tbuckley/cabot-search huggingface dataset:
In vitro effects of methotrexate on peripheral blood monocytes: modulation by folinic acid and S-adenosylmethionine.
Authors: G Nesher, T.L Moore, R.W Dorner
Journal: Annals of the Rheumatic Diseases (1991)

The mechanism of action of low dose methotrexate in rheumatoid arthritis has not been established. It has been shown to have an anti-inflammatory effect and to inhibit neutrophil chemotaxis, but the effect on monocytes has not been widely studied. Normal donor peripheral blood monocytes were incubated with methotrexate in vitro and their superoxide production, chemotaxis, and phagocytosis subsequently assessed. Additionally, the influence of different culture media, and of folinic acid, and the methyl donor S-adenosylmethionine, and spermidine on the methotrexate mediated effects were evaluated. It was found that methotrexate in low concentrations inhibited in vitro monocyte chemotaxis and superoxide production but only after prolonged incubation. This inhibition was augmented by incubation in medium containing a low methionine concentration and was abolished by folinic acid and S-adenosylmethionine, suggesting that methotrexate may interfere with specific methylation reactions.
PROGNOSTIC STRATIFICATION OF BIOPSY-PROVEN ACTIVE MYOCARDITIS PRESENTING WITH HEART FAILURE: ARE THERE PREDICTORS OF LONG TERM PROGNOSIS?
Authors: Marco Merlo, Gastone Sabbadini, Bruno Pinamonti, Gherardo Finocchiaro, Alessandra Buiatti, Giulia Barbati, Andrea Di Lenarda, Gianfranco Sinagra
Journal: Journal of the American College of Cardiology (2010)
Ventilatory function in the Eisenmenger syndrome.
Authors: C G MacArthur, D Hunter, G J Gibson
Journal: Thorax (1979)

Ventilatory function and carbon monoxide transfer factor were studied in nine adult patients with post-tricuspid intracardiac defects and the Eisenmenger syndrome. A consistent mild defect of ventilatory function was found, with raised residual volume and closing capacity and reduction of other lung volumes and maximal expiratory flows. Maximal expiratory flow was particularly reduced at low lung volumes. One of the four subjects in whom pressure-volume studies were performed showed loss of normal elastic recoil at low lung volumes. A significant poorly ventilated space was excluded since the volume of distribution of helium during a 10 second breath-hold at full inspiration was close to plethysmographically measured total lung capacity. Carbon monoxide transfer factor, after correction for haemoglobin concentration, was 77% of predicted normal values. Sequential assessment of carbon monoxide transfer factor might be useful in the early diagnosis of pulmonary vascular disease in infants with large intracardiac defects, since it is likely to be raised early due to high pulmonary blood flow and will fall with the development of pulmonary vascular disease.
Compartmentalization of extracellular cGMP determines absorptive or secretory responses in the rat jejunum
Authors: Xiao-Hong Jin, Helmy M. Siragy, Richard L. Guerrant, Robert M. Carey
Journal: Journal of Clinical Investigation (1999)

We examined potential mechanisms by which angiotensin subtype-2 (AT2) receptor stimulation induces net fluid absorption and serosal guanosine cyclic 3',5'-monophosphate (cGMP) formation in the rat jejunum. L-arginine (L-ARG) given intravenously or interstitially enhanced net fluid absorption and cGMP formation, which were completely blocked by the nitric oxide (NO) synthase inhibitor, N-nitro-L-arginine methylester (L-NAME), but not by the specific AT2 receptor antagonist, PD-123319 (PD). Dietary sodium restriction also increased jejunal interstitial fluid cGMP and fluid absorption. Both could be blocked by PD or L-NAME, suggesting that the effects of sodium restriction occur via ANG II at the AT2 receptor. L-ARG-stimulated fluid absorption was blocked by the soluble guanylyl cyclase inhibitor 1-H-[1,2,4]oxadiazolo[4, 2-alpha]quinoxalin-1-one (ODQ). Cyclic GMP-specific phosphodiesterase in the interstitial space decreased extracellular cGMP content and prevented the absorptive effects of L-ARG. Angiotensin II (ANG II) caused an increase in net Na+ and Cl- ion absorption and 22Na+ unidirectional efflux (absorption) from the jejunal loop. In contrast, intraluminal heat-stable enterotoxin of Escherichia coli (STa) increased loop cGMP and fluid secretion that were not blocked by either L-NAME or ODQ. These findings suggest that ANG II acts at the serosal side via AT2 receptors to stimulate cGMP production via soluble guanylyl cyclase activation and absorption through the generation of NO, but that mucosal STa activation of particulate guanylyl cyclase causes secretion independently of NO, thus demonstrating the opposite effects of cGMP in the mucosal and serosal compartments of the jejunum.
Production of Arrhythmias by Elevated Carboxyhemoglobin in Patients with Coronary Artery Disease
Authors: David S. Sheps
Journal: Annals of Internal Medicine (1990)

Objective: To assess the effects of exposure to 4% and 6% carboxyhemoglobin on ventricular arrhythmias in patients with coronary artery disease. Design: Randomized, double-blind, crossover design. Setting: Exercise laboratory with an environmentally controlled exposure. Patients: Forty-one nonsmokers with documented coronary artery disease. Intervention: On day 1, a training session with no exposure, the baseline carboxyhemoglobin level was measured, and a supine bicycle exercise test was done. On days 2 to 4, patients were exposed to room air, 100 ppm carbon monoxide (target, 4% carboxyhemoglobin) or 200 ppm carbon monoxide (target, 6% carboxyhemoglobin), and they then did supine bicycle exercise with radionuclide ventriculography. Ambulatory electrocardiogram recordings were made during the 4 consecutive days to determine the frequency of ventricular premature depolarization (VPD) at various intervals. Measurements and Main Results: The frequency of single VPD/h was significantly greater on the 6% carboxyhemoglobin day than on the room air day during the exercise period (167.72 ± 37.99 for 6% carboxyhemoglobin compared with 127.32 ± 28.22 for room air, P = 0.03). During exercise, the frequency of multiple VPD/h was greater on the 6% carboxyhemoglobin day compared with room air (9.59 ± 3.70 on the 6% carboxyhemoglobin compared with 3.18 ± 1.67 on room air, P = 0.02). Patients who developed increased single VPD during exercise on the 6% carboxyhemoglobin day were significantly older than those who had no increased arrhythmia, whereas patients who developed complex arrhythmias were also older and, in addition, exercised longer and had a higher peak workload during exercise. Conclusion: The number and complexity of ventricular arrhythmias increases significantly during exercise after carbon monoxide exposure producing 6% carboxyhemoglobin compared with room air but not after exposure producing 4% carboxyhemoglobin.
Life history as an integrative theoretical framework advancing the understanding of the attachment system
Authors: Daniel J. Kruger
Journal: Behavioral and Brain Sciences (2009)

Abstract Evolutionary Life History Theory (LHT) is a powerful framework that can be used for understanding behavioral strategies as contingent adaptations to environmental conditions. Del Giudice uses LHT as a foundation for describing the attachment process as an evolved psychological system which evaluates life conditions and chooses reproductive strategies appropriate in the developmental environment, integrating findings across several literatures.
Fulminating arterial hypertension with pulmonary edema from release of adrenomedullary catecholamines after lesions of the anterior hypothalamus in the rat.
Authors: M A Nathan, D J Reis
Journal: Circulation Research (1975)

Bilateral electrolytic lesions of the anterior hypothalamus in unrestrained rats resulted in the development, within 2 hours, of arterial hypertension, tachycardia, hyperthermia, and increased locomotor activity, often leading to pulmonary edema and death. Similar lesions in paralyzed, artificially ventilated rats produced comparable changes in arterial blood pressure and body temperature with a similar time course. The arterial hypertension was a consequence of an increase in total peripheral resistance to 15% of control with a reduction in cardiac output to 49% of control. Arterial hypertension, elevated peripheral resistance, and diminished cardiac output were reversed toward normal by alpha-receptor blockade with phentolamine (1 mg/kg, iv). Bilateral adrenalectomy, adrenal demedullation, or adrenal denervation performed prior to lesion placement prevented the development of arterial hypertension and pulmonary edema as well as the changes in peripheral resistance, cardiac output, and body temperature. We conclude that arterial hypertension following lesions of the anterior hypothalamus is due to a neurally mediated increase in peripheral resistance initiated by the release of adrenal medullary catecholamines and that pulmonary edema is due to myocardial failure secondary to the ensuing ventricular overload. Structures originating in or passing through the anterior hypothalamus may exert selective control over the adrenal medulla independent of vasomotor neurons.
Evaluation of synovial angiogenesis in patients with rheumatoid arthritis using<sup>68</sup>Ga-PRGD2 PET/CT: a prospective proof-of-concept cohort study
Authors: Zhaohui Zhu, Yufeng Yin, Kun Zheng, Fang Li, Xiaoyuan Chen, Fengchun Zhang, Xuan Zhang
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> The study aimed to evaluate the use of positron emission tomography/computed tomography (PET/CT) with <sup>68</sup>Ga-PRGD2 as the tracer for imaging of synovial angiogenesis in patients with rheumatoid arthritis (RA). <h3>Methods</h3> Twenty untreated active patients with RA underwent <sup>68</sup>Ga-PRGD2 PET/CT and <sup>18</sup>F-FDG PET/CT before treatment; two patients with osteoarthritis served as controls. Among the 20 patients with RA, 12 repeated the evaluations after 3-month treatment. The image findings were correlated with core variables of disease activity, including the clinical disease activity index (cDAI). <h3>Results</h3> Our findings demonstrated that <sup>68</sup>Ga-PRGD2 specifically accumulated in the synovia with active inflammation rich in neovasculature with high-level α<sub>v</sub>β<sub>3</sub>-integrin expression, but not in the <sup>18</sup>F-FDG-avid inflammatory lymph nodes. In patients with intense <sup>18</sup>F-FDG uptake in muscles caused by arthritic pain, we observed that <sup>68</sup>Ga-PRGD2 PET/CT was better able to evaluate disease severity than <sup>18</sup>F-FDG PET/CT. Both <sup>68</sup>Ga-PRGD2 accumulation and <sup>18</sup>F-FDG uptake changed in response to therapeutic intervention, whereas the changes of <sup>68</sup>Ga-PRGD2, not <sup>18</sup>F-FDG, significantly correlated with clinical measures of changes in the form of cDAI. <h3>Conclusions</h3> This is the first integrin imaging study conducted in patients with RA that preliminarily indicates the effectiveness of the novel method for evaluating synovial angiogenesis. <h3>Clinical trial registration</h3> This study has been registered online at NIH ClinicalTrial.gov (NCT01940926).
Dehydroepiandrosterone Reverses Systemic Vascular Remodeling Through the Inhibition of the Akt/GSK3-β/NFAT Axis
Authors: Sébastien Bonnet, Roxane Paulin, Gopinath Sutendra, Peter Dromparis, Melanie Roy, Kristalee O. Watson, Jayan Nagendran, Alois Haromy, Jason R.B. Dyck, Evangelos D. Michelakis
Journal: Circulation (2009)

Background— The remodeled vessel wall in many vascular diseases such as restenosis after injury is characterized by proliferative and apoptosis-resistant vascular smooth muscle cells. There is evidence that proproliferative and antiapoptotic states are characterized by a metabolic (glycolytic phenotype and hyperpolarized mitochondria) and electric (downregulation and inhibition of plasmalemmal K + channels) remodeling that involves activation of the Akt pathway. Dehydroepiandrosterone (DHEA) is a naturally occurring and clinically used steroid known to inhibit the Akt axis in cancer. We hypothesized that DHEA will prevent and reverse the remodeling that follows vascular injury. Methods and Results— We used cultured human carotid vascular smooth muscle cell and saphenous vein grafts in tissue culture, stimulated by platelet-derived growth factor to induce proliferation in vitro and the rat carotid injury model in vivo. DHEA decreased proliferation and increased vascular smooth muscle cell apoptosis in vitro and in vivo, reducing vascular remodeling while sparing healthy tissues after oral intake. Using pharmacological (agonists and antagonists of Akt and its downstream target glycogen-synthase-kinase-3β [GSK-3β]) and molecular (forced expression of constitutively active Akt1) approaches, we showed that the effects of DHEA were mediated by inhibition of Akt and subsequent activation of GSK-3β, leading to mitochondrial depolarization, increased reactive oxygen species, activation of redox-sensitive plasmalemmal voltage-gated K + channels, and decreased [Ca 2+ ] i . These functional changes were accompanied by sustained molecular effects toward the same direction; by decreasing [Ca 2+ ] i and inhibiting GSK-3β, DHEA inhibited the nuclear factor of activated T cells transcription factor, thus increasing expression of Kv channels (Kv1.5) and contributing to sustained mitochondrial depolarization. These results were independent of any steroid-related effects because they were not altered by androgen and estrogen inhibitors but involved a membrane G protein–coupled receptor. Conclusions— We suggest that the orally available DHEA might be an attractive candidate for the treatment of systemic vascular remodeling, including restenosis, and we propose a novel mechanism of action for this important hormone and drug.
Investigation into <i>FOXE1</i> genetic variations in cutaneous squamous cell carcinoma
Authors: I. Venza, M. Visalli, B. Tripodo, M. Lentini, D. Teti, M. Venza
Journal: British Journal of Dermatology (2009)

Background FOXE1 is a candidate tumour suppressor gene at human chromosome locus 9q22. This is a region frequently lost in squamous cell cancer. Objectives To assess the influence of FOXE1 variations on genetic susceptibility to cutaneous squamous cell carcinoma (SCC). Methods We performed mutational analysis of FOXE1 in 320 DNA samples isolated from 60 SCC specimens, 60 adjacent histologically normal skin samples and 200 blood samples. Results No somatic mutations were evident. Instead the polyalanine tract showed marked variation in its length between samples from patients with SCC and normal controls. Conclusions These results imply that another tumour suppressor gene at this locus may be more important than FOXE1 in skin carcinogenesis and suggest that variation in the FOXE1 polyalanine tract length predisposes to cutaneous SCC.
The Changing Pattern of Hypertension and the Declining Incidence of Stroke
Authors: W. Michael Garraway
Journal: JAMA (1987)

We studied whether changes in recognition and control of hypertension could be detected in the population of Rochester, Minn, from 1950 to 1979, a period in which a major decrease in the incidence rate of stroke was observed. Prevalence of diastolic blood pressure greater than or equal to 105 mm Hg fell 26% and 70% in men and women, respectively, between 1950 to 1959 and 1970 to 1979. Prevalence of pressures greater than or equal to 95 mm Hg decreased 5% in men and 58% in women. Increasing control of hypertension had an almost inverse linear relationship with the decreasing incidence of stroke in women, but the incidence of stroke in men did not decrease until ten years after improvement in the control of blood pressure began. We conclude that improvements in the detection and control of hypertension contributed to the declining incidence of stroke and that differences in management of hypertension could account for the difference between men and women in the trend of stroke decline. (<i>JAMA</i>1987;258:214-217)
BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum
Authors: T Kambara
Journal: Gut (2004)

<b>Background and aims:</b> Mutations in <i>BRAF</i> have been linked with colorectal cancers (CRC) showing high level microsatellite instability (MSI-H). However, the distribution of <i>BRAF</i> mutations in MSI-H cancers remains to be clarified with respect to precursor lesions and the CpG island methylator phenotype (CIMP). <b>Methods:</b> Forty three hyperplastic polyps (HP), nine mixed polyps (MP), five serrated adenomas (SA), 28 conventional adenomas (AD), 18 hereditary non-polyposis colorectal cancers (HNPCC), and 127 sporadic CRC (46 MSI-H and 81 non-MSI-H) were collected from patients undergoing colectomy for either CRC or hyperplastic polyposis. Twenty five of 57 serrated lesions were derived from four patients with hyperplastic polyposis. HP were further subdivided according to recently documented morphological criteria into 27 classical HP and 16 variant lesions described as "sessile serrated adenoma" (SSA). All tumours were screened for <i>BRAF</i> activating mutations. <b>Results:</b> The <i>BRAF</i> mutation was more frequent in SSA (75%) and MP (89%) than in classical HP (19%), SA (20%), and AD (0%) (p&lt;0.0001), and also in sporadic MSI-H cancers (76%) compared with HNPCC (0%) and sporadic non-MSI-H cancers (9%) (p&lt;0.0001). The <i>BRAF</i> mutation was identified more often in CIMP-high serrated polyps (72%) and CIMP-high CRC (77%) than in CIMP-low (30%) and CIMP-negative (13%) polyps (p = 0.002) as well as CIMP-low (18%) and CIMP-negative (0%) CRC (p&lt;0.0001). <b>Conclusions:</b> The <i>BRAF</i> mutation was frequently seen in SSA and in sporadic MSI-H CRC, both of which were associated with DNA methylation. Sporadic MSI-H cancers may originate in SSA and not adenomas, and <i>BRAF</i> mutation and DNA methylation are early events in this "serrated" pathway.
Effectiveness of infliximab in refractory FDG PET-positive sarcoidosis
Authors: Adriane D.M. Vorselaars, Heleen A. Crommelin, Vera H.M. Deneer, Bob Meek, Anke M.E. Claessen, Ruth G.M. Keijsers, Coline H.M. van Moorsel, Jan C. Grutters
Journal: European Respiratory Journal (2015)

Inconclusive evidence for the efficacy of infliximab in sarcoidosis hinders the global use of this potentially beneficial drug. To study infliximab efficacy in a clinical setting, we performed a prospective open-label trial in patients refractory to conventional treatment. Patients (n=56) received eight infusions of 5 mg·kg -1 infliximab. Pulmonary function, disease activity measured by 18 F-fluorodeoxyglucose (FDG) by positron emission tomography (PET) and quality of life were part of the clinical work-up. Infliximab levels were measured before every infusion. After 26 weeks of infliximab treatment, mean improvement in forced vital capacity (FVC) was 6.6% predicted (p=0.0007), whereas in the 6 months before start of treatment, lung function decreased. Maximum standardised uptake value (SUV max ) of pulmonary parenchyma on 18 F-FDG PET decreased by 3.93 (p&lt;0.0001). High SUV max of pulmonary parenchyma at baseline predicted FVC improvement (R=0.62, p=0.0004). An overall beneficial response was seen in 79% of patients and a partial response was seen in 17% of patients. No correlation between infliximab trough level (mean 18.0 µg·mL -1 ) and initial response was found. In conclusion, infliximab causes significant improvement in FVC in refractory 18 F-FDG PET positive sarcoidosis. Especially in pulmonary disease, high 18 F-FDG PET SUV max values at treatment initiation predict clinically relevant lung function improvement. These results suggest that inclusion of 18 F-FDG PET is useful in therapeutic decision-making in complex sarcoidosis.
COSMC knockdown mediated aberrant O-glycosylation promotes oncogenic properties in pancreatic cancer
Authors: Bianca T. Hofmann, Laura Schlüter, Philip Lange, Baris Mercanoglu, Florian Ewald, Aljonna Fölster, Aeint-Steffen Picksak, Sönke Harder, Alexander T. El Gammal, Katharina Grupp, Cenap Güngör, Astrid Drenckhan, Hartmut Schlüter, Christoph Wagener, Jakob R. Izbicki, Manfred Jücker, Maximilian Bockhorn, Gerrit Wolters-Eisfeld
Journal: Molecular Cancer (2015)

Human pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal malignancies in the world and despite great efforts in research types of treatment remain limited. A frequently detected alteration in PDACs is a truncated O-linked N-acetylgalactosamine (GalNAc) glycosylation with expression of the Tn antigen. Changes in O-glycosylation affect posttranslationally modified O-GalNAc proteins resulting in profound cellular alterations. Tn antigen is a tumor associated glycan detected in 75-90 % of PDACs and up to 67 % in its precursor lesions. Since the role of Tn antigen expression in PDAC is insufficiently understood we analyzed the impact of COSMC mediated Tn antigen expression in two human PDAC cell lines on cellular oncogenic properties.Forced expression of Tn antigen on O-glycosylated proteins in pancreatic cancer cells was induced by lentiviral-mediated knockdown of the COSMC chaperone, which prevented O-glycan elongation beyond the initial GalNAcα1- residue on O-linked glycoproteins. Altered O-GalNAc glycosylation was analyzed in human pancreatic cancer cell lines Panc-1 and L3.6pl using Western and Far-Western blot as well as immunocytochemical techniques. To assess the biological implications of COSMC function on oncogenic properties, cell viability assays, scratch assays combined with live cell imaging, migration and apoptosis assays were performed. Lectin based glycoprotein enrichment with subsequent mass spectrometric analysis identified new cancer O-GalNAc modified proteins. Expression of Tn antigen bearing Nucleolin in patient derived PDAC tumor specimens was evaluated and correlated with clinicopathological data.Tn antigen expression was induced on various O-GalNAc glycoproteins in COSMC deficient cell lines compared to the control. Proliferation was reduced (p < 0.001) in COSMC knockdown cells, whereas migration was increased (p < 0.001) and apoptosis was decreased (p = 0.03), highlighting the importance of Tn antigen expression on metastatic and anti-apoptotic behavior of PDAC derived cells. Nucleolin was identified as O-GalNAc modified protein in COSMC deficient PDAC cell lines. Interestingly, immunohistochemical staining and co-localization studies of patient derived PDACs revealed poor survival for patients with strong co-localization of Tn antigen and Nucleolin (p = 0.037).This study substantiates the influence of altered O-glycan (Tn/STn) expression on oncogenic properties in pancreatic cancer and identifies O-GalNAc modified Nucleolin as novel prognostic marker.