tbuckley/cabot-search huggingface dataset:
Quantitative Liver-Specific Protein Fingerprint in Blood: A Signature for Hepatotoxicity
Authors: Zhiyuan Hu, Christopher Lausted, Hyuntae Yoo, Xiaowei Yan, Amy Brightman, Jiankui Chen, Weizhi Wang, Xiangli Bu, Leroy Hood
Journal: Theranostics (2014)

We discuss here a new approach to detecting hepatotoxicity by employing concentration changes of liver-specific blood proteins during disease progression.These proteins are capable of assessing the behaviors of their cognate liver biological networks for toxicity or disease perturbations.Blood biomarkers are highly desirable diagnostics as blood is easily accessible and baths virtually all organs.Fifteen liver-specific blood proteins were identified as markers of acetaminophen (APAP)-induced hepatotoxicity using three proteomic technologies: label-free antibody microarrays, quantitative immunoblotting, and targeted iTRAQ mass spectrometry.Liver-specific blood proteins produced a toxicity signature of eleven elevated and four attenuated blood protein levels.These blood protein perturbations begin to provide a systems view of key mechanistic features of APAP-induced liver injury relating to glutathione and S-adenosyl-L-methionine (SAMe) depletion, mitochondrial dysfunction, and liver responses to the stress.Two markers, elevated membrane-bound catechol-O-methyltransferase (MB-COMT) and attenuated retinol binding protein 4 (RBP4), report hepatic injury significantly earlier than the current gold standard liver biomarker, alanine transaminase (ALT).These biomarkers were perturbed prior to onset of irreversible liver injury.Ideal markers should be applicable for both rodent model studies and human clinical trials.Five of these mouse liver-specific blood markers had human orthologs that were also found to be responsive to human hepatotoxicity.This panel of liver-specific proteins has the potential to effectively identify the early toxicity onset, the nature and extent of liver injury and report on some of the APAP-perturbed liver networks.
Dietary arginine and the prevention of cardiovascular diseases
Authors: M de Lorgeril
Journal: Cardiovascular Research (1998)

Endothelium plays a primary role in local regulation of vascular activity by synthesis and release of vasoactive substances, including the endothelium-derived relaxing factor, now identified with nitric oxide (NO), a labile substance derived from l-arginine. From its discovery [1, 2], NO has been recognized as a major intercellular, and perhaps intracellular, mediator [1, 2]. NO has potent biological properties as a vasoactive, platelet-regulatory, neurotransmitter and also cytotoxic agent [3]. Disorders of the endothelial NO synthase pathway might play a role in cardiovascular disorders including systemic and pulmonary hypertension [4–8], hypercholesterolaemia [9]and atherosclerosis [10, 11]although it is still unclear whether the decrease in endothelium-dependent vasorelaxation observed in hyperlipidaemia results from an increase in NO inactivation [12, 13]or a decreased formation of this compound [14, 15].

Investigators used arginine, the substrate of NO synthase, and antagonists of NO synthase as pharmacological means to manipulate the pathway. Only recently the idea emerged that arginine is not only a substrate for the enzyme which converts it to NO and citrulline but also a nutrient whose intake is highly variable among individuals and among populations. Although arginine was recently presented as a new possible pharmacological agent for atherosclerosis [16], the hypothesis that chronic high or low intake of arginine may play a role in coronary heart disease (CHD) has not been documented yet.

In the present issue of Cardiovascular Research , Bode-Boger et al. report that dietary arginine interferes with the metabolism of eicosanoids in a rabbit model of hypercholesterolaemia [17]. The cholesterol-induced increase of thromboxane A2, a potent vasoconstrictor and activator of platelet function derived from arachidonic acid, was significantly attenuated by arginine, the formation of atherosclerotic-type lesions and platelet function were partly inhibited and the vasoconstrictor effect of serotonin on isolated aortic … 

* Tel.: +33 (4) 77828300; fax: +33 (4) 77828447; e-mail: lorgeril@univ-st-etienne.fr
Panton–Valentine leucocidin expression by Staphylococcus aureus exposed to common antibiotics
Authors: Claire E. Turner, Shiranee Sriskandan
Journal: Journal of Infection (2015)

We set out to investigate the impact of common antibiotics on Panton-Valentine Leucocidin (PVL) expression by methicillin-sensitive Staphylococcus aureus (MSSA). PVL expression by methicillin-resistant S. aureus (MRSA) is reportedly enhanced by β-lactams, but inhibited by protein-synthesis inhibitors, a fact that has influenced management of infections associated with PVL. Although PVL is more frequently associated with MSSA than MRSA in the UK, the effect of antibiotics on PVL expression by MSSA has not been fully addressed.MSSA was cultured in vitro with varying concentrations of flucloxacillin, clindamycin or linezolid and PVL expression measured by qRT-PCR and Western blotting. A murine MSSA abscess model was developed to measure leucocidin expression in vivo following antibiotic treatment.9% (27/314) of MSSA isolates from patients with uncomplicated community skin/soft tissue infections were positive for PVL genes (lukFS-PV). PVL expression by MSSA in broth was unaffected by varying concentrations of flucloxacillin, clindamycin or linezolid. In a murine abscess model, treatment with flucloxacillin did, however, enhance in vivo MSSA lukF-PV transcription and this was sustained even when flucloxacillin was combined with clindamycin, or clindamycin plus linezolid. Notwithstanding increased leucocidin transcription, functional leucotoxin activity was not enhanced. Treatment with flucloxacillin plus clindamycin significantly decreased leucotoxin activity, but the addition of a second protein synthesis inhibitor, linezolid, did not confer benefit.Our results suggest flucloxacillin in combination with a single protein-synthesis inhibitor such as clindamycin would give the best treatment outcome.
SEPALLATA3: the 'glue' for MADS box transcription factor complex formation
Authors: Richard GH Immink, Isabella AN Tonaco, Stefan de Folter, Anna Shchennikova, Aalt DJ van Dijk, Jacqueline Busscher-Lange, Jan W Borst, Gerco C Angenent
Journal: Genome biology (2009)

Plant MADS box proteins play important roles in a plethora of developmental processes. In order to regulate specific sets of target genes, MADS box proteins dimerize and are thought to assemble into multimeric complexes. In this study a large-scale yeast three-hybrid screen is utilized to provide insight into the higher-order complex formation capacity of the Arabidopsis MADS box family. SEPALLATA3 (SEP3) has been shown to mediate complex formation and, therefore, special attention is paid to this factor in this study.In total, 106 multimeric complexes were identified; in more than half of these at least one SEP protein was present. Besides the known complexes involved in determining floral organ identity, various complexes consisting of combinations of proteins known to play a role in floral organ identity specification, and flowering time determination were discovered. The capacity to form this latter type of complex suggests that homeotic factors play essential roles in down-regulation of the MADS box genes involved in floral timing in the flower via negative auto-regulatory loops. Furthermore, various novel complexes were identified that may be important for the direct regulation of the floral transition process. A subsequent detailed analysis of the APETALA3, PISTILLATA, and SEP3 proteins in living plant cells suggests the formation of a multimeric complex in vivo.Overall, these results provide strong indications that higher-order complex formation is a general and essential molecular mechanism for plant MADS box protein functioning and attribute a pivotal role to the SEP3 'glue' protein in mediating multimerization.
Third CECOG consensus on the systemic treatment of non-small-cell lung cancer
Authors: T. Brodowicz, T. Ciuleanu, J. Crawford, M. Filipits, J.R. Fischer, V. Georgoulias, C. Gridelli, F.R. Hirsch, J. Jassem, P. Kosmidis, M. Krzakowski, Ch. Manegold, J.L. Pujol, R. Stahel, N. Thatcher, J. Vansteenkiste, C. Minichsdorfer, S. Zöchbauer-Müller, R. Pirker, C.C. Zielinski
Journal: Annals of Oncology (2011)
A National Graduate Medical Center
Authors: E. Grey Dimond
Journal: JAMA (1968)

Continuing or postgraduate medical education is a well-endorsed need. Voluntary health agencies (eg, the American Heart Association), professional societies (eg, the American College of Physicians), and medical schools (eg, the University of Kansas School of Medicine) are involved effectively in this area. This listing is incomplete, and the American Medical Association, state medical societies, medical journals, books, and films have, of course, essential roles in the continuing education of physicians.  The influence of the Regional Medical Program in this field will be major. As each Regional Medical Program develops, not only will efforts similar to those at Kansas result, but also the teaching arena will extend out into the community hospital. The excellent, short, one- to four-day courses which are the present style for continuing medical education will be augmented by steady, persistent educational activities at the physician's local hospital.  These efforts, and others not mentioned, even if all operative,
Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases
Authors: Vera Eremina, Manish Sood, Jody Haigh, András Nagy, Ginette Lajoie, Napoleone Ferrara, Hans-Peter Gerber, Yamato Kikkawa, Jeffrey H. Miner, Susan E. Quaggin
Journal: Journal of Clinical Investigation (2003)

Kidney disease affects over 20 million people in the United States alone. Although the causes of renal failure are diverse, the glomerular filtration barrier is often the target of injury. Dysregulation of VEGF expression within the glomerulus has been demonstrated in a wide range of primary and acquired renal diseases, although the significance of these changes is unknown. In the glomerulus, VEGF-A is highly expressed in podocytes that make up a major portion of the barrier between the blood and urinary spaces. In this paper, we show that glomerular-selective deletion or overexpression of VEGF-A leads to glomerular disease in mice. Podocyte-specific heterozygosity for VEGF-A resulted in renal disease by 2.5 weeks of age, characterized by proteinuria and endotheliosis, the renal lesion seen in preeclampsia. Homozygous deletion of VEGF-A in glomeruli resulted in perinatal lethality. Mutant kidneys failed to develop a filtration barrier due to defects in endothelial cell migration, differentiation, and survival. In contrast, podocyte-specific overexpression of the VEGF-164 isoform led to a striking collapsing glomerulopathy, the lesion seen in HIV-associated nephropathy. Our data demonstrate that tight regulation of VEGF-A signaling is critical for establishment and maintenance of the glomerular filtration barrier and strongly supports a pivotal role for VEGF-A in renal disease.
Leucocytoclastic vasculitis induced by prolonged exercise
Authors: M. PRINS, J.C.J.M. VERAART, A.H.M. VERMEULEN, R.-F.H.J. HULSMANS, H.A.M. NEUMANN
Journal: British Journal of Dermatology (1996)

Many people develop skin symptoms after long-distance walks, but little is known about the aetiology of these. In this study we took 11 biopsies from 10 long-distance walkers who walked 80 km. All biopsies originated from purpuric lesions on the lower legs, which had appeared during walking. In all 11 specimens, signs of a leucocytoclastic vasculitis were present with leucocytoclasis, exocytosis of erythrocytes and a granulocyte/mononuclear perivascular infiltrate. Immunofluorescence investigations showed deposition of C3c in many specimens and immunoglobulin M in some. The occurrence of a leucocytoclastic vasculitis after prolonged exercise may be explained by the existence of an exercise altered cutaneous microcirculation, complement activation and an altered immune function.
Granulocyte elastase cleaves human high molecular weight kininogen and destroys its clot-promoting activity.
Authors: J Kleniewski, V Donaldson
Journal: The Journal of Experimental Medicine (1988)

Purified human granulocyte elastase cleaved purified human high molecular weight (HMW) kininogen into multiple low molecular weight fragments, and destroyed the clot-promoting activity of the HMW kininogen. Elastase digestion did not release kinin or destroy the bradykinin portion of the HMW kininogen molecule; kallikrein could release kinin from the elastase-induced low molecular weight digestion products of HMW kininogen. Purified alpha 1-antitrypsin prevented the destruction of the clot-promoting activity of HMW kininogen by elastase; it also delayed the clotting of normal plasma. Elastase may play a significant role in altered hemostasis as well as fibrinolysis, in areas of inflammation to which polymorphonuclear leukocytes have been attracted.
Noninvasive Blood Glucose Monitoring With Optical Coherence Tomography
Authors: Kirill V. Larin, Mohsen S. Eledrisi, Massoud Motamedi, Rinat O. Esenaliev
Journal: Diabetes Care (2002)

OBJECTIVE—To study the feasibility of noninvasive blood glucose monitoring using optical coherence tomography (OCT) technique in healthy volunteers. RESEARCH DESIGN AND METHODS—An OCT system with the wavelength of 1,300 nm was used in 15 healthy subjects in 18 clinical experiments. Standard oral glucose tolerance tests were performed to induce changes in blood glucose concentration. Blood samples were taken from the right arm vein every 5 or 15 min. OCT images were taken every 10–20 s from the left forearm over a total period of 3 h. The slope of the signals was calculated at the depth of 200–600 μm from the skin surface. RESULTS—A total of 426 blood samples and 8,437 OCT images and signals were collected and analyzed in these experiments. There was a good correlation between changes in the slope of noninvasively measured OCT signals and blood glucose concentrations throughout the duration of the experiments. The slope of OCT signals changed significantly (up to 2.8% per 10 mg/dl) with variation of plasma glucose values. The good correlation obtained between the OCT signal slope and blood glucose concentration is due to the coherent detection of backscattered photons, which allows measurements of OCT signal from a specific tissue layer without unwanted signal from other tissue layers. CONCLUSIONS—This pilot study demonstrated the capability of the OCT technique to monitor blood glucose concentration noninvasively in human subjects. Further studies with a larger number of subjects including diabetic subjects are planned to validate these preliminary results.
Impact of Critical Limb Ischemia on Long-Term Cardiac Mortality in Diabetic Patients Undergoing Percutaneous Coronary Revascularization
Authors: Francesco Liistro, Paolo Angioli, Simone Grotti, Rossella Brandini, Italo Porto, Lucia Ricci, Danilo Tacconi, Kenneth Ducci, Giovanni Falsini, Guido Bellandi, Leonardo Bolognese
Journal: Diabetes Care (2013)

Development of critical limb ischemia (CLI) has been reported as an independent predictor of cardiac mortality in diabetic patients. We aimed to determine whether CLI, managed in a structured setting of close collaboration between different vascular specialists and treated with early endovascular intervention, has any impact on long-term cardiac mortality of diabetic patients initially presenting with symptomatic coronary artery disease (CAD).We designed a prospective observational study of 764 consecutive diabetic patients undergoing percutaneous coronary intervention (PCI) in whom development of CLI was assessed by a dedicated diabetic foot clinic. Cardiac mortality at 4-year follow-up was the primary end point of the study.Among the 764 patients, 111 (14%) developed CLI (PCI-CLI group) and underwent revascularization of 145 limbs, with procedural success in 140 (96%). PCI-CLI patients at baseline had lower left ventricular ejection fraction (51 ± 11% vs. 53 ± 10%, P = 0.008), higher prevalence of dialysis (7% vs. 0.3%, P < 0.0001), and longer diabetes duration (13 ± 8 vs. 11 ± 7 years, P = 0.02) compared with PCI-only patients. At 4-year follow-up, cardiac mortality occurred in 10 (9%) PCI-CLI patients vs. 42 (6%) PCI-only patients (P = 0.2). Time-dependent Cox regression model for cardiac death revealed that CLI was not associated with an increased risk of cardiac mortality (hazard ratio 1.08 [95% CI 0.89-3.85]; P = 0.1).The development of promptly assessed and aggressively treated CLI was not significantly associated with increased risk of long-term cardiac mortality in diabetic patients initially presenting with symptomatic CAD.
The effect of encasings on quality of life in adult house dust mite allergic patients with rhinitis, asthma and/or atopic dermatitis
Authors: I. Terreehorst, H. J. Duivenvoorden, Z. Tempels‐Pavlica, A. J. Oosting, J. G. R. de Monchy, C. A. F. M. Bruijnzeel‐Koomen, R. Gerth van Wijk
Journal: Allergy (2005)

Background: Environmental control has been put forward as an integral part of the management of house dust mite (HDM) allergy in sensitized patients. To validate this statement allergic disorders involved in HDM allergy – allergic asthma, rhinitis and atopic eczema/dermatitis syndrome (AEDS) – should be taken together and studied in terms of the efficacy of environmental control. Because a generic quality of life questionnaire exceeds the border of disease, this may be used as major outcome parameter. Research objective: To study the effects of bedding encasings in HDM allergic patients with asthma, rhinitis and AEDS. Material and methods: A total of 224 adult HDM allergic patients with rhinitis and/or asthma and/or dermatitis were randomly allocated impermeable or nonimpermeable encasings for mattress, pillow and duvet. Short form 36 (SF‐36) was filled in at baseline and after 12 months. Results: Lower physical ( P = 0.01) and emotional ( P &lt; 0.001) sumscores were seen in females. Also, the presence of asthma resulted in lower physical sumscore ( P = 0.01). However, no effect was seen of encasings on either sumscore. Conclusion: Bedding encasings do not improve quality of life in a mixed population of subjects with combinations with rhinitis, asthma and atopic dermatitis and sensitized to HDMs.
Psychedelic Therapy Utilizing LSD in the Treatment of the Alcoholic Patient: A Preliminary Report
Authors: ALBERT A. KURLAND, SANFORD UNGER, JOHN W. SHAFFER, CHARLES SAVAGE
Journal: American Journal of Psychiatry (1967)

The rationale of psychedelic therapy with alcoholic patients is focused on the alienation-breaking potential of "peak" or psychedelic experiences induced with the aid of LSD. An exemplary LSD session report and MMPI data on 69 pilot patients are presented for illustration. While all present results indicate that psychedelic therapy does add significantly to presently available alcoholic rehabilitation resources, it is emphasized that safe and effective use of LSD requires specialized training.
Some aspects of the epidemiology of ulcerative colitis.
Authors: J F Mayberry
Journal: Gut (1985)

Progress reportSome aspects of the epidemiology of ulcerative colitisDuring the last 20 years attention has focused on the aetiology of Crohn's disease.Numerous epidemiological studies have been conducted and it is now estimated that 20 000 people may be affected by the condition in Britain.Ulcerative colitis is a much commoner disease, affecting as many as 50-60 000 people and interest in its aetiology has recently increased.The disease often affects young people after puberty and medical treatment is empirical.Surgical resection of the colon may be regarded as curative and there are at least 12 000 people with an ileostomy in the United Kingdom, many of whom have difficulty in coping with their stoma.'This review examines epidemiological data which may give some indication of possible causal factors. Studies of incidence and prevalenceComparison of epidemiological studies is often complicated by the exclusion of patients with proctitis (Table 1).Many patients with proctitis have a mild illness and never attend hospital.As a consequence the diagnosis may not be confirmed and such cases have seldom been considered in epidemiological studies.Before the recognition of campylo- bacter colitis in the mid 1970s30 it is likely that such cases were occasionally included in some studies.In recent investigtions only patients with recurrent attacks of colitis or proctitis have been included.In most communities of Anglo Saxon origin in north western Europe, North America, and New Zealand the incidence of ulcerative colitis ranges from five to eight cases/100 000/year (Table 1), but in some areas of northern England3 and Scotland4 the disease is commoner with figures as high as 11 and 15/105/year.A study from Norway12 has reported a similar incidence in Bergen.Despite the identification of new bacterial causes of diarrhoea the incidence of ulcerative colitis has either remained constant or even increased gradually over the decades and this is in contrast to Crohn's disease (Table 1).31In Scotland,5 Norway, " Sweden'4 and Iceland'6 studies conducted over periods of up to 30 years have shown a steady rise in incidence.This increased diagnosis of ulcerative colitis in some areas may be due to identification of milder cases rather than a real phenomenon, but further studies of incidence and mortality may resolve the problem.Ulcerative colitis is uncommon in eastern European countries such as Czechoslovakia'9 and Bulgaria20 and in Southern Europe.21This pattern is 968 on August 10,
Demystify Statistical Significance--Time to Move on From the P Value to Bayesian Analysis
Authors: J. J. Lee
Journal: JNCI Journal of the National Cancer Institute (2010)

Compared to the long histories of mathematics, physics, chemistry, and biology, statistics is a young science. Rooted in mathematics, statistics is a science of quantitative reasoning. It provides a formal framework for assessing the strength of evidence in the midst of uncertainty. More specifically, statistics allows one to quantify the probability of an event to make proper inference. It provides tools that we can use to sift through mountains of information to identify the signal and filter out the noise. Recently, the United Nations declared October 20, 2010, as “World Statistics Day.” The declaration stated “On 20 October 2010, the World will celebrate the first World Statistics Day, to raise awareness of the many achievements of official statistics premised on the core values of service, integrity and professionalism” (1).
Central hypoventilation with PHOX2B expansion mutation presenting in adulthood
Authors: S Barratt, A H Kendrick, F Buchanan, A T Whittle
Journal: Thorax (2007)

Congenital central hypoventilation syndrome most commonly presents in neonates with sleep related hypoventilation; late onset cases have occurred up to the age of 10 years. It is associated with mutations in the PHOX2B gene, encoding a transcription factor involved in autonomic nervous system development. The case history is described of an adult who presented with chronic respiratory failure due to PHOX2B mutation-associated central hypoventilation and an impaired response to hypercapnia.