tbuckley/cabot-search huggingface dataset:
Increased oxidative stress in obesity and its impact on metabolic syndrome
Authors: Shigetada Furukawa, Takuya Fujita, Michio Shimabukuro, Masanori Iwaki, Yukio Yamada, Yoshimitsu Nakajima, Osamu Nakayama, Makoto Makishima, Morihiro Matsuda, Iichiro Shimomura
Journal: Journal of Clinical Investigation (2004)

Obesity is a principal causative factor in the development of metabolic syndrome. Here we report that increased oxidative stress in accumulated fat is an important pathogenic mechanism of obesity-associated metabolic syndrome. Fat accumulation correlated with systemic oxidative stress in humans and mice. Production of ROS increased selectively in adipose tissue of obese mice, accompanied by augmented expression of NADPH oxidase and decreased expression of antioxidative enzymes. In cultured adipocytes, elevated levels of fatty acids increased oxidative stress via NADPH oxidase activation, and oxidative stress caused dysregulated production of adipocytokines (fat-derived hormones), including adiponectin, plasminogen activator inhibitor–1, IL-6, and monocyte chemotactic protein–1. Finally, in obese mice, treatment with NADPH oxidase inhibitor reduced ROS production in adipose tissue, attenuated the dysregulation of adipocytokines, and improved diabetes, hyperlipidemia, and hepatic steatosis. Collectively, our results suggest that increased oxidative stress in accumulated fat is an early instigator of metabolic syndrome and that the redox state in adipose tissue is a potentially useful therapeutic target for obesity-associated metabolic syndrome.
Pathogenesis of Human Mitochondrial Diseases Is Modulated by Reduced Activity of the Ubiquitin/Proteasome System
Authors: Alexandra Segref, Éva Kevei, Wojciech Pokrzywa, Kathrin Schmeisser, Johannes Mansfeld, Nurit Livnat-Levanon, Regina Ensenauer, Michael H. Glickman, Michael Ristow, Thorsten Hoppe
Journal: Cell Metabolism (2014)
Location of variable and conserved epitopes among the multiple serotypes of streptococcal M protein.
Authors: K F Jones, B N Manjula, K H Johnston, S K Hollingshead, J R Scott, V A Fischetti
Journal: The Journal of Experimental Medicine (1985)

In studies primarily confined to the amino-terminal region of the fibrillar group A streptococcal M protein, only limited immunological crossreactions have been observed among M serotypes. In this investigation, two monoclonal antibodies generated against nearly the entire M6 molecule (LysM6) were used to determine the extent of crossreactions among M serotyping strains and to localize their epitopes on the M molecule. Colony blot and immunoblot analyses revealed that an epitope responsible for crossreactions among 5 of the 56 strains of different M serotypes tested is located in the amino-terminal half of the molecule, distal to the cell surface. In contrast, a more common crossreactive epitope, reacting with 20 of the 56 strains, is located near the middle of the M molecule. These studies also reveal that the more conserved determinant, located more proximally to the cell surface, is accessible to the immune system, even on the whole organism, and, thus, may be useful in devising means to protect against infections by multiple group A streptococcal M serotypes.
Mentoring for NHS doctors: perceived benefits across the personal–professional interface
Authors: A Steven, J Oxley, WG Fleming
Journal: Journal of the Royal Society of Medicine (2008)

Summary Objective To investigate NHS doctors' perceived benefits of being involved in mentoring schemes and to explore the overlaps and relationships between areas of benefit. Design Extended qualitative analysis of a multi-site interview study following an interpretivist approach. Setting Six NHS mentoring schemes across England. Main outcome measures Perceived benefits. Results While primary analysis resulted in lists of perceived benefits, the extended analysis revealed three overarching areas: professional practice, personal well-being and development. Benefits appear to go beyond a doctor's professional role to cross the personal–professional interface. Problem solving and change management seem to be key processes underpinning the raft of personal and professional benefits reported. A conceptual map was developed to depict these areas and relationships. In addition secondary analysis suggests that in benefitting one area mentoring may lead to consequential benefits in others. Conclusions Prior research into mentoring has mainly taken place in a single health care sector. This multi-site study suggests that the perceived benefits of involvement in mentoring may cross the personal/professional interface and may override organizational differences. Furthermore the map developed highlights the complex relationships which exist between the three areas of professional practice, personal wellbeing and personal and professional development. Given the consistency of findings across several studies it seems probable that organizations would be strengthened by doctors who feel more satisfied and confident in their professional roles as a result of participation in mentoring. Mentoring may have the potential to take us beyond individual limits to greater benefits and the conceptual map may offer a starting point for the development of outcome criteria and evaluation tools for mentoring schemes.
The Patient Who Falls
Authors: Mary E. Tinetti, Chandrika Kumar
Journal: JAMA (2010)

Falls are common health events that cause discomfort and disability for older adults and stress for caregivers. Using the case of an older man who has experienced multiple falls and a hip fracture, this article, which focuses on community-living older adults, addresses the consequences and etiology of falls; summarizes the evidence on predisposing factors and effective interventions; and discusses how to translate this evidence into patient care. Previous falls; strength, gait, and balance impairments; and medications are the strongest risk factors for falling. Effective single interventions include exercise and physical therapy, cataract surgery, and medication reduction. Evidence suggests that the most effective strategy for reducing the rate of falling in community-living older adults may be intervening on multiple risk factors. Vitamin D has the strongest clinical trial evidence of benefit for preventing fractures among older men at risk. Issues involved in incorporating these evidence-based fall prevention interventions into outpatient practice are discussed, as are the trade-offs inherent in managing older patients at risk of falling. While challenges and barriers exist, fall prevention strategies can be incorporated into clinical practice.
An estimate of fetal autonomic state by spectral analysis of human umbilical artery flow velocity waveforms
Authors: Nicolette T.C Ursem, Mark H Kempski, Maria A.J de Ridder, Edward B Clark, Juriy W Wladimiroff
Journal: Cardiovascular Research (1998)

Objective: Determination of gestational age-related fluctuations in heart rate in the umbilical artery of the early human fetus. Methods: Doppler velocity recordings from human umbilical artery were obtained, in a cross-sectional study design in 137 singleton pregnancies at 10–20 weeks of gestation. After exclusion criteria were applied, data on 117 normal pregnancies were available and subdivided into group I: 10–12 weeks (n=49); group II: 13–16 weeks (n=43); and group III: 17–20 weeks (n=25). Blood flow velocity waveforms were reconstructed from Doppler audio signals. Variability in heart rate was calculated using Fast Fourier Transforms (FFT). Individual heart rate variability power spectra were subdivided into frequency bands. Results: Fetal heart rate variability decreases at 10–20 weeks and demonstrates a shift to lower frequencies at 17–20 weeks. Conclusions: Fetal heart rate variability is related to gestational age and shows a shift to lower frequencies which may reflect autonomic functional development.
Processing of chromogranin A by plasmin provides a novel mechanism for regulating catecholamine secretion
Authors: Robert J. Parmer, Manjula Mahata, Yun Gong, Sushil K. Mahata, Qijiao Jiang, Daniel T. O’Connor, Xiao-Ping Xi, Lindsey A. Miles
Journal: Journal of Clinical Investigation (2000)

Chromogranin A (CgA) is the major soluble protein in the core of catecholamine-storage vesicles and is also distributed widely in secretory vesicles throughout the neuroendocrine system. CgA contains the sequences for peptides that modulate catecholamine release, but the proteases responsible for the release of these bioactive peptides from CgA have not been established. We show here that the major fibrinolytic enzyme, plasmin, can cleave CgA to form a series of large fragments as well as small trichloroacetic acid-soluble peptides. Peptides generated by plasmin-mediated cleavage of CgA significantly inhibited nicotinic cholinergic stimulation of catecholamine release from PC12 cells and primary bovine adrenal chromaffin cells. We also show that the zymogen, plasminogen, as well as tissue plasminogen activator bind saturably and with high capacity to catecholaminergic (PC12) cells. Occupancy of cell surface binding sites promoted the cleavage of CgA by plasmin. Positive and negative modulation of the local cellular fibrinolytic system resulted in substantial alterations in catecholamine release. These results suggest that catecholaminergic cells express binding sites that localize fibrinolytic molecules on their surfaces to promote plasminogen activation and proteolytic processing of CgA in the environment into which CgA is secreted to generate peptides which may regulate neuroendocrine secretion. Interactions between CgA and plasmin(ogen) define a previously unrecognized autocrine/paracrine system that may have a dramatic impact upon catecholamine secretion.
Pertussis toxin-sensitive G protein mediates coronary microvascular control during autoregulation and ischemia in canine heart.
Authors: T Komaru, Y Wang, K Akai, K Sato, N Sekiguchi, A Sugimura, T Kumagai, H Kanatsuka, K Shirato
Journal: Circulation Research (1994)

GTP-binding regulatory proteins (G proteins) regulate various biological functions, but their participation in controlling coronary microvascular tone has not been established yet. The goal of the present study was to elucidate the role of pertussis toxin (PTX)-sensitive G protein in regulating coronary microvascular tone during autoregulation and ischemia. In 42 open-chest dogs, coronary arterial microvessels on the surface of the left ventricle were directly observed by epi-illuminated fluorescence microangiography using a floating objective system. PTX (300 ng/mL) was superfused onto the surface of the left ventricle for 2 hours to block Gi and G(o) protein in epimyocardial coronary microvessels in vivo. PTX superfusion caused no change in the resting diameters of microvessels and significantly blocked the vasoconstriction induced by BHT 920 (a selective alpha 2-agonist). After pretreatment with PTX or its vehicle, the left anterior descending coronary artery (LAD) was occluded by a hydraulic occluder to reduce coronary perfusion pressure (CPP) in a stepwise fashion. A mild stenosis (CPP, 60 mm Hg), a severe stenosis (CPP, 40 mm Hg), and complete occlusion were sequentially produced. Coronary flow velocity in the LAD distal to the stenotic site was continuously monitored. In both PTX and vehicle groups, flow velocity did not significantly decrease during mild stenosis, proving that transmural coronary autoregulatory function was well preserved in the preparation. During severe stenosis and complete occlusion, the coronary flow velocity significantly decreased. In the vehicle group, microvessels &lt; 100 microns in inner diameter significantly dilated in response to the reduction in perfusion pressure (mild stenosis, 6.2 +/- 1.9%; severe stenosis, 21.1 +/- 4.4%; and complete occlusion, 16.8 +/- 5.9%; P &lt; .05 versus baseline diameters). In the PTX group, microvessels did not dilate during each occlusion level (mild stenosis, -2.0 +/- 0.9%; severe stenosis, -3.9 +/- 1.9%; and complete occlusion, -13.4 +/- 2.9%; P &lt; .05 versus vehicle group). PTX did not affect the microvascular dilation caused by nitroprusside. The present data indicate that PTX-sensitive G protein is crucially involved in microvascular control during autoregulation and ischemia.
Neuropeptide Y and peptide YY inhibit lipolysis in human and dog fat cells through a pertussis toxin-sensitive G protein.
Authors: P Valet, M Berlan, M Beauville, F Crampes, J L Montastruc, M Lafontan
Journal: Journal of Clinical Investigation (1990)

Neuropeptide Y (NPY) and peptide YY (PYY) are regulatory peptides that have considerable sequence homology with pancreatic polypeptide. Because (a) NPY has been shown to be colocalized with noradrenaline in peripheral as well as central catecholaminergic neurons, and (b) alpha 2-adrenergic receptors of adipocytes play a major role in the regulation of lipolysis, we investigated the effect of NPY and PYY on isolated fat cells. In human fat cells NPY and PYY promoted a dose-dependent inhibition of lipolysis elicited by 2 micrograms/ml adenosine deaminase (removal of adenosine) whatever the lipolytic index used (glycerol or nonesterified fatty acids). In dog fat cells NPY and PYY inhibited adenosine deaminase-, isoproterenol- and forskolin-induced lipolysis. In humans and dogs the effects of NPY or PYY were abolished by treatment of cells with Bordetella pertussis toxin, clearly indicating the involvement of a Gi protein in the antilipolytic effects. This study indicates that, in addition to alpha 2-adrenergic agonists, NPY and PYY are also involved in the regulation of lipolysis in human and dog adipose tissue as powerful antilipolytic agents. Further studies are needed to characterize the pharmacological nature of the receptor mediating the inhibitory effect of NPY and PYY in fat cells.
A Randomized Controlled Trial of Resistance Exercise Training to Improve Glycemic Control in Older Adults With Type 2 Diabetes
Authors: Carmen Castaneda, Jennifer E. Layne, Leda Munoz-Orians, Patricia L. Gordon, Joseph Walsmith, Mona Foldvari, Ronenn Roubenoff, Katherine L. Tucker, Miriam E. Nelson
Journal: Diabetes Care (2002)

OBJECTIVE—To determine the efficacy of high-intensity progressive resistance training (PRT) on glycemic control in older adults with type 2 diabetes. RESEARCH DESIGN AND METHODS—We performed a 16-week randomized controlled trial in 62 Latino older adults (40 women and 22 men; mean ± SE age 66 ± 8 years) with type 2 diabetes randomly assigned to supervised PRT or a control group. Glycemic control, metabolic syndrome abnormalities, body composition, and muscle glycogen stores were determined before and after the intervention. RESULTS—Sixteen weeks of PRT (three times per week) resulted in reduced plasma glycosylated hemoglobin levels (from 8.7 ± 0.3 to 7.6 ± 0.2%), increased muscle glycogen stores (from 60.3 ± 3.9 to 79.1 ± 5.0 mmol glucose/kg muscle), and reduced the dose of prescribed diabetes medication in 72% of exercisers compared with the control group, P = 0.004–0.05. Control subjects showed no change in glycosylated hemoglobin, a reduction in muscle glycogen (from 61.4 ± 7.7 to 47.2 ± 6.7 mmol glucose/kg muscle), and a 42% increase in diabetes medications. PRT subjects versus control subjects also increased lean mass (+1.2 ± 0.2 vs. −0.1 ± 0.1 kg), reduced systolic blood pressure (–9.7 ± 1.6 vs. +7.7 ± 1.9 mmHg), and decreased trunk fat mass (−0.7 ± 0.1 vs. +0.8 ± 0.1 kg; P = 0.01–0.05). CONCLUSIONS—PRT as an adjunct to standard of care is feasible and effective in improving glycemic control and some of the abnormalities associated with the metabolic syndrome among high-risk older adults with type 2 diabetes.
Effect of Statin Therapy on Mortality in Patients With Ventilator-Associated Pneumonia
Authors: Laurent Papazian
Journal: JAMA (2013)

Observational studies have reported that statin use may be associated with improved outcomes of various infections. Ventilator-associated pneumonia (VAP) is the most common infection in the intensive care unit (ICU) and is associated with substantial mortality.To determine whether statin therapy can decrease day-28 mortality in patients with VAP.Randomized, placebo-controlled, double-blind, parallel-group, multicenter trial performed in 26 intensive care units in France from January 2010 to March 2013. For power to detect an 8% absolute reduction in the day-28 mortality rate, we planned to enroll 1002 patients requiring invasive mechanical ventilation for more than 2 days and having suspected VAP, defined as a modified Clinical Pulmonary Infection Score of 5 or greater. The futility stopping rules were an absolute increase in day-28 mortality of at least 2.7% with simvastatin compared with placebo after enrollment of the first 251 patients.Participants were randomized to receive simvastatin (60 mg) or placebo, started on the same day as antibiotic therapy and given until ICU discharge, death, or day 28, whichever occurred first.Primary outcome was day-28 mortality. Day-14, ICU, and hospital mortality rates were determined, as well as duration of mechanical ventilation and Sequential Organ Failure Assessment (SOFA) scores on days 3, 7, and 14.The study was stopped for futility at the first scheduled interim analysis after enrollment of 300 patients, of whom all but 7% in the simvastatin group and 11% in the placebo group were naive to statin therapy at ICU admission. Day-28 mortality was not lower in the simvastatin group (21.2% [95% CI, 15.4% to 28.6%) than in the placebo group (15.2% [95% CI, 10.2% to 22.1%]; P = .10; hazard ratio, 1.45 [95% CI, 0.83 to 2.51]); the between-group difference was 6.0% (95% CI, -3.0% to 14.9%). In statin-naive patients, day-28 mortality was 21.5% (95% CI, 15.4% to 29.1%) with simvastatin and 13.8% (95% CI, 8.8% to 21.0%) with placebo (P = .054) (between-group difference, 7.7% [95%CI, -1.8% to 16.8%). There were no significant differences regarding day-14, ICU, or hospital mortality rates; duration of mechanical ventilation; or changes in SOFA score.In adults with suspected VAP, adjunctive simvastatin therapy compared with placebo did not improve day-28 survival. These findings do not support the use of statins with the goal of improving VAP outcomes.clinicaltrials.gov Identifier: NCT01057758.
Frequent Downregulation of miR-34 Family in Human Ovarian Cancers
Authors: David C. Corney, Chang-Il Hwang, Andres Matoso, Markus Vogt, Andrea Flesken-Nikitin, Andrew K. Godwin, Aparna A. Kamat, Anil K. Sood, Lora H. Ellenson, Heiko Hermeking, Alexander Yu. Nikitin
Journal: Clinical Cancer Research (2010)

The miR-34 family is directly transactivated by tumor suppressor p53, which is frequently mutated in human epithelial ovarian cancer (EOC). We hypothesized that miR-34 expression would be decreased in EOC and that reconstituted miR-34 expression might reduce cell proliferation and invasion of EOC cells.miR-34 expression was determined by quantitative reverse transcription-PCR and in situ hybridization in a panel of 83 human EOC samples. Functional characterization of miR-34 was accomplished by reconstitution of miR-34 expression in EOC cells with synthetic pre-miR molecules followed by determining changes in proliferation, apoptosis, and invasion.miR-34a expression is decreased in 100%, and miR-34b*/c in 72%, of EOC with p53 mutation, whereas miR-34a is also downregulated in 93% of tumors with wild-type p53. Furthermore, expression of miR-34b*/c is significantly reduced in stage IV tumors compared with stage III (P = 0.0171 and P = 0.0029, respectively). Additionally, we observed promoter methylation and copy number variations at mir-34. In situ hybridization showed that miR-34a expression is inversely correlated with MET immunohistochemical staining, consistent with translational inhibition by miR-34a. Finally, miR-34 reconstitution experiments in p53 mutant EOC cells resulted in reduced proliferation, motility, and invasion, the latter of which was dependent on MET expression.Our work suggests that miR-34 family plays an important role in EOC pathogenesis and reduced expression of miR-34b*/c may be particularly important for progression to the most advanced stages. Part of miR-34 effects on motility and invasion may be explained by regulation of MET, which is frequently overexpressed in EOC.
Specific immunotherapy modifies allergen-specific CD4+ T-cell responses in an epitope-dependent manner
Authors: Erik Wambre, Jonathan H. DeLong, Eddie A. James, Nadia Torres-Chinn, Wolfgang Pfützner, Christian Möbs, Stephen R. Durham, Stephen J. Till, David Robinson, William W. Kwok
Journal: Journal of Allergy and Clinical Immunology (2013)
The use of prolotherapy injections for elite athletes
Authors: Simon Petrides
Journal: British Journal of Sports Medicine (2011)

Lecture 14 The clinic embraces all aspects of sports and exercise medicine from ‘exercise on prescription’ and ‘functional rehab programmes’ to specialist image guided spinal injections. Simon has a special interest in prolotherapy injections as an adjunct to intense rehab programmes for unremitting low back pain. This has culminated in successful treatment of many elite athletes and footballers. Most clinical trials on the treatment have shown significant benefits but no prominent trials have used patients with specific back pain diagnoses using selective block injections to determine which patients are most likely to benefit. Rowing has a low back pain incidence of 100% and over 20 GB rowers have been successfully treated using this technique. The lecture will summarise his experience in the use of prolotherapy in these athletes.
CA15-3 and alkaline phosphatase as predictors for breast cancer recurrence: a combined analysis of seven International Breast Cancer Study Group trials
Authors: A. Keshaviah, S. Dellapasqua, N. Rotmensz, J. Lindtner, D. Crivellari, J. Collins, M. Colleoni, B. Thürlimann, C. Mendiola, S. Aebi, K.N. Price, O. Pagani, E. Simoncini, M. Castiglione Gertsch, R.D. Gelber, A.S. Coates, A. Goldhirsch
Journal: Annals of Oncology (2007)
Are anti-cyclic citrullinated peptide autoantibodies seromarkers for rheumatoid vasculitis in a cohort of patients with systemic vasculitis?
Authors: K Laskaria, K Ahmadi-Simab, M Lamken, E Csernok, W L Gross, B Hellmich
Journal: Annals of the Rheumatic Diseases (2010)

A diverse spectrum of vasculitic syndromes exists including systemic rheumatoid vasculitis (SRV), which sometimes occurs as the first manifestation of severe rheumatoid factor (RF)-positive rheumatoid arthritis.1 So far, no convincing laboratory parameter has been determined for the diagnosis of SRV, which helps in distinguishing rheumatoid vasculitis from other types of small-sized or medium-sized vessel vasculitides. The aim of our study was to estimate the potential diagnostic value of anti-cyclic citrullinated peptide (CCP) antibodies among the systemic vasculitides.2

A total of 27 consecutive patients with SRV at vasculitis diagnosis were included in the study;3 27 patients with seropositive rheumatoid arthritis (RA) without vasculitis, matched for age, sex and disease duration with the SRV group, and 151 patients with primary systemic small vessel vasculitis (PSV) (50 patients with Wegener granulomatosis (WG), 50 patients with microscopic polyangiitis (MPA) …
Identification and Treatment of Acute Psychotic States Secondary to the Usage of Over-the-Counter Sleeping Preparations
Authors: KENNETH C. ULLMAN, ROBERT H. GROH
Journal: American Journal of Psychiatry (1972)

Within eight months, 36 patients seen at the Washington Hospital Center, Washington, D.C., presented the problem of differentiating between a toxic psychosis caused by ingestion of over-the-counter sleeping medications containing scopolamine and a schizophrenic episode. Clinical evaluations, case histories, and thin-layer chromatography were used to identify these patients. Urinalysis revealed the presence of at least two ingredients of over-the-counter sleeping medications in ten patients. Intramuscular injections of physostigmine salicylate reversed the toxic psychosis presumed to be the result of the scopolamine content in these preparations.