tbuckley/cabot-search huggingface dataset:
Amniotic Fluid Insulin at 14–20 Weeks’ Gestation
Authors: Marshall W. Carpenter, Jacob A. Canick, Joseph W. Hogan, Curtis Shellum, Margaret Somers, Jami A. Star
Journal: Diabetes Care (2001)

OBJECTIVE—To examine the hypothesis that early second trimester amniotic fluid (AF) insulin concentration is elevated and later fetal growth is augmented in gravidas demonstrating later oral glucose intolerance. RESEARCH DESIGN AND METHODS—In this prospective observational cohort study, AF was sampled at 14–20 weeks’ gestation in 247 subjects, and 1-h 50-g oral glucose challenge tests (GCTs) were performed at ≥24 weeks. AF insulin was assayed by an automated immuno-chemiluminometric assay (8). Macrosomia was defined as birth weight above the 90th centile. RESULTS—AF insulin concentration (range 1.4–44.5 pmol/l) correlated positively with gestational age and maternal weight. A logistic regression analysis, adjusted for maternal age and midpregnancy weight, showed increased AF insulin multiples of gestational age-specific medians to be associated with subsequently diagnosed gestational diabetes mellitus (GDM) (OR 1.9, CI 1.3–2.4, P = 0.029). Among 60 subjects with GCT values &amp;gt;7.2 mmol/l, each unit increase in AF insulin multiple of median (MOM) was associated with a threefold increase in fetal macrosomia incidence (3.1, 1.3–4.9, P = 0.048). CONCLUSIONS—An elevated AF insulin concentration at 14–20 weeks’ gestation is associated with subsequently documented maternal glucose intolerance. Among gravidas with GCT values &amp;gt;7.2 mmol/l, elevated early AF insulin concentration is associated with fetal macrosomia. Maternal glucose intolerance may affect fetal insulin production before 20 weeks’ gestation.
Loss of 'Complexity' and Aging
Authors: Lewis A. Lipsitz
Journal: JAMA (1992)

The concept of "complexity," derived from the field of nonlinear dynamics, can be adapted to measure the output of physiologic processes that generate highly variable fluctuations resembling "chaos." We review data suggesting that physiologic aging is associated with a generalized loss of such complexity in the dynamics of healthy organ system function and hypothesize that such loss of complexity leads to an impaired ability to adapt to physiologic stress. This hypothesis is supported by observations showing an age-related loss of complex variability in multiple physiologic processes including cardiovascular control, pulsatile hormone release, and electroencephalographic potentials. If further research supports this hypothesis, measures of complexity based on chaos theory and the related geometric concept of fractals may provide new ways to monitor senescence and test the efficacy of specific interventions to modify the age-related decline in adaptive capacity.
The distinguishing cellular and molecular features of the endometriotic ovarian cyst: from pathophysiology to the potential endometrioma-mediated damage to the ovary
Authors: A.M. Sanchez, P. Viganò, E. Somigliana, P. Panina-Bordignon, P. Vercellini, M. Candiani
Journal: Human Reproduction Update (2013)

Clinical data suggest that the presence of an ovarian endometrioma may cause per se damage to the surrounding otherwise healthy ovarian tissue. However, the basic research has so far done a limited job in trying to understand the potential detrimental effect of an endometrioma presence in the context of the ovarian physiology. We have reviewed the literature with the aim of characterizing the pathophysiology of the endometrioma focusing mostly on factors and mechanisms potentially affecting the surrounding, otherwise normal, ovarian tissue. Comprehensive searches of PUBMED were conducted to identify human studies published from 1991 to 2013 in the English language on the cellular and molecular characterization of the various endometrioma components. An endometrioma contains free iron, reactive oxygen species (ROS), proteolytic enzymes and inflammatory molecules in concentrations from tens to hundreds of times higher than those present in peripheral blood or in other types of benign cysts. The cyst fluid causes substantial changes in the endometriotic cells that it baths from gene expression modifications to genetic mutations The physical barrier between the cyst contents and the normal ovarian tissue is a thin wall composed of the ovarian cortex itself or fibroreactive tissue. ROS potentially permeating the surrounding tissues and proteolytic substances degrading the adjacent areas are likely to cause the substitution of normal ovarian cortical tissue with fibrous tissue in which the cortex-specific stroma is reduced. The fibrosis is associated with smooth muscle metaplasia and followed by follicular loss and intraovarian vascular injury. Follicular density in tissue surrounding the endometriotic cyst was consistently shown to be significantly lower than in healthy ovaries but this pathological change does not appear to be caused by the stretching of surrounding tissues owing to the presence of a cyst. There is sufficient molecular, histological and morphological evidence, in part deriving from knowledge of the pathophysiology, to support a deleterious effect of the endometrioma on the adjacent ovarian cortical tissue, independent of the mere mechanical stretching owing to its size.
Concomitant chemoradiation versus neoadjuvant chemotherapy in locally advanced cervical carcinoma: results from two consecutive phase II studies
Authors: A. Duenas-Gonzalez, C. Lopez-Graniel, A. Gonzalez-Enciso, A. Mohar, L. Rivera, A. Mota, R. Guadarrama, G. Chanona, J. de la Garza
Journal: Annals of Oncology (2002)
Cytokines and arachidonic metabolites produced during human immunodeficiency virus (HIV)-infected macrophage-astroglia interactions: implications for the neuropathogenesis of HIV disease.
Authors: P Genis, M Jett, E W Bernton, T Boyle, H A Gelbard, K Dzenko, R W Keane, L Resnick, Y Mizrachi, D J Volsky
Journal: The Journal of Experimental Medicine (1992)

Human immunodeficiency virus (HIV) infection of brain macrophages and astroglial proliferation are central features of HIV-induced central nervous system (CNS) disorders. These observations suggest that glial cellular interactions participate in disease. In an experimental system to examine this process, we found that cocultures of HIV-infected monocytes and astroglia release high levels of cytokines and arachidonate metabolites leading to neuronotoxicity. HIV-1ADA-infected monocytes cocultured with human glia (astrocytoma, neuroglia, and primary human astrocytes) synthesized tumor necrosis factor (TNF-alpha) and interleukin 1 beta (IL-1 beta) as assayed by coupled reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, and biological activity. The cytokine induction was selective, cell specific, and associated with induction of arachidonic acid metabolites. TNF-beta, IL-1 alpha, IL-6, interferon alpha (IFN-alpha), and IFN-gamma were not produced. Leukotriene B4, leukotriene D4, lipoxin A4, and platelet-activating factor were detected in large amounts after high-performance liquid chromatography separation and correlated with cytokine activity. Specific inhibitors of the arachidonic cascade markedly diminished the cytokine response suggesting regulatory relationships between these factors. Cocultures of HIV-infected monocytes and neuroblastoma or endothelial cells, or HIV-infected monocyte fluids, sucrose gradient-concentrated viral particles, and paraformaldehyde-fixed or freeze-thawed HIV-infected monocytes placed onto astroglia failed to induce cytokines and neuronotoxins. This demonstrated that viable monocyte-astroglia interactions were required for the cell reactions. The addition of actinomycin D or cycloheximide to the HIV-infected monocytes before coculture reduced, &amp;gt; 2.5-fold, the levels of TNF-alpha. These results, taken together, suggest that the neuronotoxicity associated with HIV central nervous system disorders is mediated, in part, through cytokines and arachidonic acid metabolites, produced during cell-to-cell interactions between HIV-infected brain macrophages and astrocytes.
Doctors warn of premature move to polyclinics
Authors: Adrian O’Dowd
Journal: BMJ (2008)

Fears are growing among doctors that many primary care trusts (PCTs) are already preparing for polyclinics—large centres with GPs and specialists under one roof—even before the government gives the final go ahead later this year.

Doctors’ leaders believe that, despite promises from the government that local areas will be able to choose how they modernise primary care, implementation of the policy of polyclinics is inevitable.

PCTs are placing a growing number of advertisements in trade publications such as the Health Service Journal and GP magazine for GPs or companies to run such clinics, says the BMA. It is worried that polyclinics are unstoppable and may undermine the basis of general practice.

The BMA expects that polyclinics will feature large in junior health minister Ara Darzi’s final proposals, which are due by June with the publication of his second stage review.

Professor Darzi first mentioned polyclinics in the report Healthcare for London: A Framework for Action , published in July last year ( BMJ 2007;335:61; doi: 10.1136/bmj.39273.467697.DB). The report provided a blueprint for “cradle to grave” health care, with super-surgeries or polyclinics across London that would, by 2017, carry out up to half of outpatient treatment currently handled by hospitals.

Then last October Professor Darzi published an interim report of his review into the future of the NHS in England as a whole. This …
Clinical efficacy, radiographic and safety findings through 5 years of subcutaneous golimumab treatment in patients with active psoriatic arthritis: results from a long-term extension of a randomised, placebo-controlled trial (the GO-REVEAL study)
Authors: Arthur Kavanaugh, Iain B McInnes, Philip Mease, Gerald G Krueger, Dafna Gladman, Désirée van der Heijde, Yiying Zhou, Jiandong Lu, Jocelyn H Leu, Neil Goldstein, Anna Beutler
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Objectives</h3> Assess golimumab9s long-term efficacy/safety in psoriatic arthritis (PsA). <h3>Methods</h3> Adults with active PsA (≥3 swollen and tender joints, active psoriasis) were randomly assigned to subcutaneous placebo, golimumab 50 mg, or golimumab 100 mg every 4 weeks (q4wks) through wk20. All patients received golimumab 50 mg or 100 mg q4wks from wk24 forward. Methotrexate was allowed and taken by approximately half the patients. Findings through 5 years are reported herein. Efficacy assessments included ≥20% improvement in American College of Rheumatology (ACR20) response, C-reactive-protein-based, 28-joint-count Disease Activity Score (DAS28-CRP) response, ≥75% improvement in Psoriasis Area and Severity Index (PASI75) scores, and PsA-modified Sharp/van der Heijde scores (SHSs). <h3>Results</h3> 126/405 (31%) randomised patients discontinued treatment through wk252. Golimumab was effective in maintaining clinical improvement through year-5 (ACR20: 62.8–69.9%, DAS28-CRP: 75.2-84.9% for randomised patients; PASI75: 60.8–72.2% among randomised patients with ≥3% body surface area involvement) and inhibiting radiographic progression (mean changes in PsA-modified SHS: 0.1–0.3) among patients with radiographic data. While concomitant methotrexate did not affect ACR20/PASI75, it appeared to reduce radiographic progression. No new safety signals were identified. Antibodies-to-golimumab occurred in 1.8%/10.0% of patients with/without methotrexate). <h3>Conclusions</h3> Long-term golimumab safety/efficacy in PsA was demonstrated through 5 years. <h3>Trial registration number</h3> NCT00265096.
Interactions of glucocorticoids and beta 2-agonists
Authors: IM Adcock, DA Stevens, PJ Barnes
Journal: European Respiratory Journal (1996)

Beta 2-adrenoreceptor agonists and glucocorticosteroids are the two most effective treatments for asthma and are often used in combination. Glucocorticoids mediate their anti-inflammatory effects through the action of activated glucocorticoid receptors (GRs). Many of the effects of GRs on the synthesis of cytokines and other inflammatory mediators are due to a direct interaction with other deoxyribonucleic acid (DNA)-binding proteins belonging to the basic leucine zipper (bZIP) group of transcription factors, such as activator protein-1 (AP-1) and nuclear factor-kappa B (NF-kappa B). Beta 2-agonists are potent bronchodilators at low doses and at high doses can activate gene transcription via a bZIP protein, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB). Activated GRs and CREB can interact with each other within the nucleus to modulate both DNA-binding and gene transcription in either a positive or inhibitory manner, depending on cell type. In lung cells, high doses of beta 2-agonists reduce the ability of GR to bind DNA, a process which is mediated by CREB activation. Inhibition of GR DNA-binding by CREB raises the possibility that high-dose beta 2-agonists could have functional antiglucocorticoid activity and may be a basis for the reported increase in asthma morbidity and mortality in industrialized countries, which have increasing per capita beta 2-agonist use.
A Mouse Model for Liddle's Syndrome
Authors: SYLVAIN PRADERVAND, QING WANG, MICHEL BURNIER, FRIEDRICH BEERMANN, JEAN DANIEL HORISBERGER, EDITH HUMMLER, BERNARD C. ROSSIER
Journal: Journal of the American Society of Nephrology (1999)

Abstract. Liddle's syndrome (or pseudoaldosteronism) is an autosomal dominant form of salt-sensitive hypertension, due to abnormal sodium transport by the renal tubule. To study the pathophysiology of salt sensitivity, a mouse model for Liddle's syndrome has been generated by Cre/ loxP -mediated recombination. Under normal salt diet, mice heterozygous (L/+) and homozygous (L/L) for Liddle mutation (L) develop normally during the first 3 mo of life. In these mice, BP is not different from wild type despite evidence for increased sodium reabsorption in distal colon and low plasma aldosterone, suggesting chronic hypervolemia. Under high salt intake, the Liddle mice develop high BP, metabolic alkalosis, and hypokalemia accompanied by cardiac and renal hypertrophy. This animal model reproduces to a large extent a human form of salt-sensitive hypertension and establishes a causal relationship between dietary salt, a gene expressed in kidney and hypertension.
Simultaneous measurements of action potential duration and intracellular ATP in isolated ferret hearts exposed to cyanide.
Authors: A C Elliott, G L Smith, D G Allen
Journal: Circulation Research (1989)

Shortening of the cardiac action potential during ischemia and anoxia is likely to contribute to the decline in contractility that occurs under such conditions. It has been hypothesized that a decrease in the intracellular ATP concentration ([ATP]i) underlies the changes in the action potential. The recently discovered potassium channel activated at low ATP concentrations might provide the link between action potential shortening and low [ATP]i. However, it has yet to be shown that [ATP]i falls to the range required for channel activation at the time when action potential shortening occurs. We have measured action potentials and [ATP]i simultaneously in isolated ferret hearts during inhibition of both oxidative phosphorylation and anaerobic glycolysis (metabolic blockade). Metabolic blockade caused a rapid decline in cardiac contractility, accompanied by a rapid fall in action potential duration. [ATP]i fell only slightly and remained well above the range where activation of the ATP-sensitive K+ channel would be expected to occur. Moreover, reintroduction of glucose to the perfusate led to a substantial recovery in both contraction and in action potential duration, again in the absence of any great change in [ATP]i. These results suggest that the action potential shortening observed in metabolic blockade cannot be explained by the simple hypothesis of K+ channel opening as a consequence of a decrease in bulk [ATP]i unless the Km for suppression of channel activity by ATP is very much higher in intact cells than in any of the patch configurations studied. An alternative explanation is that the channel may be regulated under these conditions by mechanisms other than a change in [ATP]i.
British surgeons' experiences of mandatory online workplace-based assessment
Authors: Erlick AC Pereira, Benjamin JF Dean
Journal: Journal of the Royal Society of Medicine (2009)

Summary Objectives An online workplace-based assessment tool, the Intercollegiate Surgical Curriculum Programme (ISCP), has become mandatory for all British surgical trainees appointed since August 2007. A compulsory £125 annual trainee fee has also been introduced to fund its running costs. The study sought to evaluate user satisfaction with the ISCP. Design and setting A total of 539 users across all surgical specialties (including 122 surgeons acting as assessors) were surveyed in late 2008 by online questionnaire regarding their experiences with the ISCP. Results Sixty-seven percent had used the tool for at least one year. It was rated above average by only 6% for its registration process and only 11% for recording meetings and objectives. Forty-nine percent described its online assessments as poor or very poor, only 9% considering them good or very good. Seventy-nine percent rated the website's user friendliness as average or worse, as did 72% its peer-assessment tool and 61% its logbook of procedures. Seventy-six percent of respondents had carried out paper assessments due to difficulties using the website. Six percent stated that the ISCP had impacted negatively on their training opportunities, 41% reporting a negative impact overall upon their training; only 6% reported a positive impact. Ninety-four percent did not consider the trainee fee good value, only 2% believing it should be paid by the trainee. Conclusions The performance of the ISCP leaves large numbers of British surgeons unsatisfied. Its assessments lack appropriate evidence of validity and its introduction has been problematic. With reducing training hours, the increased online bureaucratic burden exacerbates low morale of trainees and trainers, adversely impacting potentially upon both competency and productivity.
Improved survival and amelioration of nephrotoxic nephritis in intercellular adhesion molecule-1 knockout mice.
Authors: U Janssen, T Ostendorf, S Gaertner, F Eitner, H J Hedrich, K J Assmann, J Floege
Journal: Journal of the American Society of Nephrology (1998)

Intercellular adhesion molecule-1 (ICAM-1) expression is upregulated in nephrotoxic nephritis, a model of human rapidly progressive glomerulonephritis. To evaluate the pathogenetic relevance of ICAM-1 in this model, nephrotoxic nephritis was induced in ICAM-1 knockout mice and genetic controls. Mice were preimmunized with rabbit IgG in complete Freund's adjuvant. Seven days later they received rabbit anti-mouse glomerular basement membrane IgG. The early humoral immune responses (levels of circulating mouse anti-rabbit IgG, glomerular deposition of rabbit and mouse IgG and mouse C3c) were not altered in ICAM-1 knockout mice. During 28 d of follow-up, 3 of 19 control nephritic mice and 0 of 16 ICAM-1 knockout mice died. Proteinuria was high in nephritic control mice (means 10 to 12 mg/24 h at all time points investigated) and significantly reduced in nephritic ICAM-1 knockout mice (means <4.4 mg). Mean serum creatinine rose from 29 micromol/L at day -7 to 48 micromol/L (day 28) in nephritic control mice. This increase in serum creatinine was significantly lower in ICAM-1 knockout mice: 27 (day -7) and 36 micromol/L (day 28). Histologic analysis at day 28 revealed that ICAM-1 deficiency in nephrotoxic nephritis mice led to significantly reduced glomerular crescent formation (2+/-3% in ICAM-1 knockout mice versus 13+/-8% in nephritic controls) and tubulointerstitial injury (score 0.4+/-0.4 versus 2.0+/-1.1). By immunohistochemistry, ICAM-1 deficiency in nephritic mice led to significantly reduced (peri-)glomerular and/or interstitial macrophage influx, alpha-smooth muscle actin expression, and type IV collagen accumulation. These data indicate that ICAM-1 is a central mediator of glomerular and tubulointerstitial injury in murine nephrotoxic nephritis.
Transverse myelitis: a reversible complication of bronchial artery embolisation in cystic fibrosis
Authors: K. L. Fraser, H. Grosman, R. H. Hyland, D. E. Tullis
Journal: Thorax (1997)

The case history is presented of a young woman with cystic fibrosis and life threatening haemoptysis. Angiography revealed enlarged bronchial vessels, one of which supplied the contralateral lung. Transverse myelitis developed following bronchial artery embolisation but recovery was rapid and nearly complete. Haemoptysis did not recur during four years of follow up.
Overcoming Trastuzumab Resistance in Breast Cancer by Targeting Dysregulated Glucose Metabolism
Authors: Yuhua Zhao, Hao Liu, Zixing Liu, Yan Ding, Susan P. LeDoux, Glenn L. Wilson, Richard Voellmy, Yifeng Lin, Wensheng Lin, Rita Nahta, Bolin Liu, Oystein Fodstad, Jieqing Chen, Yun Wu, Janet E. Price, Ming Tan
Journal: Cancer Research (2011)

Trastuzumab shows remarkable efficacy in treatment of ErbB2-positive breast cancers when used alone or in combination with other chemotherapeutics. However, acquired resistance develops in most treated patients, necessitating alternate treatment strategies. Increased aerobic glycolysis is a hallmark of cancer and inhibition of glycolysis may offer a promising strategy to preferentially kill cancer cells. In this study, we investigated the antitumor effects of trastuzumab in combination with glycolysis inhibitors in ErbB2-positive breast cancer. We found that trastuzumab inhibits glycolysis via downregulation of heat shock factor 1 (HSF1) and lactate dehydrogenase A (LDH-A) in ErbB2-positive cancer cells, resulting in tumor growth inhibition. Moreover, increased glycolysis via HSF1 and LDH-A contributes to trastuzumab resistance. Importantly, we found that combining trastuzumab with glycolysis inhibition synergistically inhibited trastuzumab-sensitive and -resistant breast cancers in vitro and in vivo, due to more efficient inhibition of glycolysis. Taken together, our findings show how glycolysis inhibition can dramatically enhance the therapeutic efficacy of trastuzumab in ErbB2-positive breast cancers, potentially useful as a strategy to overcome trastuzumab resistance.
Coating nanocarriers with hyaluronic acid facilitates intravitreal drug delivery for retinal gene therapy
Authors: Thomas F Martens, Katrien Remaut, Hendrik Deschout, Johan F J Engbersen, Wim E Hennink, Mies J van Steenbergen, Jo Demeester, Stefaan C De Smedt, Kevin Braeckmans
Journal: Journal of Controlled Release (2015)
Experimental amyloidosis: the inducer is a polyclonal B-cell activator to which susceptibility is under genetic control.
Authors: S Britton
Journal: The Journal of Experimental Medicine (1975)

Experimental amyloidosis in mice can be induced by repeated injections of casein. It has now been demonstrated that casein induces strong polyclonal antibody synthesis in mouse B spleen lymphocytes. This effect is much more pronounced in spleen cells from anyloid-susceptible mice (CBA/J) than amyloid-resistant mice (A/J). It is suggested that amyloidosis can be due in some instances to a constant exposure for molecules which induce polyclonal B-cell activation.