tbuckley/cabot-search huggingface dataset:
Reversal of infectious mononucleosis-associated suppressor T cell activity by D-mannose.
Authors: G Tosato, S E Pike, R M Blaese
Journal: The Journal of Experimental Medicine (1983)

Epstein-Barr virus-induced infectious mononucleosis (IM) is associated with the activation of suppressor T lymphocytes that profoundly inhibit immunoglobulin (Ig) production in vitro. We have examined the nature of signals operating in the interaction between IM suppressor T cells and their targets, and explored the possibility that a lectin-like receptor molecule and its specific sugar might provide specificity to this interaction. When D-mannose or some of its derivatives, including alpha-methyl-D-mannoside, mannose-6-phosphate, and mannan, were added to suppressed cultures containing IM T lymphocytes and pokeweed mitogen (PWM)-stimulated normal mononuclear cells, a significant enhancement of Ig production was observed. These sugars had little or no effect on Ig production by the PWM-stimulated responder cells alone and thus the enhanced Ig production could be attributed to the reversal of suppression in the co-cultures by these sugars. This was further confirmed by the observation that the sugars were effective only if present during the first 24 h of culture, a time when IM suppressor T cells exert their principal effect. The effect of sugars on Ig production by suppressed cultures was similar to that achieved by decreasing by about fourfold the number of IM T cells in culture. The effect of the sugars is unlikely to represent a form of nonspecific toxicity, since inhibited cultures become responders in the presence of the sugar. Furthermore, toxicity restricted to the suppressor T cells is unlikely, since preincubation of the T cells with the sugars did not reduce their subsequent ability to suppress in secondary indicator cultures. In addition, there was no correlation between the effect of the sugars on T cell proliferation and their effect on T cell-mediated suppression. The reversal of suppression by sugars was dose dependent and demonstrated stereo-specificity in that L-mannose was without effect while D-mannose reversed suppression. These data indicate that D-mannose and some of its derivatives consistently reverse suppression of Ig production by IM T cells and strongly suggest a role for saccharides as critical components in the cellular receptors involved in certain physiologic immune cell interactions.
A Major Outbreak of Severe Acute Respiratory Syndrome in Hong Kong
Authors: Nelson Lee, David Hui, Alan Wu, Paul Chan, Peter Cameron, Gavin M. Joynt, Anil Ahuja, Man Yee Yung, C.B. Leung, K.F. To, S.F. Lui, C.C. Szeto, Sydney Chung, Joseph J.Y. Sung
Journal: New England Journal of Medicine (2003)

There has been an outbreak of the severe acute respiratory syndrome (SARS) worldwide. We report the clinical, laboratory, and radiologic features of 138 cases of suspected SARS during a hospital outbreak in Hong Kong.From March 11 to 25, 2003, all patients with suspected SARS after exposure to an index patient or ward were admitted to the isolation wards of the Prince of Wales Hospital. Their demographic, clinical, laboratory, and radiologic characteristics were analyzed. Clinical end points included the need for intensive care and death. Univariate and multivariate analyses were performed.There were 66 male patients and 72 female patients in this cohort, 69 of whom were health care workers. The most common symptoms included fever (in 100 percent of the patients); chills, rigors, or both (73.2 percent); and myalgia (60.9 percent). Cough and headache were also reported in more than 50 percent of the patients. Other common findings were lymphopenia (in 69.6 percent), thrombocytopenia (44.8 percent), and elevated lactate dehydrogenase and creatine kinase levels (71.0 percent and 32.1 percent, respectively). Peripheral air-space consolidation was commonly observed on thoracic computed tomographic scanning. A total of 32 patients (23.2 percent) were admitted to the intensive care unit; 5 patients died, all of whom had coexisting conditions. In a multivariate analysis, the independent predictors of an adverse outcome were advanced age (odds ratio per decade of life, 1.80; 95 percent confidence interval, 1.16 to 2.81; P=0.009), a high peak lactate dehydrogenase level (odds ratio per 100 U per liter, 2.09; 95 percent confidence interval, 1.28 to 3.42; P=0.003), and an absolute neutrophil count that exceeded the upper limit of the normal range on presentation (odds ratio, 1.60; 95 percent confidence interval, 1.03 to 2.50; P=0.04).SARS is a serious respiratory illness that led to significant morbidity and mortality in our cohort.
Effectiveness and retention rates of methotrexate in psoriatic arthritis in comparison with methotrexate-treated patients with rheumatoid arthritis
Authors: E. Lie, D. van der Heijde, T. Uhlig, M. S. Heiberg, W. Koldingsnes, E. Rodevand, C. Kaufmann, K. Mikkelsen, T. K. Kvien
Journal: Annals of the Rheumatic Diseases (2009)

To examine the effectiveness and 2-year retention rates of methotrexate (MTX) in MTX naïve patients with psoriatic arthritis (PsA).Data on 430 patients with PsA participating in an ongoing longitudinal observational multicentre study in Norway were analysed. 1218 MTX naïve patients with rheumatoid arthritis (RA) from the same study served as a reference population. Assessments included measures of disease activity (28 joint counts, acute phase reactants), health status and utility scores. Six-month effectiveness data were compared both by crude analyses and with adjustments for age, sex and the respective baseline values. Two-year drug survival was compared by Kaplan-Meier and Cox regression analyses.After 6 months of MTX treatment, both patients with PsA and those with RA improved in most disease activity measures and patient reported outcomes. In the adjusted analysis, patients with PsA tended to have less improvement, but changes were in the same range as in patients with RA. Two-year retention rates of MTX therapy in patients with PsA and RA were 65% and 66%, respectively, with only minor differences in reported reasons for discontinuation. Lower age, longer disease duration and higher Modified Health Assessment Questionnaire (MHAQ) score and patient global assessment were independent predictors of MTX termination within the first 2 years of treatment.In this real-life study, MTX treatment was associated with improvement in disease activity and health-related quality of life in patients with PsA after 6 months of treatment. Retention rates of MTX were similar in PsA and RA.
PWE-224 Challenges in recruiting to clinical trials in the UK: the toppic experience
Authors: G-R Jones, I Arnott, J Satsangi
Journal: Gut (2012)

<h3>Introduction</h3> The Trial of Prevention of Post-operative Crohn9s disease (TOPPIC) is a multi-centre, randomised, Medical Research Council (MRC) funded, controlled trial of mercaptopurine (MP) vs placebo in preventing post-operative recurrence. It is the largest and only double-blinded trial conducted to date assessing thiopurine treatment in this setting. To complete the study in five centres we assumed that 60% of eligible patients would be enrolled into the study. Our experience of the challenges to recruitment has relevance to all other clinical trials in the area. <h3>Methods</h3> Patients undergoing intestinal resection for Crohn9s disease (CD) were prospectively recruited and randomised (1:1) within 3 months of surgery to either placebo or 1–1.5 mg/kg/day MP. 234 patients are sought to detect a 20% difference with 80% power between the two groups. The primary outcome means to assess the ability of MP to delay or prevent post-operative recurrence. This is assessed clinically at 12 study visits over 36 months and endoscopically at 12 and 36 months. Recruitment is due to finish in 2012. <h3>Results</h3> The initial enrolment of patients was disappointing with only 60 patients recruited at 22 months (predicted 180 patients). Within the study centres anti-TNF use increased over the same period fivefold (p The study was therefore extended for a further 18 months from 5 Scottish centres, to involve 25 new sites across England and Wales. As of February 2012 223 patients have been randomised representing 20.5% of the 1085 patients undergoing resection at participating centres. Of those not randomised, 530 (49%) were ineligible and 243 (22%) declined pre-screening, 71 (6%) were ineligible/declined during screening. Of the 530 patients ineligible pre-screening 158 (30%) had a stoma, 110 (21%) were not included for reasons not specified, 55 (10%) had a condition the clinician felt placed them at unacceptable risk, 53 (10%) had MP hypersensitivity, 32 (6%) had no known diagnosis of CD, 28 (5%) failed to have ileocolonic resection within 3 months, 19 (4%) had active or untreated malignancy. The remainder 14% consisted of multiple other factors; including previous pancreatitis, and length small bowel resected. Of the 44 randomised patients whom have since dropped out since randomisation; 23 withdrew early from the trial, 13 were lost to follow-up, six other reasons not specified and one mortality from coronary heart disease. <h3>Conclusion</h3> Our experience illustrates a number of challenges in investigator lead studies in IBD. Although we had accurately predicted the number of resections our initial projections had dramatically underestimated the proportion of patients willing or eligible to participate in a placebo controlled study. This study has however, highlighted the merits of multi-centre collaboration, not least due to the acceptance onto the NIHR portfolio. <h3>Competing interests</h3> None declared.
Transgenic Overexpression of Vascular Endothelial Growth Factor-B Isoforms by Endothelial Cells Potentiates Postnatal Vessel Growth In Vivo and In Vitro
Authors: Arne W. Mould, Sonia A. Greco, Marian M. Cahill, Ian D. Tonks, Daniela Bellomo, Carol Patterson, Anna Zournazi, Andrew Nash, Pierre Scotney, Nicholas K. Hayward, Graham F. Kay
Journal: Circulation Research (2005)

Vascular endothelial growth factors (VEGFs) play significant roles in endothelial growth, survival, and function, and their potential use as therapeutic agents to promote the revascularization of ischemic tissues in being avidly explored. VEGF-A has received most attention, as it is a potent stimulator of vascular growth. Results in clinical trials of VEGF-A as a therapeutic agent have fallen short of high expectations because of serious edematous side effects caused by its activity in promoting vascular permeability. VEGF-B, a related factor, binds some of the VEGF-A receptors but not to VEGF receptor 2, which is implicated in the vascular permeability promoting activity of VEGF-A. Despite little in vitro evidence to date for the ability of Vegf-B to directly promote angiogenesis, recent data indicate that it may promote postnatal vascular growth in mice, suggesting that it may have potential therapeutic application. We have specifically studied the effects of VEGF-B on vascular growth in vivo and on angiogenesis in vitro by analyzing transgenic mice in which individual isoforms ( VEGFB 167 Tg and VEGFB 186 Tg) of VEGF-B are overexpressed in endothelial cells. VEGFB 167 Tg and VEGFB 186 Tg mice displayed enhanced vascular growth in the Matrigel assay in vivo and during cutaneous wound healing. In the aortic explant assay, explants from VEGFB 167 Tg and VEGFB 186 Tg mice displayed elevated vascular growth, suggesting a direct effect of VEGF-B isoforms in potentiating angiogenesis. These data support the use of VEGF-B as a therapeutic agent to promote vascular growth, in part, by potentiating angiogenesis. Furthermore, the lack of vascular permeability activity associated with either transgenic overexpression of the VEGF-B gene in endothelial cells or application of VEGF-B protein to the skin of mice in the Miles assay indicates that use of VEGF-B as a therapy should not be associated with edematous side effects.
Contribution of endothelin and its receptors to the regulation of vascular tone during exercise is different in the systemic, coronary and pulmonary circulation
Authors: D Merkus
Journal: Cardiovascular Research (2003)

Objectives: Exercise-induced vasodilation is thought to be mediated through various vasodilator substances, but blunting the influence of vasoconstrictors such as ET may also play a role. However, the role of ET and its receptors in the regulation of systemic, pulmonary and coronary vascular resistance is incompletely understood. The aim of this study was to identify the contribution of ET-1 through the ETA and ETB receptors to the regulation of tone in the systemic, coronary and pulmonary beds at rest and during exercise. Methods: Ten chronically instrumented swine were studied while running on a treadmill before and after ETA blockade (EMD122946) or ETAB blockade (tezosentan). Results: At rest, EMD122946 resulted in vasodilation in the coronary and systemic circulation, evidenced by a decrease in coronary and systemic vascular resistance and an increase in coronary and mixed venous O2-saturation. These effects waned during exercise. The effect of tezosentan on the systemic vasculature was similar to that of EMD122946, whereas it was smaller in the coronary circulation. EMD122946 had no effect on the pulmonary vasculature, whereas tezosentan decreased pulmonary resistance but only during exercise. Conclusions: ET exerts a constrictor influence on the coronary and systemic circulation through the ETA-receptor, which decreases during exercise thereby contributing to metabolic vasodilation. ET exerts a tonic vasodilator influence on coronary resistance vessels through the ETB-receptor. Finally, ET exerts an ETB-mediated constrictor influence in the pulmonary vasculature during exercise.
Sympathetic Blocking Agents
Authors: Fredrick F. Yonkman
Journal: Annual Review of Medicine (1956)

Until approximately a decade ago a sympathetic blocking agent was little more than a scientific curiosity but today the picture has been con­ siderably altered; certain sympathetic blocking chemicals have come into their own as valuable therapeutic agents. They have become available to us through the fine cooperation of our research scientists, a group which includes the chemist, the biologist, and the clinical investigator. In the development of these important drugs as available to physicians today is the pharmacologist who early recognized, with the inquisitive clinician, the important role that sympathetic predominance plays in the symptomatology of certain disorders which reflect imbalance of the autonomic nervous system. Some of these include neurogenic hypertension, certain peripheral vascular diseases, especially Raynaud's and probably Buerger's disease, herpes zoster, hyperthyroidism, tachycardia, glaucoma, exophthalmia, migraine headaches (spastic type), neurodermatoses, renal hypertension (in part neurogenic in origin?), vasospastic dysmenorrhea, causalgia, and probably some types of epilepsy. There is little doubt today that the autonomic nervous system plays a very important role, either directly or indirectly in many diseases, in terms of overactivity or underactivity of either portion of the autonomic nervous system, that is, of the parasympathetic or the sympathetic divisions. Our attention at the moment is directed toward suppressing, within desirable physiologic limits, the overactivity of the sympathetic portion of this system in certain undesirable conditions. This goal can be achieved by cer­ tain recently developed chemical compounds which have already established their value as therapeutic agents. Inspection of Fig. 1, a diagram by Hafkenschie1 & Sellers (1), which is an excellent modification of that previously employed (2), reveals various focal points of attack in the establishing of sympathetic or adrenergic blockade. The synonymous or interchanging use of the terms sympathetic and adrener­ gic blockade, a procedure which will be followed throughout this presentation should be noted. Adrenergic refers to that portion of the autonomic nervous system, namely the sympathetic portion, which responds to the action of adrenaline or adrenaline-like substances. These include epinephrine and norepinephrine in particular; any agent that blocks these substances which act in the region of the final arborization or distribution of sympathetic nerve fibers, that is, within the receptive substance of the end organs asso­ ciated with sympathetic innervation, is classified as a sympathetic or adrenergic blocking agent. On the other hand, one must bear in mind that
ERYTHEMA GYRATUM PERSTANS (COLCOTT FOX): A CASE REPORT, WITH DISCUSSION ON RELATIONS WITH ERYTHEMA CENTRIFUGUM ANNULARE (DARIER) AND DERMATITIS HERPETIFORMIS
Authors: ROBERT KLABER
Journal: British Journal of Dermatology (1946)

Journal Article ERYTHEMA GYRATUM PERSTANS (COLCOTT FOX): A CASE REPORT, WITH DISCUSSION ON RELATIONS WITH ERYTHEMA CENTRIFUGUM ANNULARE (DARIER) AND DERMATITIS HERPETIFORMIS Get access ROBERT KLABER ROBERT KLABER Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology and Syphilis, Volume 58, Issue 5-6, 1 May 1946, Pages 111–121, https://doi.org/10.1111/j.1365-2133.1946.tb16284.x Published: 01 May 1946
Progestin-Dependent Induction of Vascular Endothelial Growth Factor in Human Breast Cancer Cells
Authors: Jianbo Wu, Jennifer Richer, Kathryn B. Horwitz, Salman M. Hyder
Journal: Cancer Research (2004)

Abstract The progesterone receptor (PR) is a ligand-dependent transcription factor that promotes progestin-stimulated expression of target genes. Two functional PR isoforms, PRA and PRB, are expressed in progestin-responsive cells. PRA and PRB have distinct roles in gene expression and in mammary gland development. One role of PRs in T47-D cells is regulating expression of vascular endothelial growth factor (VEGF), a potent angiogenic growth factor. This study explores the isoform specificity of this PR function using parental T47-Dco cells that express both PRA and PRB and clonal derivatives that express either PRA (YA cells) or PRB (YB cells) or lack PR (Y cells). Treatment with progesterone induces VEGF mRNA and protein ∼2-fold in T47-Dco and YA cells and 3–7-fold in YB cells, suggesting that PRA inhibits PRB-dependent induction of VEGF. This is consistent with the observation that clinically relevant progestins induce a much higher level of VEGF in YB cells than in YA cells. Another novel finding in this report is that estradiol (10−8 m) induces VEGF production from YB cells. However, this induction is not blocked by 100-fold excess tamoxifen or ICI-182,780. Moreover, both tamoxifen (10−6 m) and ICI-182,780 (10−6 m) function as agonists for VEGF in YB cells. Small interfering RNA against PR or estrogen receptor abrogated estradiol and tamoxifen induction, indicating that the agonist-like response of these compounds in YB cells is estrogen receptor and PR dependent. Estradiol, tamoxifen, and ICI-182780 also induce VEGF in BT-474 cells when their PRB levels were elevated by transfecting an expression plasmid for PRB, but not when the cells were transfected with vector alone. These results indicate that (a) PRB preferentially regulates VEGF expression in breast cancer cells and (b) PRB-enriched tumor cells may produce more VEGF, have a better developed vasculature, and potentially are more resistant to tamoxifen and ICI-182,780 than cells that express an equivalent or higher level of PRA than PRB. These results imply that PRB-enriched breast tumors may respond well to anticancer therapies that include inhibitors of angiogenesis.
The Somatogenic Hormones and Insulin-Like Growth Factor-1: Stimulators of Lymphopoiesis and Immune Function
Authors: Ross Clark
Journal: Endocrine Reviews (1997)

I. Introduction II. Local GH Axis in Lymphoid Tissue A. Background: extrapituitary production? B. GH expression C. GH regulation D. GHRs E. GHR signaling III. GH Administration A. Effects on the thymus B. Pattern of GH exposure C. GH and immune function in humans IV. PRL A. PRL expression in lymphoid tissues B. PRL receptors C. Administration of PRL, anti-PRL antibodies, or bromocriptine V. Insulin-like Growth Factors A. Background B. IGF peptides C. Regulation of lymphocyte IGF-I D. IGF receptors on lymphocytes E. IGFBPs VI. Actions of IGF-I A. Bone marrow B. Effects on lymphoid organ size C. Effect of in vivo treatment on lymphocyte number and in vitro function D. Functional effects of IGF-I in vivo: antibody responses E. Immune reconstitution F. Mechanism of action: apoptosis VII. IGF-I in Different Physiological States A. IGF-I in pregnancy B. IGF-I in diabetes C. IGF-I in gastrointestinal disorders D. IGF-I action in polycythemia vera VIII. GH/IGF-I as Antistress Hormones IX. Therapeutic Potential X....
Targeted Radionuclide Therapy Using a Wnt-Targeted Replicating Adenovirus Encoding the Na/I Symporter
Authors: Inge Peerlinck, Andrew Merron, Patrick Baril, Sophie Conchon, Pilar Martin-Duque, Cécilia Hindorf, Jerome Burnet, Miguel Quintanilla, Mohan Hingorani, Richard Iggo, Nick R. Lemoine, Kevin Harrington, Georges Vassaux
Journal: Clinical Cancer Research (2009)

The Na/I symporter (hNIS) promotes concentration of iodine in cells. In cancer gene therapy, this transgene has potential as a reporter gene for molecular imaging of viral biodistribution and as a therapeutic protein promoting (131)I-mediated radiotherapy. Here, we combined the imaging and therapeutic potential of hNIS in an oncolytic adenoviruses targeting colorectal cancer cells.We generated an adenovirus (AdIP2) encoding hNIS and capable of selective replication in colorectal carcinoma cells. The selectivity of this virus was verified in vitro and in vivo. Its spread in tumors was monitored in vivo using single-photon emission computed tomography/CT imaging upon (99m)TcO(4)(-) injection and confirmed by immunohistochemistry. Metabolic radiotherapy was done through injection of therapeutic doses of (131)I(-).We showed in vitro and in vivo the selectivity of AdIP2 and that hNIS expression is restricted to the target cells. Imaging and immunohistochemical data showed that viral spread is limited and that the point of maximal hNIS expression is reached 48 hours after a single intratumoral injection. Administration of a single therapeutic dose of (131)I at this time point led to a dramatic reduction in tumor size not observed in hNIS-negative viruses.This report showed for the first time that the combination of the imaging and therapeutic potentials of hNIS can be applied to oncolytic adenoviruses in experimental models of cancer.
Disruption of cholesterol homeostasis by plant sterols
Authors: Chendong Yang, Liqing Yu, Weiping Li, Fang Xu, Jonathan C. Cohen, Helen H. Hobbs
Journal: Journal of Clinical Investigation (2004)

The ABC transporters ABCG5 and ABCG8 limit absorption and promote excretion of dietary plant sterols. It is not known why plant sterols are so assiduously excluded from the body. Here we show that accumulation of plant sterols in mice lacking ABCG5 and ABCG8 (G5G8–/– mice) profoundly perturbs cholesterol homeostasis in the adrenal gland. The adrenal glands of the G5G8–/– mice were grossly abnormal in appearance (brown, not white) due to a 91% reduction in cholesterol content. Despite the very low cholesterol levels, there was no compensatory increase in cholesterol synthesis or in lipoprotein receptor expression. Moreover, levels of ABCA1, which mediates sterol efflux, were increased 10-fold in the G5G8–/– adrenals. Adrenal cholesterol levels returned to near-normal levels in mice treated with ezetimibe, which blocks phytosterol absorption. To determine which plant sterol(s) caused the metabolic changes, we examined the effects of individual plant sterols on cholesterol metabolism in cultured adrenal cells. Addition of stigmasterol, but not sitosterol, inhibited SREBP-2 processing and reduced cholesterol synthesis. Stigmasterol also activated the liver X receptor in a cell-based reporter assay. These data indicate that selected dietary plant sterols disrupt cholesterol homeostasis by affecting two critical regulatory pathways of lipid metabolism.