tbuckley/cabot-search huggingface dataset:
Macrophage Inflammatory Protein 3α Is Involved in the Constitutive Trafficking of Epidermal Langerhans Cells
Authors: Anne-Sophie Charbonnier, Norbert Kohrgruber, Ernst Kriehuber, Georg Stingl, Antal Rot, Dieter Maurer
Journal: The Journal of Experimental Medicine (1999)

Certain types of dendritic cells (DCs) appear in inflammatory lesions of various etiologies, whereas other DCs, e.g., Langerhans cells (LCs), populate peripheral organs constitutively. Until now, the molecular mechanism behind such differential behavior has not been elucidated. Here, we show that CD1a(+) LC precursors respond selectively and specifically to the CC chemokine macrophage inflammatory protein (MIP)-3alpha. In contrast, CD14(+) precursors of DC and monocytes are not attracted by MIP-3alpha. LCs lose the migratory responsiveness to MIP-3alpha during their maturation, and non-LC DCs do not acquire MIP-3alpha sensitivity. The notion that MIP-3alpha may be responsible for selective LC recruitment into the epidermis is further supported by the following observations: (a) MIP-3alpha is expressed by keratinocytes and venular endothelial cells in clinically normal appearing human skin; (b) LCs express CC chemokine receptor (CCR)6, the sole MIP-3alpha receptor both in situ and in vitro; and (c) non-LC DCs that are not found in normal epidermis lack CCR6. The mature forms of LCs and non-LC DCs display comparable sensitivity for MIP-3beta, a CCR7 ligand, suggesting that DC subtype-specific chemokine responses are restricted to the committed precursor stage. Although LC precursors express primarily CCR6, non-LC DC precursors display a broad chemokine receptor repertoire. These findings reflect a scenario where the differential expression of chemokine receptors by two different subpopulations of DCs determines their functional behavior. One type, the LC, responds to MIP-3alpha and enters skin to screen the epidermis constitutively, whereas the other type, the "inflammatory" DC, migrates in response to a wide array of different chemokines and is involved in the amplification and modulation of the inflammatory tissue response.
UK response to H1N1 pandemic was highly satisfactory, independent review says
Authors: J. Wise
Journal: BMJ (2010)

The United Kingdom’s response to the 2009 H1N1 flu pandemic, which cost £1.2bn (€1.5bn; $1.8bn), was highly satisfactory and good value for money, concludes an independent review. But any purchasing for future pandemics should allow greater flexibility, it adds.

The review, by Deirdrie Hine, a former chief medical officer for Wales, says that preparations, including stockpiling drugs and plans to buy up to 132 million doses of vaccine, were “soundly based in terms of value for money, reflecting the inherently low cost of vaccination in relation to the value of lives saved.”

Around £1bn was spent on pharmaceuticals, including antivirals, antibiotics, and vaccines. More than 30 million doses of vaccine are believed to be left over, as the swine flu pandemic virus proved far milder in its effects than expected.

Dame Deirdrie said that lessons needed to be learnt …
Abstract 1235: Targeting the DNA binding domain of the androgen receptor as a potential therapy for prostate cancer
Authors: Kush Dalal, Huifang Li, Mani R. Moniri, Fuqiang Ban, Aishwariya Sharma, Artem Cherkasov, Paul S. Rennie
Journal: Cancer Research (2014)

Abstract The Androgen Receptor (AR) is a ligand inducible transcription factor that drives expression of genes contributing to the growth, recurrence and metastasis of prostate cancer (PCa). The AR is activated by steroid hormones (androgens) that bind to a C-terminal ligand-binding domain (LBD) and cause the transcription factor to enter the nucleus, dimerize and interact with DNA via its conserved DNA-binding domain (DBD). Accordingly, treatment for PCa involves reducing DHT production or using small molecules (i.e. antiandrogens) to compete with the specific interaction between hormones and the AR-LBD, preventing AR activation. This treatment will eventually fail as recurrent PCa changes into a castration resistant form (CRPC) where AR signalling continues even in the absence of androgens. The occurrence of CRPC is driven, in part, by mutations in the AR-LBD that alter the binding of antiandrogens, or by the presence of constitutively active AR splice variants that lack the LBD, effectively removing the site of action of conventional antiandrogens. Here, we describe a surface exposed pocket on the AR-DBD, based on its 3D-crystal structure, which may qualify as an alternative target for small molecule inhibitors of AR transcriptional activity. Following virtual screening of many compounds, we characterize the interaction of the AR-DBD with various potential inhibitors and measure the efficacy of these agents to block the transcriptional activity of both full-length and splice variant AR in cell culture. Drug-inhibition was reduced upon site-directed mutagenesis of amino-acid residues in the DBD that are suspected of interacting with the compounds. Biochemical approaches are used to further examine the physical interaction of the purified AR-DBD protein with small molecules and to investigate their effect on protein-DNA interactions in vitro. Lastly, we use confocal microscopy of live PCa cells to investigate the effect of our compounds on the spatial localization and dimerization of fluorescently tagged AR proteins. These results illustrate the feasibility of targeting the AR-DBD to potentially inhibit the reactivation of AR transcriptional activity that is observed in CRPC. Citation Format: Kush Dalal, Huifang Li, Mani R. Moniri, Fuqiang Ban, Aishwariya Sharma, Artem Cherkasov, Paul S. Rennie. Targeting the DNA binding domain of the androgen receptor as a potential therapy for prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1235. doi:10.1158/1538-7445.AM2014-1235
Resources must be diverted to allow people to die at home
Authors: C. Dyer
Journal: BMJ (2008)

Thousands of dying patients a year are unnecessarily admitted to hospital in England even though the money spent could be used to provide the care at home that most people want at the end of their lives, according to a report this week from the National Audit Office.

The watchdog for public spending blamed the lack of 24 hour response services and poor coordination between health and social care services for condemning many people who would prefer to die at home to ending their lives in hospital.

Research indicates that between 56% and 74% of people would prefer to die at home. But 58% …
Abstract A53: Alpha particles and induction of an antitumor immune response.
Authors: Jean-Baptiste Gorin, Sébastien Gouard, Michel Chérel, Alain Faivre-Chauvet, Jérémie Ménager, Alfred Morgenstern, Frank Bruchertseifer, François Davodeau, Joëlle Gaschet
Journal: Cancer Research (2013)

Abstract Objectives: Radioimmunotherapy (RIT) is an approach allowing targeting of radioelements to tumours, usually through the use of antibodies specific for tumour antigens. The radiations emitted by the radioelements then induce direct killing of the targeted cells as well as indirect killing through bystander effect. Interestingly, it has been shown that ionizing radiation, in some settings of external radiotherapy, can foster an immune response directed against tumour cells. Our research team is dedicated to the development of alpha RIT, i.e RIT using alpha particle emitters, we therefore decided to study the effects of such particles on tumour cells in regards to their immunogenicity. Material and Methods: We studied the effects of bismuth-213, an alpha emitter, on cellular death and autophagy in a mouse (5T33) and a human (LP-1) myeloma cell line. Using flow cytometry analysis, we measured the expression of MHC molecules and several DAMPs at the cell surface to determine whether irradiation with bismuth-213 could cause the tumour cells to be recognized by the immune system. We also tested the irradiated cell culture media by ELISA to check whether DAMPs were secreted after treatment with bismuth-213. Finally, a co-culture of dendritic cells with irradiated tumour cells or their culture media was performed to test whether it would induce dendritic cell activation. Results: Only slight levels of apoptosis and necrosis were detected within the 48 hours following irradiation in the studied cell lines, however they both exhibited signs of autophagy. No increase in membrane or extracellular expression of DAMPs was observed after treatment with bismuth-213, or in the expression of MHC class I and II. However, the co-culture experiments indicated that soluble factors are released in the culture media after irradiation with bismuth-213, which are able to induce dendritic cell activation. Conclusion: These data suggest that alpha particles would be of interest in rising an immune response associated to RIT. Citation Format: Jean-Baptiste Gorin, Sébastien Gouard, Michel Chérel, Alain Faivre-Chauvet, Jérémie Ménager, Alfred Morgenstern, Frank Bruchertseifer, François Davodeau, Joëlle Gaschet. Alpha particles and induction of an antitumor immune response. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr A53.
Shark cartilage in the water
Authors: Jonathan Waxman
Journal: BMJ (2006)

It is estimated that up to 80% of all patients with cancer take a complementary treatment or follow a dietary programme to help treat their cancer. These treatments may often delay the institution of conventional therapy and may result from pressure from family and friends to try an alternative approach to the conventional. 

The NHS Directory of Complementary and Alternative Practitioners lists 29 directories, which include “Flower Therapy” and “Dowsing.” Alternative Medicine is big business, with a market value in the UK alone of £250m in the year 2005. The current prediction is that sales will increase by 7% per annum. The rationale for the use of many of these approaches is obtuse—one might even be tempted to write misleading. It is difficult to provide any sort of objective rationale whatsoever for the sales of any of these products. Indeed the claims made by companies to support the sales of such products may be overtly and malignly incorrect …
Sympathetic Control of Cerebral Blood Flow in Dogs
Authors: Louis G. D'Alecy, Eric O. Feigl
Journal: Circulation Research (1972)

The effect of sympathetic stimulation on cerebral blood flow was investigated in dogs anesthetized with chloralose. A preparation has been developed for the moment-to-moment measurement of cerebral venous outflow with an electromagnetic flow transducer. The brain's arterial supply was left undisturbed. The sympathetic innervation of the cerebral vessels was stimulated at the stellate ganglion (3-9 v, 3 msec, and 1, 3, 6, 10, and 15 Hz for 60 or 90 seconds). Stimulation at 15 Hz resulted in an average decrease in cerebral blood flow of 79.7%. During stimulation the arterial oxygen tension decreased from 93.2 to 84.9 mm Hg, the arterial carbon dioxide tension increased from 32.9 to 34.6 mm Hg, and arterial pH fell from 7.392 to 7.378. These changes in blood gas variables all opposed the observed vasoconstriction. Interactions between intracranial pressure and sympathetic cerebral vasoconstriction were evaluated by measuring cerebrospinal fluid pressure and cerebral venous outflow pressure. Stimulation of the left sympathetic stellate ganglion produced a 64% decrease in cerebral blood flow and an 8 mm Hg increase in intracranial pressure. Infusion of saline into the cisterna magna, raising intracranial pressure to 47 mm Hg, produced a 3% decrease in cerebral blood flow. Opening the cerebrospinal fluid space and thus fixing intracranial pressure at zero (atmospheric pressure) did not alter the cerebral blood flow response to sympathetic stimulation. It was concluded that stimulation of the sympathetic stellate ganglion resulted in cerebral vasoconstriction which was independent of changes in arterial P CO 2 , Po 2 , and pH and was also independent of changes in cerebrospinal fluid pressure.
Pathologic Effects of Exposure to High Oxygen Tensions
Authors: J. Douglas Balentine
Journal: New England Journal of Medicine (1966)

FOR the past several decades there has been increasing interest in the therapeutic use of hyperbaric oxygenation in many hypoxic and some infectious and neoplastic diseases in man.1 2 3 4 5 6 7 Although the overall application of such a therapeutic approach has not been fully assessed, there have been some encouraging results, and it is likely that there will be continued interest in this field.Oxygen at high pressure has been known for some time to have detrimental effects that impose definite limiting factors on its usefulness. Biochemically, oxygen has been well established as a toxin that interferes with certain specific enzyme systems.8 9 10 Pathologic . . .
The problems of cognitive dynamical models
Authors: Jean Petitot
Journal: Behavioral and Brain Sciences (1995)

Abstract Amit's “Attractor Neural Network” perspective on cognition raises difficult technical problems already met by prior dynamical models. This commentary sketches briefly some of them concerning the internal topological structure of attractors, the constituency problem, the possibility of activating simultaneously several attractors, and the different kinds of dynamical structures one can use to model brain activity: point attractors, strange attractors, synchronized arrays of oscillators, synfire chains, and so forth.
Hypoglycemia and Counterregulation in Insulin-Dependent Diabetic Patients: A Comparison of Continuous Subcutaneous Insulin Infusion and Conventional Insulin Injection Therapy
Authors: S Ng Tang Fui, J C Pickup, J J Bending, Andrea C G Collins, H Keen, N Dalton
Journal: Diabetes Care (1986)

Eleven insulin-dependent diabetic patients were treated in random order by 2-mo continuous subcutaneous insulin infusion (CSII) or 2-mo conventional injection treatment (CIT)with crossover to the alternative regimen. Mean plasma glucose concentrations throughout the day were significantly lower during CSII than during CIT, but the percentage of plasma glucose values &amp;lt;2.5 mmol/L, obtained from outpatient self-collected diurnal profiles, was similar for both treatments (CSII vs. CIT: 5.9 and 4.8%, respectively). Reported symptomatic hypoglycemia at home was not significantly different in the whole group of patients treated by CSII or CIT but was reduced by a mean of 57% (P &amp;lt; .02) in the five patients on CSII who experienced frequent symptomatic hypoglycemic episodes (&amp;gt;4/2 mo) during CIT. Neither the plasma glucose concentration at which the patients recognizedinduced hypoglycemia nor the glycemic or counterregulatory hormone responses for 60 min thereafter were changed by CSII treatment.
Potential Dangers in the Uncontrolled Use of Shoe-Fitting Fluoroscopes
Authors: L. H. Hempelmann
Journal: New England Journal of Medicine (1949)

THREE types of radiation injuries may result from the uncontrolled use of low-voltage x-ray machines in shoe stores in the manner described by Dr. Williams in the preceding article. The most likely injuries are interference with normal foot development of children who are fluoroscoped repeatedly when being fitted with new shoes; acute radiation burns of the customer's feet resulting in late permanent skin damage; chronic radiation injury of the blood-forming tissue of store employees who work with improperly shielded x-ray machines. Little is known concerning possible effects of this type of radiation on the sex glands. Some of the unusual . . .
Association of Adenotonsillectomy with Asthma Outcomes in Children: A Longitudinal Database Analysis
Authors: Rakesh Bhattacharjee, Beatrix H. Choi, David Gozal, Babak Mokhlesi
Journal: PLoS Medicine (2014)

Rakesh Bhattacharjee and colleagues use data from a US private health insurance database to compare asthma severity measures in children one year before and one year after they underwent adenotonsillectomy with asthma measures in those who did not undergo adenotonsillectomy. Please see later in the article for the Editors' Summary
AN ELECTROPHORETIC STUDY OF URINARY PROTEIN IN THE RAT
Authors: Alvin L. Sellers, Sidney Roberts, Irene Rask, Stephen Smith, Jessie Marmorston, Howard C. Goodman
Journal: The Journal of Experimental Medicine (1952)

The nature of the proteins present in the urine of the normal rat has been investigated by electrophoretic analysis and by fractional precipitation of these proteins by ammonium sulfate. Components similar to serum alpha- and beta-globulin constitute the major portion of the urinary protein in both male and female rats. Following the intraperitoneal injection of renin, a massive proteinuria occurs. The proteins excreted are similar in proportion and electric mobility to those of normal rat serum.
RELEASE OF CARTILAGE MUCOPOLYSACCHARIDE-DEGRADING NEUTRAL PROTEASE FROM HUMAN LEUKOCYTES
Authors: A. Oronsky, L. Ignarro, R. Perper
Journal: The Journal of Experimental Medicine (1973)

The granule fraction of human leukocytes contains neutral protease capable of degrading the noncollagenous protein mucopolysaccharide matrix of cartilage at neutral pH in physiological salt solution. Cartilage degradation was monitored by quantitating the release of (35)S from labeled rabbit ear cartilage. Degradation of cartilage matrix occurs when intact viable human leukocytes are incubated with cartilage opsonized with aggregated human gamma globulin (AHGG). During a similar 4 h incubation period cells did not degrade uncoated cartilage or cartilage coated with nonaggregated gamma globulin. Cells remain viable during the enzyme release process as evidenced by the absence of a cytoplasmic enzyme marker (lactic dehydrogenase) in the supernatant and dye exclusion studies. The release of (35)S from labeled cartilage by human leukocytes in the presence of cartilage coated with AHGG (nonphagocytic enzyme release) was compared with the cartilage degrading activity of the supernatant from the same number of cells preincubated with a suspension of AHGG (phagocytic enzyme release). Nonphagocytic enzyme release by 5 x 10(6) cells provoked two to four times more (35)S and beta-glucuronidase (beta-G) release from cartilage than phagocytic enzyme release conditions. beta-glucuronidase was used as an indicator of the release of lysosomal granule enzymes. By the use of selected pharmacological agents it was possible to dissociate the enzyme release process from intrinsic enzyme (neutral protease) activity. Neutral protease and beta-G release by human cells in the presence of AHGG-coated cartilage was inhibited by 10(-5)M colchicine, whereas the protease activity, but not the release process, was inhibited by 10(-6)M gold thiomalate and 10% human serum. It is suggested that the release of a cartilage degrading neutral protease by viable human cells when exposed to AHGG might be a relevant model for the study of cartilage destruction as it occurs in rheumatoid arthritis.
At the Doctor's Office
Authors: Andrew N. Wilner
Journal: Annals of Internal Medicine (1995)

Ad Libitum1 September 1995At the Doctor's OfficeAndrew N. Wilner, MDAndrew N. Wilner, MDCharlotte, NC 28203Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-123-5-199509010-00012 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail “I can't thread the needle, doctor.”“She can't even see the TV,” daughter says.“I'm afraid to drive, doctor.”“She can't cross the street alone,” daughter laments.“I trip on the stairs, doctor.”“The cataract surgery didn't help,” daughter sighs.And then, in darkness the doctor performs the examination. Lights on, and one question:“How old are you?”“Ninety-three next week, with God's help,” she replies hesitantly, still secretive from a lifetime of girlish habit.“I'd like some new glasses for my birthday,” she adds.And then, the diagnosis:It's old age. No glasses, no operation, nothing ... Author, Article, and Disclosure InformationAffiliations: Charlotte, NC 28203 PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 September 1995Volume 123, Issue 5Page: 388-388KeywordsCataract surgeryHabitsMacular degenerationRetinaThoraxVision ePublished: 15 August 2000 Issue Published: 1 September 1995 Copyright & PermissionsCopyright © 1995 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
821. Successful Adaptation of the RCAS-TVA Gene Transfer System for Use in a Bovine Mammary Epithelial Cell Culture Model
Authors: Peta M. Phillips, Peter C. Wynn, Paul A. Sheehy
Journal: Molecular Therapy (2006)

The RCAS-TVA gene transfer system is based on a recombinant avian leucosis virus which is produced by the replication-competent avian splice acceptor vector, RCAS, and requires the presence of the avian subtype A receptor, TVA, for infection. Mammalian cells can be infected, however this requires these cells to be engineered to express the TVA receptor. Significant biosafety features include the virus being replication competent only in avian cells as there is inefficient viral assembly in mammalian cells even in those modified for infection.
US changes polio vaccination programme
Authors: D. Johnson
Journal: BMJ (1997)

The United States Centers for Disease Control and Prevention has issued new guidelines for administering the polio vaccine after determining that nearly all cases of paralytic polio contracted recently in the country were caused by the oral polio vaccine.

Two types of polio vaccine are available: the Sabin vaccine consists of live attenuated virus, which is administered orally, and the Salk vaccine consists of inactivated …
Ageing, smoking and oxidative stress
Authors: J F Donohue
Journal: Thorax (2006)

The complex relationship between age, oxidative stress, duration of smoking cessation, and inflammatory markers

Chronic obstructive pulmonary disease (COPD) is the fifth leading cause of death worldwide and further increases in its prevalence and mortality are expected in the coming decades.1 Continued exposure to tobacco promotes a more rapid decline in lung function and, if exposure is stopped, the disease may still progress due to ageing and persistence of inflammation. The paper by Nagai et al 2 in this issue of Thorax adds to the growing body of evidence about damage from oxidative stress due to cigarette smoking. Changes can persist even after the last cigarette is extinguished. The effects are more noticeable in older smokers because of long term exposure to toxic gases and particles as they concurrently age. Oxidised glutathione associated with excessive protein carbonylation accumulates in the lungs of older smokers, raising the possibility that antioxidant defences could be overwhelmed.

The lungs are exposed continuously to oxidants generated either endogenously from phagocytes and other cell types or exogenously from air pollutants or cigarette smoke. Cigarette smoke contains 1017 oxidant molecules per puff.3 The oxidants in cigarette smoke cause lung injury by a number of mechanisms including the depletion of glutathione and other antioxidants, the initiation of redox cycling mechanisms, enhancement of the respiratory burst in neutrophils and macrophages, inactivation of protease inhibitors such as α1-antitrypsin inhibitor, and direct damage to lipids, nucleic acids and proteins.4 There is considerable evidence that the oxidative burden is increased in the lungs of patients with COPD and may be involved in the pathogenetic processes in the lung and in the systemic manifestations of …