tbuckley/cabot-search huggingface dataset:
Placental-related diseases of pregnancy: involvement of oxidative stress and implications in human evolution
Authors: Eric Jauniaux, Lucilla Poston, Graham J. Burton
Journal: Human Reproduction Update (2006)

Miscarriage and pre-eclampsia are the most common disorders of human pregnancy. Both are placental-related and exceptional in other mammalian species. Ultrasound imaging has enabled events during early pregnancy to be visualized in vivo for the first time. As a result, a new understanding of the early materno–fetal relationship has emerged and, with it, new insight into the pathogenesis of these disorders. Unifying the two is the concept of placental oxidative stress, with associated necrosis and apoptosis of the trophoblastic epithelium of the placental villous tree. In normal pregnancies, the earliest stages of development take place in a low oxygen (O2) environment. This physiological hypoxia of the early gestational sac protects the developing fetus against the deleterious and teratogenic effects of O2 free radicals (OFRs). In miscarriage, development of the placento–decidual interface is severely impaired leading to early and widespread onset of maternal blood flow and major oxidative degeneration. This mechanism is common to all miscarriages, with the time at which it occurs in the first trimester depending on the aetiology. In contrast, in pre-eclampsia the trophoblastic invasion is sufficient to allow early pregnancy phases of placentation but too shallow for complete transformation of the arterial utero–placental circulation, predisposing to a repetitive ischaemia–reperfusion (I/R) phenomenon. We suggest that pre-eclampsia is a three-stage disorder with the primary pathology being an excessive or atypical maternal immune response. This would impair the placentation process leading to chronic oxidative stress in the placenta and finally to diffuse maternal endothelial cell dysfunction.
Segmental alpha-receptor-mediated vasoconstriction in the canine coronary circulation.
Authors: K O Kelley, E O Feigl
Journal: Circulation Research (1978)

Recent studies from this laboratory have indicated that sympathetic alpha-receptor-mediated coronary vasoconstriction can compete with local metabolic vasodilation to reduce the oxygen supply to the myocardium. In vitro studies from other laboratories on isolated coronary vessel strips suggest that large epicardial vessels are the dominant site of adrenergic alpha-receptor activity. In this study we used anesthetized, open-chest dogs to test the hypothesis that alpha-receptor-mediated vasoconstriction occurs predominantly in epicardial vessels, which are partially removed from the metabolic milieu in the myocardium. Adrenergic beta-receptor blockade was achieved by propranolol (3 mg/kg, iv). The circumflex coronary artery was pump-perfused at constant pressure to minimize passive changes in large vessel resistance. Pressure was measured at the tip of the perfusion cannula sealed in the circumflex artery, and in an apical branch of the circumflex artery. Large vessel resistance was calculated as the pressure gradient along the vessel segment divided by the coronary flow. Intracoronary injections of nitroglycerin were used as an independent measure of the vasomotor responsiveness of the large vessel segment. Adrenergic alpha-receptor activation was produced by intracoronary bolus injections of norepinephrine and by electrical stimulation of the left stellate ganglion. Alpha-receptor stimulation caused an increase in total coronary vascular resistance; however, the relative increase in the resistance of the large vessel was only about 60% of that seen for the entire coronary bed. These data suggest that, contrary to the proposed hypothesis, adrenergic alpha-receptor-mediated vasoconstriction in the large coronary vessels is not proportionally greater than that observed in the total coronary vascular bed.
Integration of Two Ancestral Chaperone Systems into One: The Evolution of Eukaryotic Molecular Chaperones in Light of Eukaryogenesis
Authors: David Bogumil, David Alvarez-Ponce, Giddy Landan, James O. McInerney, Tal Dagan
Journal: Molecular Biology and Evolution (2013)

Eukaryotic genomes are mosaics of genes acquired from their prokaryotic ancestors, the eubacterial endosymbiont that gave rise to the mitochondrion and its archaebacterial host. Genomic footprints of the prokaryotic merger at the origin of eukaryotes are still discernable in eukaryotic genomes, where gene expression and function correlate with their prokaryotic ancestry. Molecular chaperones are essential in all domains of life as they assist the functional folding of their substrate proteins and protect the cell against the cytotoxic effects of protein misfolding. Eubacteria and archaebacteria code for slightly different chaperones, comprising distinct protein folding pathways. Here we study the evolution of the eukaryotic protein folding pathways following the endosymbiosis event. A phylogenetic analysis of all 64 chaperones encoded in the Saccharomyces cerevisiae genome revealed 25 chaperones of eubacterial ancestry, 11 of archaebacterial ancestry, 10 of ambiguous prokaryotic ancestry, and 18 that may represent eukaryotic innovations. Several chaperone families (e.g., Hsp90 and Prefoldin) trace their ancestry to only one prokaryote group, while others, such as Hsp40 and Hsp70, are of mixed ancestry, with members contributed from both prokaryotic ancestors. Analysis of the yeast chaperone-substrate interaction network revealed no preference for interaction between chaperones and substrates of the same origin. Our results suggest that the archaebacterial and eubacterial protein folding pathways have been reorganized and integrated into the present eukaryotic pathway. The highly integrated chaperone system of yeast is a manifestation of the central role of chaperone-mediated folding in maintaining cellular fitness. Most likely, both archaebacterial and eubacterial chaperone systems were essential at the very early stages of eukaryogenesis, and the retention of both may have offered new opportunities for expanding the scope of chaperone-mediated folding.
Are reports of “man flu” just <i>Nuts?</i>
Authors: Petra Boynton
Journal: BMJ (2006)

What's more worrying, the public believing in a manufactured illness or their not trusting genuine health research? 

We may have dismissed men as being overly dramatic when they claimed a cold as flu but last week a press release from Nuts magazine revealed that “man flu” does exist. The magazine, Britain's biggest men's weekly title, made the claim after conducting an online survey of its readers. 

The poll of 2131 readers showed that 64% of men suffer from a viral illness compared with just 45% of women. Men take on average three days to recover and women take on average …
Additive blockade of 2-integrin adhesion of eosinophils by salmeterol and fluticasone propionate
Authors: S. Myo, X. Zhu, S. Myou, A.Y. Meliton, J. Liu, E. Boetticher, A.T. Lambertino, C. Xu, N.M. Muñoz, A.R. Leff
Journal: European Respiratory Journal (2004)

Migration of human eosinophils is regulated by integrin expression, conformational change, and activation of cytosolic phospholipase A 2 (cPLA 2 ). Corticosteroids have been shown to inhibit cPLA 2 hydrolysis in human eosinophils. The objective of this study was to determine the mechanisms of fluticasone propionate (FP) alone or in combination with salmeterol (SM) in blocking adhesion mediated by β 2 ‐integrin in human eosinophils. Human eosinophils were isolated by negative magnetic selection. β 2 ‐integrin-mediated eosinophil adhesion was measured by residual eosinophil peroxidase activity. Eosinophils were pretreated for 12 h to 24 h with FP and with or without SM for 30 min. Both SM alone and FP alone inhibited eosinophil adhesion in concentration- and time-dependent manner. SM alone modestly (∼30%) inhibited interleukin (IL)‐5‐induced eosinophil adhesion. Blockade of IL‐5‐induced eosinophil adhesion caused by 10 −7 M FP at 24 h was augmented by 10 −7 M SM from 41.5% to 72.5%. Similar blockade was also observed for eotaxin-induced eosinophil adhesion. Neither SM, FP, nor FP+SM blocked either: 1) upregulation of CD11b surface expression; or 2) phosphorylation of cPLA 2 . Blockade of β 2 ‐integrin-mediated eosinophil adhesion by fluticasone propionate is augmented by salmeterol. Decreased adhesion results from augmented blockade of nuclear translocation of cytosolic phospholipase A 2 caused by addition of salmeterol to fluticasone.
Defective platelet aggregation and increased resistance to thrombosis in purinergic P2Y1 receptor–null mice
Authors: Catherine Léon, Béatrice Hechler, Monique Freund, Anita Eckly, Catherine Vial, Philippe Ohlmann, Andrée Dierich, Marianne LeMeur, Jean-Pierre Cazenave, Christian Gachet
Journal: Journal of Clinical Investigation (1999)

ADP is a key agonist in hemostasis and thrombosis. ADP-induced platelet activation involves the purinergic P2Y1 receptor, which is responsible for shape change through intracellular calcium mobilization. This process also depends on an unidentified P2 receptor (P2cyc) that leads to adenylyl cyclase inhibition and promotes the completion and amplification of the platelet response. P2Y1-null mice were generated to define the role of the P2Y1 receptor and to determine whether the unidentified P2cyc receptor is distinct from P2Y1. These mice are viable with no apparent abnormalities affecting their development, survival, reproduction, or the morphology of their platelets, and the platelet count in these animals is identical to that of wild-type mice. However, platelets from P2Y1-deficient mice are unable to aggregate in response to usual concentrations of ADP and display impaired aggregation to other agonists, while high concentrations of ADP induce platelet aggregation without shape change. In addition, ADP-induced inhibition of adenylyl cyclase still occurs, demonstrating the existence of an ADP receptor distinct from P2Y1. P2Y1-null mice have no spontaneous bleeding tendency but are resistant to thromboembolism induced by intravenous injection of ADP or collagen and adrenaline. Hence, the P2Y1 receptor plays an essential role in thrombotic states and represents a potential target for antithrombotic drugs.
Superparamagnetic maghemite nanoparticles from solid-state synthesis – Their functionalization towards peroral MRI contrast agent and magnetic carrier for trypsin immobilization
Authors: Katerina Kluchova, Radek Zboril, Jiri Tucek, Michaela Pecova, Ludmila Zajoncova, Ivo Safarik, Miroslav Mashlan, Ingrid Markova, Dalibor Jancik, Marek Sebela, Helena Bartonkova, Vassiliki Bellesi, Pavel Novak, Dimitris Petridis
Journal: Biomaterials (2009)
Drugs and oral disorders
Authors: Terry D. Rees
Journal: Periodontology 2000 (1998)

This chapter affirms that drugs and medicaments may have a profound effect on the periodontal structures. In some instances, such as drug-induced melanosis, the effect may be insignificant to the health of the patient. In other circumstances, drug-induced disorders may initiate painful, destructive disease processes that will not be successfully managed unless the causal role of drugs is recognized and altered. Finally, the clinician must remain aware of the contribution of drug-induced xerostomia and smoking to increased susceptibility to dental and periodontal diseases.
A Combination of Chemoimmunotherapies Can Efficiently Break Self-Tolerance and Induce Antitumor Immunity in a Tolerogenic Murine Tumor Model
Authors: Hyun-Jeong Ko, Yeon-Jeong Kim, Yun-Sun Kim, Woo-Sung Chang, Sung-Youl Ko, Sun-Young Chang, Shimon Sakaguchi, Chang-Yuil Kang
Journal: Cancer Research (2007)

Abstract Her-2/neu is a well-characterized tumor-associated antigen overexpressed in human carcinomas such as breast cancer. Because Her-2/neu is a self-antigen with poor immunogenicity due to immunologic tolerance, active immunotherapy targeting Her-2/neu should incorporate methods to overcome immunologic tolerance to self-proteins. In this study, we developed a tolerogenic tumor model in mice using mouse Her-2/neu as self-antigen and investigated whether genetic vaccination with DNA plasmid and/or adenoviral vector expressing the extracellular and transmembrane domain of syngeneic mouse Her-2/neu or xenogenic human Her-2/neu could induce mouse Her-2/neu–specific CTL responses. Interestingly, adenoviral vectors expressing xenogenic human Her-2/neu (AdhHM) proved capable of breaking immune tolerance and of thereby inducing self-reactive CTL and antibodies, but not to the degree required to induce therapeutic antitumor immunity. In attempting to generate therapeutic antitumor immunity against established tumors, we adopted several approaches. Treatment with agonistic anti-glucocorticoid-induced TNFR family-related receptor (GITR) antibody plus AdhHM immunization significantly increased self-reactive CTL responses, and α-galactosylceramide (αGalCer)–loaded dendritic cells (DC) transduced with AdhHM were shown to break self-tolerance in a tolerogenic murine tumor model. Furthermore, gemcitabine treatment together with either AdhHM plus agonistic anti-GITR antibody administration or αGalCer-loaded DC transduced with AdhHM showed potent therapeutic antitumor immunity and perfect protection against preexisting tumors. Gemcitabine treatment attenuated the tumor-suppressive environment by eliminating CD11b+/Gr-1+ myeloid-derived suppressor cells. When combined with immunotherapies, gemcitabine offers a promising strategy for the Ag-specific treatment of human cancer. [Cancer Res 2007;67(15):7477–86]
Measures of Arterial Stiffness in Youth With Type 1 and Type 2 Diabetes
Authors: R. Paul Wadwa, Elaine M. Urbina, Andrea M. Anderson, Richard F. Hamman, Lawrence M. Dolan, Beatriz L. Rodriguez, Stephen R. Daniels, Dana Dabelea
Journal: Diabetes Care (2010)

OBJECTIVE Arterial stiffness occurs early in the atherosclerotic process; however, few data are available concerning risk factors for arterial stiffness in youth with diabetes. We identified factors associated with arterial stiffness in youth with diabetes and assessed the effects of these factors on the relationship between arterial stiffness and diabetes type (type 1 vs. type 2). RESEARCH DESIGN AND METHODS A subset of patients from the SEARCH for Diabetes in Youth study with type 1 (n = 535) and type 2 diabetes (n = 60), aged 10–23 years (52% male; 82% non-Hispanic white; diabetes duration 65 ± 49 months) had arterial stiffness, anthropometrics, blood pressure, fasting lipids, and A1C measured. Arterial stiffness was measured by brachial distensibility (brachD), pulse wave velocity (PWV), and augmentation index adjusted to heart rate of 75 beats/min (AI75). RESULTS Youth with type 2 diabetes had worse brachD (5.2 ± 0.9 vs. 6.1 ± 1.2%/mmHg), PWV (6.4 ± 1.3 vs. 5.3 ± 0.8 m/s), and AI75 (6.4 ± 9.9 vs. 2.2 ± 10.2%) than those with type 1 diabetes (P &amp;lt; 0.01 for each). These differences were largely mediated through increased central adiposity and higher blood pressure in youth with type 2 diabetes. We also found a pattern of association of arterial stiffness measures with waist circumference and blood pressure, independent of diabetes type. CONCLUSIONS Youth with type 2 diabetes have worse arterial stiffness than similar youth with type 1 diabetes. Increased central adiposity and blood pressure are associated with measures of arterial stiffness, independent of diabetes type. Whether these findings indicate that youth with type 2 diabetes will be at higher risk for future complications requires longitudinal studies.
Structural basis for the killing of human beta cells by CD8+ T cells in type 1 diabetes
Authors: Anna M Bulek, David K Cole, Ania Skowera, Garry Dolton, Stephanie Gras, Florian Madura, Anna Fuller, John J Miles, Emma Gostick, David A Price, Jan W Drijfhout, Robin R Knight, Guo C Huang, Nikolai Lissin, Peter E Molloy, Linda Wooldridge, Bent K Jakobsen, Jamie Rossjohn, Mark Peakman, Pierre J Rizkallah, Andrew K Sewell
Journal: Nature Immunology (2012)
p21-Activated Kinase Increases the Calcium Sensitivity of Rat Triton-Skinned Cardiac Muscle Fiber Bundles via a Mechanism Potentially Involving Novel Phosphorylation of Troponin I
Authors: Nina Buscemi, D. Brian Foster, Irina Neverova, Jennifer E. Van Eyk
Journal: Circulation Research (2002)

Phosphorylation of myofilament proteins by kinases such as cAMP-dependent protein kinase and protein kinase C has been shown to lead to altered thin-filament protein-protein interactions and modulation of cardiac function in vitro. In the present study, we report that a small GTPase-dependent kinase, p21-activated kinase (PAK), increases the calcium sensitivity of Triton-skinned cardiac muscle fiber bundles. Constitutively active PAK3 caused an average 1.25-fold (25.0±6.0%, n=6) increase in force at pCa 5.75, 1.44-fold (44.0±7.78%, n=6) at pCa 6.25, and 2.41-fold (141.2±23.7%, n=4) at pCa 6.5, representing a change in pCa 50 value of approximately 0.25. Constitutively active PAK3 produced no change in force under conditions of relaxation (pCa 8.0) or maximal contraction (pCa 4.5). Furthermore, an inactive, kinase-dead form of PAK3 failed to produce any change in force development at any pCa value. The myofilament proteins phosphorylated by PAK3, at pCa 6.5, are desmin, troponin T, troponin I, and an unidentified 70-kDa protein. Importantly, cardiac troponin I was found to be phosphorylated at serine 149 of human cardiac troponin I, representing a novel phosphorylation site. These findings suggest a novel mechanism of modulating the calcium sensitivity of cardiac muscle contraction.
A Viral Vaccine Encoding Prostate-Specific Antigen Induces Antigen Spreading to a Common Set of Self-Proteins in Prostate Cancer Patients
Authors: Nancy J. Nesslinger, Alvin Ng, Kwong-Yok Tsang, Theresa Ferrara, Jeffrey Schlom, James L. Gulley, Brad H. Nelson
Journal: Clinical Cancer Research (2010)

We previously reported a randomized phase II clinical trial combining a poxvirus-based vaccine encoding prostate-specific antigen (PSA) with radiotherapy in patients with localized prostate cancer. Here, we investigate whether vaccination against PSA induced immune responses to additional tumor-associated antigens and how this influenced clinical outcome.Pretreatment and posttreatment serum samples from patients treated with vaccine + external beam radiation therapy (EBRT) versus EBRT alone were evaluated by Western blot and serologic screening of a prostate cancer cDNA expression library (SEREX) to assess the development of treatment-associated autoantibody responses.Western blotting revealed treatment-associated autoantibody responses in 15 of 33 (45.5%) patients treated with vaccine + EBRT versus 1 of 8 (12.5%) treated with EBRT alone. SEREX screening identified 18 antigens, which were assembled on an antigen array with 16 previously identified antigens. Antigen array screening revealed that 7 of 33 patients (21.2%) treated with vaccine + EBRT showed a vaccine-associated autoantibody response to four ubiquitously expressed self-antigens: DIRC2, NDUFS1, MRFAP1, and MATN2. These responses were not seen in patients treated with EBRT alone, or other control groups. Patients with autoantibody responses to this panel of antigens had a trend toward decreased biochemical-free survival.Vaccine + EBRT induced antigen spreading in a large proportion of patients. A subset of patients developed autoantibodies to a panel of four self-antigens and showed a trend toward inferior outcomes. Thus, cancer vaccines directed against tumor-specific antigens can trigger autoantibody responses to self-proteins, which may influence the efficacy of vaccination.
Lung Function in Rescue Workers at the World Trade Center after 7 Years
Authors: Thomas K. Aldrich, Jackson Gustave, Charles B. Hall, Hillel W. Cohen, Mayris P. Webber, Rachel Zeig-Owens, Kaitlyn Cosenza, Vasilios Christodoulou, Lara Glass, Fairouz Al-Othman, Michael D. Weiden, Kerry J. Kelly, David J. Prezant
Journal: New England Journal of Medicine (2010)

The terrorist attacks on the World Trade Center on September 11, 2001, exposed thousands of Fire Department of New York City (FDNY) rescue workers to dust, leading to substantial declines in lung function in the first year. We sought to determine the longer-term effects of exposure.Using linear mixed models, we analyzed the forced expiratory volume in 1 second (FEV(1)) of both active and retired FDNY rescue workers on the basis of spirometry routinely performed at intervals of 12 to 18 months from March 12, 2000, to September 11, 2008.Of the 13,954 FDNY workers who were present at the World Trade Center between September 11, 2001, and September 24, 2001, a total of 12,781 (91.6%) participated in this study, contributing 61,746 quality-screened spirometric measurements. The median follow-up was 6.1 years for firefighters and 6.4 years for emergency-medical-services (EMS) workers. In the first year, the mean FEV(1) decreased significantly for all workers, more for firefighters who had never smoked (a reduction of 439 ml; 95% confidence interval [CI], 408 to 471) than for EMS workers who had never smoked (a reduction of 267 ml; 95% CI, 263 to 271) (P<0.001 for both comparisons). There was little or no recovery in FEV(1) during the subsequent 6 years, with a mean annualized reduction in FEV(1) of 25 ml per year for firefighters and 40 ml per year for EMS workers. The proportion of workers who had never smoked and who had an FEV(1) below the lower limit of the normal range increased during the first year, from 3% to 18% for firefighters and from 12% to 22% for EMS workers, stabilizing at about 13% for firefighters and 22% for EMS workers during the subsequent 6 years.Exposure to World Trade Center dust led to large declines in FEV(1) for FDNY rescue workers during the first year. Overall, these declines were persistent, without recovery over the next 6 years, leaving a substantial proportion of workers with abnormal lung function.
Genital porokeratosis: a series of 10 patients and review of the literature
Authors: T-J. Chen, Y-C. Chou, C-H. Chen, T-T. Kuo, H-S. Hong
Journal: British Journal of Dermatology (2006)

Background Porokeratosis (PK) is an uncommon disorder of epidermal keratinization with a unique clinical appearance, unknown aetiology, and an unpredictable outcome. Genital PK (defined as localized PK confined to the genital area in this study) is extremely rare and is not well documented. Objectives To evaluate the clinical manifestations, histopathology, clinical course and treatment response for genital PK. Methods We reviewed the clinicohistological data from 10 patients with genital PK seen at Chang Gung Memorial Hospital from 1990 to 2005. Results Seven patients had lesions only in the genital area, and three patients had genital and adjacent areas involved. All patients were male and the mean age at initial diagnosis was 46·0 years (range 36–59). All but one patient presented with pruritic lesions. Three patients (30%) had diabetes mellitus. No malignant transformation was observed. Surgical excision was the most effective treatment if it could be performed. Conclusions Genital PK appeared more frequently in the Asian population than in reports from western countries. Genital PK presented mostly as pruritic lesions in Taiwan, with a wide age distribution. Long-term follow-up might be needed.