT-11, resulting in high tumor exposure. This resulted in higher and longer-lasting tumor exposure of free SN38 in mice given EZN-2208 compared with those given CPT-11.Preclinical data suggest that EZN-2208 may be a promising anticancer agent in a wide variety of clinical settings, including tumors refractory to CPT-11 treatment.