tbuckley/cabot-search huggingface dataset:
Failed CTL/NK cell killing and cytokine hypersecretion are directly linked through prolonged synapse time
Authors: Misty R. Jenkins, Jesse A. Rudd-Schmidt, Jamie A. Lopez, Kelly M. Ramsbottom, Stuart I. Mannering, Daniel M. Andrews, Ilia Voskoboinik, Joseph A. Trapani
Journal: The Journal of Experimental Medicine (2015)

Failure of cytotoxic T lymphocytes (CTLs) or natural killer (NK) cells to kill target cells by perforin (Prf)/granzyme (Gzm)-induced apoptosis causes severe immune dysregulation. In familial hemophagocytic lymphohistiocytosis, Prf-deficient infants suffer a fatal “cytokine storm” resulting from macrophage overactivation, but the link to failed target cell death is not understood. We show that prolonged target cell survival greatly amplifies the quanta of inflammatory cytokines secreted by CTLs/NK cells and that interferon-γ (IFN-γ) directly invokes the activation and secondary overproduction of proinflammatory IL-6 from naive macrophages. Furthermore, using live cell microscopy to visualize hundreds of synapses formed between wild-type, Prf-null, or GzmA/B-null CTLs/NK cells and their targets in real time, we show that hypersecretion of IL-2, TNF, IFN-γ, and various chemokines is linked to failed disengagement of Prf- or Gzm-deficient lymphocytes from their targets, with mean synapse time increased fivefold, from ∼8 to &amp;gt;40 min. Surprisingly, the signal for detachment arose from the dying target cell and was caspase dependent, as delaying target cell death with various forms of caspase blockade also prevented their disengagement from fully competent CTLs/NK cells and caused cytokine hypersecretion. Our findings provide the cellular mechanism through which failed killing by lymphocytes causes systemic inflammation involving recruitment and activation of myeloid cells.
Employing vasopressin during cardiopulmonary resuscitation and vasodilatory shock as a lifesaving vasopressor
Authors: V Wenzel
Journal: Cardiovascular Research (2001)

Epinephrine during cardiopulmonary resuscitation (CPR) is being discussed controversially due to its β-receptor mediated adverse effects such as increased myocardial oxygen consumption, ventricular arrhythmias, ventilation-perfusion defect, postresuscitation myocardial dysfunction, ventricular arrhythmias and cardiac failure. In the CPR laboratory simulating adult pigs with ventricular fibrillation or postcountershock pulseless electrical activity, vasopressin improved vital organ blood flow, cerebral oxygen delivery, resuscitability, and neurological recovery better than did epinephrine. In paediatric preparations with asphyxia, epinephrine was superior to vasopressin, whereas in both paediatric pigs with ventricular fibrillation, and adult porcine models with asphyxia, combinations of vasopressin and epinephrine proved to be highly effective. This may suggest that a different efficiency of vasopressors in paediatric vs. adult preparations; and different effects of dysrhythmic vs. asphyxial cardiac arrest on vasopressor efficiency may be of significant importance. Whether these theories can be extrapolated to humans is unknown at this point in time. In patients with out-of-hospital ventricular fibrillation, a larger proportion of patients treated with vasopressin survived 24 h compared with patients treated with epinephrine; during in-hospital CPR, comparable short-term survival was found in groups treated with either vasopressin or epinephrine. Currently, a large trial of out-of-hospital cardiac arrest patients being treated with vasopressin vs. epinephrine is ongoing in Germany, Austria and Switzerland. The new CPR guidelines of both the American Heart Association, and European Resuscitation Council recommend 40 U vasopressin intravenously, and 1 mg epinephrine intravenously as equally effective for the treatment of adult patients in ventricular fibrillation; however, no recommendation for vasopressin was made to date for adult patients with asystole and pulseless electrical activity, and paediatrics due to lack of clinical data. When adrenergic vasopressors were unable to maintain arterial blood pressure in patients with vasodilatory shock, continuous infusions of vasopressin (∼0.04 to ∼0.1 U/min) stabilised cardiocirculatory parameters, and even ensured weaning from catecholamines.
NEK2 Induces Drug Resistance Mainly through Activation of Efflux Drug Pumps and Is Associated with Poor Prognosis in Myeloma and Other Cancers
Authors: Wen Zhou, Ye Yang, Jiliang Xia, He Wang, Mohamed E. Salama, Wei Xiong, Hongwei Xu, Shashirekha Shetty, Tiehua Chen, Zhaoyang Zeng, Lei Shi, Maurizio Zangari, Rodney Miles, David Bearss, Guido Tricot, Fenghuang Zhan
Journal: Cancer Cell (2013)
Effects of Early, Abrupt Weaning on HIV-free Survival of Children in Zambia
Authors: Louise Kuhn, Grace M. Aldrovandi, Moses Sinkala, Chipepo Kankasa, Katherine Semrau, Mwiya Mwiya, Prisca Kasonde, Nancy Scott, Cheswa Vwalika, Jan Walter, Marc Bulterys, Wei-Yann Tsai, Donald M. Thea
Journal: New England Journal of Medicine (2008)

In low-resource settings, many programs recommend that women who are infected with the human immunodeficiency virus (HIV) stop breast-feeding early. We conducted a randomized trial to evaluate whether abrupt weaning at 4 months as compared with the standard practice has a net benefit for HIV-free survival of children.We enrolled 958 HIV-infected women and their infants in Lusaka, Zambia. All the women planned to breast-feed exclusively to 4 months; 481 were randomly assigned to a counseling program that encouraged abrupt weaning at 4 months, and 477 to a program that encouraged continued breast-feeding for as long as the women chose. The primary outcome was either HIV infection or death of the child by 24 months.In the intervention group, 69.0% of the mothers stopped breast-feeding at 5 months or earlier; 68.8% of these women reported the completion of weaning in less than 2 days. In the control group, the median duration of breast-feeding was 16 months. In the overall cohort, there was no significant difference between the groups in the rate of HIV-free survival among the children; 68.4% and 64.0% survived to 24 months without HIV infection in the intervention and control groups, respectively (P=0.13). Among infants who were still being breast-fed and were not infected with HIV at 4 months, there was no significant difference between the groups in HIV-free survival at 24 months (83.9% and 80.7% in the intervention and control groups, respectively; P=0.27). Children who were infected with HIV by 4 months had a higher mortality by 24 months if they had been assigned to the intervention group than if they had been assigned to the control group (73.6% vs. 54.8%, P=0.007).Early, abrupt cessation of breast-feeding by HIV-infected women in a low-resource setting, such as Lusaka, Zambia, does not improve the rate of HIV-free survival among children born to HIV-infected mothers and is harmful to HIV-infected infants.(ClinicalTrials.gov number, NCT00310726.)
Steps forward in LRTI and tuberculosis: update from the ERS Respiratory Infections Assembly
Authors: F. Blasi, R. Cosentini, G. B. Migliori, W. Boersma
Journal: European Respiratory Journal (2009)

Lower respiratory tract infections (LRTIs) and tuberculosis are among the leading reasons for seeking medical care. In the present report, the most recent advances in the fields of clinical research and basic science of LRTIs and tuberculosis are presented through analysis of some of the best abstracts presented at the 18th European Respiratory Society Annual Congress in Berlin. The role of viruses in chronic obstructive pulmonary disease exacerbations and the importance of new biomarkers in the diagnosis of bacterial infections in LRTI are discussed. New tools for the diagnosis of latent and active tuberculosis in special subgroups of patients (children, immunocompromised individuals, etc.), and the new epidemiological threat of multidrug-resistant and extensively drug-resistant tuberculosis cases is analysed.
Regulation of Angiopoietin-2 mRNA Levels in Bovine Microvascular Endothelial Cells by Cytokines and Hypoxia
Authors: Stefano J. Mandriota, Michael S. Pepper
Journal: Circulation Research (1998)

Abstract —Angiopoietin-2 (Ang2) is a ligand for the endothelial cell tyrosine kinase receptor Tie2 and counteracts blood vessel maturation/stability mediated by angiopoietin-1 (Ang1), the other known ligand of Tie2. Using degenerate oligonucleotides and reverse transcriptase–polymerase chain reaction, we have screened bovine microvascular endothelial (BME), aortic, lymphatic, pulmonary artery, and transformed fetal aortic endothelial cells, as well as rat smooth muscle cells for Ang1 and Ang2 expression. Except for high Ang2 mRNA levels found in BME cells, none of the endothelial cell types studied expressed appreciable levels of Ang1 or Ang2 mRNAs, whereas smooth muscle cells expressed both Ang1 and Ang2. BME cell Ang2 mRNA levels were increased by vascular endothelial growth factor (1.9- to 2.9-fold), basic fibroblast growth factor (1.6- to 2-fold), both cytokines in combination (2.9- to 4-fold), and hypoxia (3.1- to 5.6-fold) and were decreased by Ang1 (31% to 70%) or transforming growth factor-β 1 (64% to 81%). Ang2 also decreased (60% to 82%) BME cell Ang2 mRNA. mRNA levels for the Tie1 or Tie2 receptors were only slightly modulated under the conditions described above. These findings suggest that the angiogenic effect of a number of regulators may be achieved in part through the regulation of an autocrine loop of Ang2 activity in microvascular endothelial cells.
Advice on driving after groin hernia surgery in the United Kingdom: questionnaire survey
Authors: W. Ismail
Journal: BMJ (2000)

Editorial by Amid 

Ambulatory surgery using modern repair techniques has changed the pattern of convalescence after repair of groin hernia by reducing postoperative pain and allowing early mobility.1 Driving after herniorrhaphy has potential safety, financial, and social implications. We surveyed the advice given to patients on driving after groin hernia surgery.

In 1998 we sent a questionnaire covering various aspects of hernia repair to a random sample of 200 consultant general surgeons in the United Kingdom selected from a list provided by the Royal College of Surgeons. A similar questionnaire was sent to the general managers of 30 day surgery units randomly selected from a list provided by the British Association of Day Surgery. We report their responses to questions concerning advice on driving after repair of groin hernia (under …
Allogeneic MHC Gene Transfer Enhances Antitumor Activity of Allogeneic Hematopoietic Stem Cell Transplantation without Exacerbating Graft-versus-Host Disease
Authors: Masaki Ohashi, Akihiko Kobayashi, Hidehiko Hara, Yoshiaki Miura, Kimiko Yoshida, Miwa Kushida, Yoshinori Ikarashi, Masaki Mandai, Masaki Kitajima, Teruhiko Yoshida, Kazunori Aoki
Journal: Clinical Cancer Research (2006)

Abstract Enhancement of the specific antitumor activity of allogeneic hematopoietic stem cell transplantation (alloHSCT) against solid cancers is a major issue in the clinical oncology. In this study, we examined whether intratumoral allogeneic MHC (alloMHC) gene transfer can enhance the recognition of tumor-associated antigens by donor T cells and augment the antitumor activity of alloHSCT. In minor histocompatibility antigen–mismatched alloHSCT (DBA/2→BALB/c: H-2d) recipients, alloMHC gene (H-2Kb) was transduced directly into a s.c. tumor of CT26 colon cancer cells. Because CT26 cells have an aggressive tumorigenicity in syngeneic BALB/c mice, an H-2Kb gene transfer provides only a limited antitumor effect after syngeneic (BALB/c→BALB/c) HSCT. By contrast, the H-2Kb gene transfer caused significant tumor suppression in the alloHSCT recipients, and this suppression was evident not only in the gene-transduced tumors but also in simultaneously inoculated distant tumors without gene transduction. In vitro cytotoxicity assay showed specific tumor cell lysis by donor T cells responding to the H-2Kb gene transfer. Graft-versus-host disease was not exacerbated serologically or clinically in the treated mice, demonstrating that alloMHC gene transfer enhances the antitumor effects of alloHSCT without exacerbating graft-versus-host disease. This combination strategy has important implications for the development of therapies for human solid cancers.
Synovial synthesis of rheumatoid factors and immune complex constituents in early arthritis.
Authors: V Jones, P C Taylor, R K Jacoby, T B Wallington
Journal: Annals of the Rheumatic Diseases (1984)

Synovial synthesis of immune complex constituents and rheumatoid factors has been estimated in rheumatoid arthritis (RA) and in unclassifiable inflammatory arthritis (IA) and related to duration of symptoms. Within 6 months of onset of symptoms both RA and IA patients synthesised (or trapped) immune complexes locally. However, local synthesis of the rheumatoid factors was almost exclusive to RA patients and mainly in patients with symptoms of more than 6 months9 duration. Thus all arthritis patients may respond immunologically to an initial trigger in the affected joint but only RA patients develop localised chronic autoimmunity later.
c-ANCA-induced neutrophil-mediated lung injury: a model of acute Wegener's granulomatosis
Authors: K. Hattar, S. Oppermann, C. Ankele, N. Weissmann, R.T. Schermuly, R.M. Bohle, R. Moritz, B. Krögel, W. Seeger, F. Grimminger, U. Sibelius, U. Grandel
Journal: European Respiratory Journal (2009)

Anti-neutrophil cytoplasmic antibodies (c-ANCA) targeting proteinase 3 (PR3) are implicated in the pathogenesis of Wegener's granulomatosis (WG). Fulminant disease can present as acute lung injury (ALI). In this study, a model of ALI in WG was developed using isolated rat lungs. Isolated human polymorphonuclear leukocytes (PMNs) were primed with tumour necrosis factor (TNF) to induce surface expression of PR3. Co-perfusion of TNF-primed neutrophils and monoclonal anti-PR3 antibodies induced a massive weight gain in isolated lungs. This effect was not observed when control immunoglobulin G was co-perfused with TNF-primed PMNs. The c-ANCA-induced oedema formation was paralleled by an increase in the capillary filtration coefficient as a marker of increased pulmonary endothelial permeability. In contrast, pulmonary artery pressure was not affected. In the presence of the oxygen radical scavenger superoxide dismutase and a NADPH oxidase inhibitor, c-ANCA-induced lung oedema could be prevented. Inhibition of neutrophil elastase was equally effective in preventing c-ANCA-induced lung injury. In conclusion, anti-PR3 antibodies induced neutrophil mediated, elastase- and oxygen radical-dependent ALI in the isolated lung. This experimental model supports the hypothesis of a pathogenic role for c-ANCA in WG and offers the possibility of the development of therapeutic strategies for the treatment of lung injury in fulminant WG.
What's nice about the new NICE guideline?
Authors: J. O'Reilly, M. Rudolf
Journal: Thorax (2010)

A new national guideline for the management of chronic obstructive pulmonary disease (COPD) was published by the National Institute for Health and Clinical Excellence (NICE) in June.1 Although technically only applicable to England and Wales (and even then only if adopted by the Welsh Assembly), it will be perceived by many international authorities as ‘the British guideline’ (with apologies to our Scottish colleagues), and it therefore seems appropriate to comment on what's new and relevant. It is over 6 years since the last NICE COPD guideline was published,2 and it is important to note that this 2010 version is only a partial update, concentrating on various aspects of diagnosis and severity classification and the management of stable disease. The management of acute exacerbations was specifically excluded from the scope of the guideline revision. This has had the consequence of producing a lengthy document (the full web-based version is over 600 pages!), much of which will be regarded by many readers as out of date. The Guideline Development Group (GDG) and the publishers have gone to great lengths to make as obvious as possible which parts of the guideline are new and which are not, but many will feel that this was a lost opportunity in not revising other sections as well.

One of the major strengths of a NICE guideline is that its recommendations are based on systematic reviews of the best available evidence (using extremely strict criteria for assessing the evidence), and also giving explicit consideration to cost effectiveness.3 In addition, the GDG is truly multidisciplinary, comprising healthcare professionals (doctors, nurses, physiotherapists) from primary and secondary care and patient representation.

It is good to see that the …
Is religion adaptive?
Authors: Richard Sosis, Candace Alcorta
Journal: Behavioral and Brain Sciences (2004)

We argue that religious ritual's ability to facilitate communication and the pervasiveness of its basic characteristics across societies, as well as its precedence in other social species, suggests that religious behavior is more than a mere by-product. Religious constructs constitute associationally conditioned mnemonics that trigger neuroendocrine responses which motivate religious behaviors. The adaptive value of these constructs resides in their utility as memorable and emotionally evocative primes.
Augmented Expression of a Human Gene for 8-oxoguanine DNA Glycosylase (MutM) in B Lymphocytes of the Dark Zone in Lymph Node Germinal Centers
Authors: Frank C. Kuo, Jeffrey Sklar
Journal: The Journal of Experimental Medicine (1997)

B cells that mediate normal, T cell–dependent, humoral immune responses must first pass through germinal centers (GCs) within the cortex of antigenically stimulated lymph nodes. As they move through the dark zone and then the light zone in the GC, B cells are subjected to somatic hypermutation and switch recombination within their rearranged immunoglobulin genes and also participate in a number of other processes that control development into memory cells or cells specialized for antibody secretion. To investigate the molecular mechanisms that contribute to B cell development within GCs, we constructed a recombinant DNA library enriched for cDNAs derived from human genes expressed in B cells at this site. This library was found to contain a cDNA structurally and functionally related to genes in bacteria and yeast for the DNA repair enzyme 8-oxoguanine DNA glycosylase. Northern blot analysis indicated that the human gene is expressed as two alternatively spliced messenger RNAs within GC B cells at levels greatly exceeding that found in other tissues. In situ hybridization studies revealed that expression of this gene is most abundant within the dark zones of GCs. Both the function and localized expression of this gene suggest that it may play a role in somatic hypermutation of immunoglobulin genes.
The Impact of Fossils and Taxon Sampling on Ancient Molecular Dating Analyses
Authors: Laura A. Hug, Andrew J. Roger
Journal: Molecular Biology and Evolution (2007)

The number and complexity of molecular dating studies has increased over the past decade. Along with a broadening acceptance of their utility has come significant controversy over the methods and models that are appropriate, as well as the accuracy of the estimates yielded by molecular clock analyses. Radically different age estimates have been published for the same divergences from analyses of different datasets with different fossil constraints obtained with different methods, and the underlying explanation for these differences is often unclear. Here we utilize two previously published datasets to examine the effect of fossil calibrations and taxon sampling on the age estimates for two deep eukaryote divergences in an attempt to discern the relative impact of these factors. Penalized likelihood, non-parametric rate smoothing, and Bayesian methods were utilized to generate age estimates for the origin of the Metazoa from a 7-gene dataset and for the divergence of Eukaryotes from a 129-gene dataset. From these analyses, it is clear that the fossil calibrations chosen and the method for applying constraints to these nodes have a large impact on age estimates, while the degree of taxon sampling within a dataset is less important in terms of the resulting age estimates. Concerns and recommendations for addressing these two factors when initiating a dating analysis are discussed.
Putting GWAS to the functional test: NR5A2 and pancreatic cancer risk
Authors: L Charles Murtaugh
Journal: Gut (2013)

Pancreatic ductal adenocarcinoma (PDAC) is among the worst diagnoses in medicine, with a 5-year survival rate of 4%, in part because most cases are detected well after metastasis has occurred. Models of PDAC evolutionary history have emerged from DNA sequencing studies of metastases and primary tumours and reveal a progressive elaboration of malignant and metastatic cells that takes 20 or more years.1 Interestingly, at least half of this time is spent in a premalignant state, termed pancreatic intraepithelial neoplasia (PanIN), suggesting that a decade-long window exists for prediction, detection and prevention of pancreatic cancer. Two papers published in Gut use mouse models to derive new insights into human-relevant genetic and environmental influences that drive PanIN formation and progression, and highlight the importance of differentiation as a barrier to tumourigenesis.2 ,3

The first genetic event on the road to invasive pancreatic cancer is mutational activation of KRAS , which occurs in the earliest precancerous PanIN-1 lesions. Experimental research on PDAC initiation was transformed 10 years ago, when a mouse model of PanIN–PDAC progression was developed based on pancreas-specific, Cre recombinase-mediated activation of endogenous mouse Kras .4 This model has been used to validate and dissect both rare genetic risk factors for PDAC, such as Ink4a/Arf deficiency,5 and environmental risk factors …
Press: Coming up roses
Authors: T. Jackson
Journal: BMJ (2002)

Who won the war of Rose's head? Both Tory and Labour politicians feel that they have scored vital points in what has perhaps been the most crucial recent battle over the most crucial public service in electoral terms. The war of Rose's head is the new war of Jennifer's ear—which erupted in 1992 when a Labour election broadcast used the case of a five year old girl who had waited months for an ear operation to highlight problems in the health service. Although Jennifer Bennett was not named in the broadcast, her case notes were leaked, and Labour stood accused of sacrificing patient confidentiality for party political purposes. The Tories went on to win the general election.

The war of Rose's head concerns the case of 94 year old Rose Addis. Under the headline “Abandoned in casualty,” London's Evening Standard reported on 21 January that Mrs Addis had waited three days at the Whittington Hospital “caked in blood” after “gashing her head in a fall at home.” In …