tbuckley/cabot-search huggingface dataset:
The N-Terminal Juxtamembranous Domain of KCNQ1 Is Critical for Channel Surface Expression
Authors: Shehrazade Dahimène, Sébastien Alcoléa, Patrice Naud, Philippe Jourdon, Denis Escande, Robert Brasseur, Annick Thomas, Isabelle Baró, Jean Mérot
Journal: Circulation Research (2006)

N-terminal mutations in the KCNQ1 channel are frequently linked to fatal arrhythmias in newborn children and adolescents but the cellular mechanisms involved in this dramatic issue remain, however, to be discovered. Here, we analyzed the trafficking of a series of N-terminal truncation mutants and identified a critical trafficking motif of KCNQ1. This determinant is located in the juxtamembranous region preceding the first transmembrane domain of the protein. Three mutations (Y111C, L114P and P117L) implicated in inherited Romano-Ward LQT1 syndrome, are embedded within this domain. Reexpression studies in both COS-7 cells and cardiomyocytes showed that the mutant proteins fail to exit the endoplasmic reticulum. KCNQ1 subunits harboring Y111C or L114P exert a dominant negative effect on the wild-type KCNQ1 subunit by preventing plasma membrane trafficking of heteromultimeric channels. The P117L mutation had a less pronounced effect on the trafficking of heteromultimeric channels but altered the kinetics of the current. Furthermore, we showed that the trafficking determinant in KCNQ1 is structurally and functionally conserved in other KCNQ channels and constitutes a critical trafficking determinant of the KCNQ channel family. Computed structural predictions correlated the potential structural changes introduced by the mutations with impaired protein trafficking. In conclusion, our studies unveiled a new role of the N-terminus of KCNQ channels in their trafficking and its implication in severe forms of LQT1 syndrome.
Inhalation toxicity of vinyl chloride and Vinylidene chloride
Authors: C. C. Lee, J. C. Bhandari, J. M. Winston, W. B. House, P. J. Peters, R. L. Dixon, J. S. Woods
Journal: Environmental Health Perspectives (1977)

Exposure of mice to 1000 ppm of vinyl chloride (VC), 6 hr/day, 5 days/week, caused some acute deaths with toxic hepatitis and marked tubular necrosis of the renal cortex. Starting the sixth month, mice exposed to 1000, 250, or 50 ppm of VC became lethargic, lost weight quickly, and died. Only a few mice exposed to 50 ppm survived for 12 months. Pulmonary macrophage count was elevated in some mice. There was a high incidence of bronchiolo-alveolar adenoma, mammary gland tumors including ductular adenocarcinoma, squamous and anaplastic cell carcinomas with metastasis to the lung, and hemangiosarcoma in the liver, and, to a lesser extent, in some other organs. The incidence of these tumors quickly increased, and the severity was in direct proportion to the levels of VC and the length of exposure. Malignant lymphoma involving various organs was observed in a few mice.Rats were more resistant to the toxic effects of VC. Exposure to 1000 ppm slightly depressed the body weight of the females. Exposures of 250 or 1000 ppm caused a number of deaths and hemangiosarcoma in the liver starting the ninth month. Most rats with hepatic hemangiosarcoma also developed hemangiosarcoma in the lung. Hemangiosarcoma occasionally occurred in other tissues of one or two rats exposed to 50 ppm or higher level of VC.Exposure of mice to 55 ppm of vinylidene chloride (VDC) also caused a few acute deaths and a few hepatic hemangiosarcomas. Inflammatory, degenerative, and mitotic changes occurred in the liver. No mouse exposed to VDC developed any mammary gland tumors. Several mice had bronchioloalveolar adenoma. Exposure of rats to 55 ppm of VDC slightly depressed the body weight. Hemangiosarcoma occurred in the mesenteric lymph node or subcutaneous tissue in two rats.
Death, Dying, and the Biological Revolution: Our Last Quest for Responsibility
Authors: L. D. Hankoff
Journal: JAMA (1977)

In this volume Veatch has presented a well-knit review of the recent developments in the ethical and legal aspects surrounding the care of the dying person. He includes such topics as the definitions of death, lifeprolonging care of the moribund, the patient's rights to refuse treatment and to be informed of a fatal illness, and the medical uses of bodily parts. The book turns heavily (and somewhat repetitiously) on the various legal judgments derived from test cases in the different areas during the past two decades. The author perceives the subject as essentially a matter of law and makes a number of specific recommendations for legislation. He proposes, for example, a statutory definition of death (p 76) and a draft bill to permit refusal of medical treatment (p 199). As a readable compendium of these recent legal decisions pertaining to medical ethics in these areas, the book is extremely useful.
Role of adenosine in the maintenance of coronary vasodilation distal to a severe coronary artery stenosis. Observations in conscious domestic swine.
Authors: H Gewirtz, D L Brautigan, R A Olsson, P Brown, A S Most
Journal: Circulation Research (1983)

The purpose of this study was to test the hypothesis that adenosine is required to maintain arteriolar vasodilation distal to a severe coronary stenosis. Eight closed-chest conscious pigs were prepared by placing a 7.5-mm long stenosis (82% lumenal diameter reduction) in the proximal left anterior descending coronary artery. Regional myocardial blood flow (microsphere technique) was measured at control 1, after 10 minutes of intracoronary infusion of adenosine deaminase (7-10 U/kg per min) distal to the stenosis, and 20-30 minutes after stopping adenosine deaminase infusion. Studies with 125I-labeled adenosine deaminase were conducted in six additional pigs to document the extent to which infused adenosine deaminase penetrated the interstitial space. 125I-labeled adenosine deaminase was infused for 10 minutes (10-11 U/kg per min) into the left anterior descending coronary artery. Calculated interstitial fluid concentrations of adenosine deaminase ranged between 71 and 272 U/ml and were at least one order of magnitude greater than that required to deaminate all the adenosine which would be released into the interstitium in response to 15-30 seconds of coronary occlusion. In the primary group of animals (n = 8), endocardial flow (ml/min per g) distal to stenosis at control 1 (1.15 +/- 0.33) was reduced vs. endocardial flow in the nonobstructed circumflex zone (1.59 +/- 0.38, P less than 0.05). Flows in epicardial layers were comparable at control 1 (distal zone = 1.40 +/- 0.36 vs. circumflex zone = 1.45 +/- 0.41). Distal zone endocardial and epicardial flows did not change vs. control 1 in response to infusion of adenosine deaminase. However, the distal: circumflex epicardial flow ratio declined vs. control 1 (0.98 +/- 0.14) during adenosine deaminase infusion (0.87 +/- 0.17, P less than 0.05). The distal:circumflex endocardial flow ratio during adenosine deaminase (0.72 +/- 0.20) was unchanged vs. control 1 (0.76 +/- 0.22) but was less than control 2 (0.80 +/- 0.18, P less than 0.05). Thus, destruction of all or most interstitial adenosine caused only slight relative reduction in regional myocardial blood flow distal to a severe coronary artery stenosis. Accordingly, adenosine contributes only modestly to maintenance of arteriolar vasodilation in this setting or else its absence is almost fully compensated for by another mechanism(s).
Predicting Fetal Maturity
Authors: O. A. N. Husain, L. Sinclair
Journal: BMJ (1971)

nodes.This may well link up with the work done by Hawley et al.2 and Paile5 suggesting that some patients may do better because their cellular immune mechanisms are putting up resistance to the primary, and they may do well even if some metastases have reached a few local nodes.This is an important problem, because the surgeon at laparotomy who finds some palpable nodes near a resectable gastric tumour may well decide against radical local dis- section on the basis of an apparently hopeless prognosis ("glandular metastases").My study showed that where surgeons reported "malignant glands present," the histological findings in no less than 1: 3 patients were of OX or LTH status (and therefore a better prognosis).In other words, there are two reasons to continue with radical lymphatic surgery, even with palpable nodes.Firstly, they may be benign, and secondly, they may represent the minimal invasion and quite good prognosis situation.For those who can stand awful doggerel this may be sum- marized: "All that bulge are not maligne, Even be some so, do not pyne."May I also point out the fact that early diagnosis of gastric cancer, and greatly im- proved results in treatment, have been taken a stage further by the use of gastric cytology, with or without fibrescope collecting methodS.6 7-I am, etc.,
Abstract 1561: Leukemia cell-derived exosomes targeted dendritic cells can induce more strong anti-leukemia response than exosomes alone
Authors: Jing Sun, Linjun Chen, Xiaohui Deng, Siguo Hao
Journal: Cancer Research (2012)

Abstract Exosomes are the newest family number of ‘bioactive vesicles’ that play important roles in antigen presentation. Recent clinical trials about exosomes have shown minor clinical benefit. However, exosomes derived from leukemia cell lines were less studied, In this study, we investigated the biological properties and anti-leukemia immunity of leukemia cell-derived exosomes (LEX). The results showed that like other tumor cells, similarly, leukemia cells can release exosomes too. Transmission electron microscopy showed that exosomes derived from NB4 cell, a promyloblastic leukemia cell line and K562 cell, a chronic myeloid leukemia cell line were membrane vesicles with diameter about 50-100μm, and loading their specific moleculars such as RAR-α and ABL and adherent moleculars such as ICAM-1. Similarly, our data also demonstrated the presence of Hsp70 in these two leukemia cell-derived exosomes. The data from two-dimensional electrophoresis of K562 cell-derived exosomes showed that most of molecules expressing on leukemia cells were detected on their exosomes, indicating that LEX load most of proteins expressed on their original leukemia cells. Out data also demonstrated that LEX can induce anti-leukemia CTL response and LEX-targeted DC can induce more efficient anti-leukemia immunity compared with LEX alone. In conclusion, exosome-based therapies could be considered as a promising strategy to prolong disease-free survival in patients with leukemia after consolidation or hematopoietic stem cell transplantation. Note: This research work was supported by research grants from Shanghai Pujiang Project of Science and Technology Commission of Shanghai Municipality. Keywords: Exosome, leukemia cell, anti-leukemia immunity Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1561. doi:1538-7445.AM2012-1561
Thioredoxin reduces C‐C chemokine‐induced chemotaxis of human eosinophils
Authors: N. Kobayashi, Y. Yamada, W. Ito, S. Ueki, H. Kayaba, H. Nakamura, J. Yodoi, J. Chihara
Journal: Allergy (2009)

Human thioredoxin (TRX) is one of redox-active proteins that regulate reactive oxidative metabolisms. In recent study, we found that serum levels of TRX were elevated in asthmatic patients with exacerbation; however, few details are known about the physiological role of TRX in allergic inflammation, involving eosinophil infiltration.In the present study, we examined whether TRX modulated C-C chemokine-induced chemotaxis of human eosinophils.Eosinophils were isolated from subjects with mild eosinophilia by modified CD16 negative selection. After incubation with or without recombinant TRX, chemotaxis of human eosinophils was measured using Boyden chamber.Preincubation with TRX suppressed eotaxin- and regulated on activation, normal T-cell expressed and secreted (RANTES)-induced chemotaxis of eosinophils. Although, TRX had no effect on the expression of C-C chemokine receptor 3, which is a receptor of eotaxin and RANTES, we demonstrated that the activation of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinases, which play an important role in eosinophil migration, was attenuated by the treatment with TRX.Our results suggest that the elicited TRX is beneficial to reduce allergic inflammation through negative regulation of eosinophil functions and has potential in the treatment of allergic diseases, such as asthma.
Bethlem seeks home for collection of art by psychiatric patients
Authors: W. Moore
Journal: BMJ (2008)

A campaign to raise funds to provide a permanent new home for nearly 1000 works of art by psychiatric patients was launched in London this week. The collection, belonging to one of the world’s oldest hospitals, includes paintings by Richard Dadd and Louis Wain.

The Bethlem Museum, in Beckenham, south London, holds the United Kingdom’s only dedicated psychiatric art collection. The archives date back to 1559 from the Royal Bethlem Hospital, the original Bedlam, which was founded in London in …
Agonist-induced aggregation of Chinese hamster ovary cells coexpressing the human receptors for fibrinogen (integrin αIIbβ3) and the platelet-activating factor: dissociation between adhesion and aggregation
Authors: Susana Larrucea, Consuelo González-Manchón, Nora Butta, Elena G. Arias-Salgado, Linnan Shen, Matilde S. Ayuso, Roberto Parrilla
Journal: Blood (2002)

Abstract This work reports the establishment of a Chinese hamster ovary (CHO) cell line stably coexpressing the human αIIbβ3 integrin and the platelet-activating factor receptor (PAFR). These cells aggregate in response to PAF in a Ca++, αIIbβ3, and soluble fibrinogen (Fg)–dependent manner that is prevented by PAF antagonists or αIIbβ3 blockade. The aggregating response is accompanied by enhanced binding of fibrinogen and the activation-dependent IgM PAC1. This model has permitted us to identify, for the first time, intracellular signals distinctly associated with either αIIbβ3-mediated adhesion or aggregation. Nonreceptor activation of protein kinase C (PKC) by phorbol ester produced cellular adhesion and spreading onto immobilized Fg, but it was not a sufficient signal to provoke cellular aggregation. Moreover, inhibition of PKC impeded the PAF stimulation of cellular adhesion, whereas the aggregation was not prevented. The PAF-induced cellular aggregation was distinctly associated with signaling events arising from the liganded Fg receptor and the agonist-induced stimulation of a calcium/calmodulin-dependent signaling pathway. Sustained tyrosine phosphorylation of both mitogen-activated protein kinase (MAPK) and an approximately 100-kd protein was associated with the PAF-induced aggregation, whereas phosphorylation of focal adhesion kinase (FAK) was preferably associated with cellular adherence and spreading onto immobilized Fg.
Radiation Hazard in Industry
Authors: R. R. Newell
Journal: JAMA (1961)

PROTECTION from radiation cannot be complete, for we are convinced that even the radiation from the necessary potassium in our bodies produces random biological changes. However, we can hope to avoid unacceptable risks to the person exposed and to the genetic constitution of the race. We aim to avoid effects that a physician would deem unacceptable, and to incur no more than a negligible probability of severe injury. The probability of leukemia and carcinoma and of nonspecific injuries that shorten the average life-time does rise to an unacceptable level, we believe, after exposures that produce no observable acute effect. It is these late sequelae and the induction of gene mutations that determines our radiation hygiene. The requirement: "nothing that a physician would deem unacceptable"<sup>1</sup>is a concession to the general sentiment that even a little radiation is harmful. This is an inevitable paraphrase of what has become a scientific
Clinical benefits of long-term angiotensin II receptor blockade in patients with severe symptoms of congestive heart failure despite full angiotensin converting enzyme inhibition
Authors: G. Hamroff, I. Blaufarb, D. Mancini, S. Katz, R. Bijou, G. Jondeau, M.-T. Olivari, S. Thomas, T. LeJemtel
Journal: Journal of the American College of Cardiology (1998)
Is your MP concerned about public health?
Authors: A. Braillon, G. Dubois
Journal: BMJ (2011)

WHO has pledged to urge more countries to adopt large graphic health warnings on tobacco products1 because countries vary greatly in the use of such warnings.2

Canada was the first country to implement health warnings on cigarette packages in 2001,3 long before the Framework Convention on Tobacco Control, which came into force in 2005. The convention called …
Inhibition of allorecognition by a human class II MHC–derived peptide through the induction of apoptosis
Authors: Barbara Murphy, Colm C. Magee, Stephen I. Alexander, Ana Maria Waaga, Hans W. Snoeck, John P. Vella, Charles B. Carpenter, Mohamed H. Sayegh
Journal: Journal of Clinical Investigation (1999)

The interaction of the T-cell receptor with the major histocomatibility complex (MHC)–peptide complex is central to T-cell activation. Variation in the nature of the peptide bound within the groove of the MHC molecule may result in an altered T-cell response. Because some naturally processed peptides bound within the groove of the class II MHC molecule are derived from the MHC molecules themselves, we studied the inhibitory effects of synthetic class II MHC peptides on alloimmune responses in vitro. Three peptides derived from a highly conserved region of the class II MHC α chains inhibited the rat mixed lymphocyte response (MLR) in a dose-dependent manner, with the human HLA-DQA1 peptide also inhibiting the human and mouse MLR. No effect was seen on mitogen-induced T-cell proliferation. HLA-DQA1 inhibited cytolytic T lymphocyte (CTL) generation in a dose–response fashion, with no reduction in preformed CTL killing, suggesting that the inhibitory effect is targeted at CD4+ T-cell function. Cell-cycle analysis by flow cytometry showed that restimulation of primed T cells in the presence of HLA-DQA1 resulted in increased apoptosis, whereas unstimulated cells were not affected. These data demonstrate that synthetic peptides derived from highly conserved regions of the class II MHC α chain can alter CD4+ T-lymphocyte alloimmune responses in vitro, and this effect is mediated by the induction of apoptosis in activated T cells.
AB0106 The relationship between anemia in rheumatoid arthritis and fgf-23
Authors: I. S. Yoo, S. T. Song, H. J. Lee, J. Kim, S. W. Kang
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Rheumatoid arthritis (RA) is a chronic inflammatory disease that results in localized and generalized bone loss. Osteoporosis and anemia are one of the most common complications seen in patients with RA. <h3>Objectives</h3> The aim of this study was to identify the relationship between inflammation, hemoglobin, BMD loss and fibroblast growth factor (FGF)-23 that is a phosphaturic hormone. <h3>Methods</h3> This study included 42 patients with rheumatoid arthritis fulfilling the new American college of Rheumatology/European League Against Rheumatism diagnostic criteria for rheumatoid arthritis and 26 healthy volunteers as controls. All were subjected to a complete blood count, rheumatoid factor and/or anti-cyclic citru-llinated peptide antibody. The concentration of FGF-23 was measured by ELISA (Immuntopics Inc., CA USA). Dual-energy x-ray absorptiometry was used to measure bone mineral density (BMD) of the lumbar spine (L1-L4) at the time of recruitment. <h3>Results</h3> In comparison with control group, RA patients had elevated FGF-23 (p=0.041) and ESR (p&lt;0.0001). In RA group, BMD (p=0.037), hemoglobin (p=0.004), and albumin (p&lt;0.0001) were lower than control group. In both RA and Non-RA, ESR correlated negatively with BMD (r=-0.425, p=0.001), Hemoglobin (r=-0.473, p&lt;0.0001), and albumin (r=-0.552, p&lt;0.0001) and positively with FGF-23 (r=0.326, p=0.009). Also, Hemoglobin correlated negatively with FGF23 (r=-0.452, p&lt;-0.0001) and positively with BMD(r=0.332, p=0.006). In only RA group, ESR correlated negatively with BMD (r=-0.43, p=0.005), hemoglobin (p=-0.426, p=0.005), and albumin (r=-0.489, p=0.001) but not correlated with FGF-23. However, Hemoglobin correlated negatively with FGF-23 (r=-0.442, p=0.003). <h3>Conclusions</h3> In this study, Hemoglobin rather than inflammation is a negative predictor of plasma FGF-23 that is a potent regulator of the vitamin D and phosphate metabolism. Therefore, the association between ESR, anemia, FGF-23, and BMD loss in RA suggests a pathway between disease activity and BMD loss. <h3>Disclosure of Interest</h3> None Declared
Achieving self sufficiency in blood across Europe
Authors: J. Leikola
Journal: BMJ (1998)

methodology to show that individuals can actually repress memories of traumatic experiences.Of course, some might still argue that we have not disproved the possibility that repressed memories might occur.But this objection turns logic on its head: in the 500 years since William of Ockham first propounded his principles of parsimony, scientists have acknowledged that the burden of proof rests with whomever proposes a novel theory of causation, and not the reverse.Repression may be the stuff of Victorian novels and Hollywood movies, the darling of television dramas, and an object of widespread popular belief.But popular belief in repression does not spare investigators the burden of providing a rigorous, methodologically convincing demonstration of its existence.Until such a demonstration is provided, the recommendations of the royal college seem only prudent.
A new human genotype prone to variant Creutzfeldt-Jakob disease
Authors: Kumanan Wilson, Maura N Ricketts
Journal: BMJ (2006)

From the initial discovery of variant Creutzfeldt-Jacob disease (vCJD) in the United Kingdom a decade ago, there has been concern about the ultimate extent and magnitude of the epidemic.1 Early estimates varied widely, with one model predicting up to 136 000 cases.2 Fortunately, the magnitude of the epidemic at present seems to match the lower limit of the early estimates, with 161 definite or probable cases in the United Kingdom. However, the article by Ironside and colleagues on p 1186 may rekindle fears that a larger epidemic is an ongoing threat.3

The study reports a genotype analysis that identified the presence of the homozygous valine (VV) genotype in two samples of appendix tissue that harboured prion proteins. The implication of this finding of most concern is that it raises the possibility that ongoing iatrogenic transmission of vCJD may sustain the epidemic.

Why are the findings from this study worrisome? The current estimates of the prevalence of vCJD have primarily been restricted to populations with one specific genotype (MM), and all clinical cases have occurred in these individuals. This study is the first report of infection in individuals with the VV genotype. One case of infection, but not clinical disease, had been identified in one person with a heterozygous genotype (MV).4 The fear is that the 60% of people with non-MM genotypes may be at risk of developing the condition, possibly with longer incubation periods.5 Alternatively, these people may be asymptomatic carriers who might transmit the condition to other susceptible individuals.

It is important to be cautious in interpreting the results of this study. The study shows the existence of the prion protein in two tissue samples, not clinical evidence of vCJD in two patients. The study also provides no evidence to suggest that tissue from these two people could transmit vCJD to others.