tbuckley/cabot-search huggingface dataset:
IL-6 Receptor α Defines Effector Memory CD8<sup>+</sup>T Cells Producing Th2 Cytokines and Expanding in Asthma
Authors: Naeun Lee, Sungyong You, Min Sun Shin, Won-Woo Lee, Ki Soo Kang, Sang Hyun Kim, Wan-Uk Kim, Robert J. Homer, Min-Jong Kang, Ruth R. Montgomery, Charles S. Dela Cruz, Albert C. Shaw, Patty J. Lee, Geoffrey L. Chupp, Daehee Hwang, Insoo Kang
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

Cytokine receptors can be markers defining different T-cell subsets and considered as therapeutic targets. The association of IL-6 and IL-6 receptor α (IL-6Rα) with asthma was reported, suggesting their involvement in asthma.To determine whether and how IL-6Rα defines a distinct effector memory (EM) CD8+ T-cell population in health and disease.EM CD8+ T cells expressing IL-6Rα (IL-6Rα(high)) were identified in human peripheral blood and analyzed for function, gene, and transcription factor expression. The relationship of these cells with asthma was determined using blood and sputum.A unique population of IL-6Rα(high) EM CD8+ T cells was found in peripheral blood. These cells that potently proliferated, survived, and produced high levels of the Th2-type cytokines IL-5 and IL-13 had increased levels of GATA3 and decreased levels of T-bet and Blimp-1 in comparison with other EM CD8+ T cells. In fact, GATA3 was required for IL-6Rα expression. Patients with asthma had an increased frequency of IL-6Rα(high) EM CD8+ T cells in peripheral blood compared with healthy control subjects. Also, IL-6Rα(high) EM CD8+ T cells exclusively produced IL-5 and IL-13 in response to asthma-associated respiratory syncytial virus and bacterial superantigens.Human IL-6Rα(high) EM CD8+ T cells is a unique cell subset that may serve as a reservoir for effector CD8+ T cells, particularly the ones producing Th2-type cytokines, and expand in asthma.
Bevacizumab 5 mg/kg Can Be Infused Safely Over 10 Minutes
Authors: Diane L. Reidy, Ki Y. Chung, John P. Timoney, Vivian J. Park, Ellen Hollywood, Nancy T. Sklarin, Raymond J. Muller, Leonard B. Saltz
Journal: Journal of Clinical Oncology (2007)

Purpose Bevacizumab is a humanized monoclonal antibody that targets vascular endothelial growth factor. As a result of concerns for potential infusion-related hypersensitivity reactions (HSRs), initial phase I trials used a 90-, 60-, 30-minute initial infusion sequence. We sought to determine if the initial prolonged infusion was still necessary and if an infusion time of fewer than 30 minutes could be safely used. Methods We used computerized pharmacy records to identify all patients who received bevacizumab at our institution in the first 2 years of commercial availability (February 1, 2004, to June 30, 2006). Our institutional adverse drug reaction reporting program was used to identify any infusion reactions possibly related to bevacizumab, and patient medical records were reviewed for confirmation. Results A total of 1,077 patients were treated with 10,606 doses of bevacizumab, and 765 of these patients received a 5-mg/kg dose (total of 8,494 doses). No HSRs occurred with the 90-, 60-, 30-minute infusion sequence in the first 202 patients. The standard infusion rate was then modified to 30 minutes for all bevacizumab doses. No HSRs were encountered. The infusion was again modified to a rate of 0.5 mg/kg/min. Of the 370 patients who received a total of 2,311 doses of bevacizumab at 5 mg/kg over 10 minutes, six (1.6%) experienced events of minor clinical consequence that were possibly consistent with nonserious HSRs. Conclusion Ninety- and 60-minute initial infusion times are unnecessary. Use of a standard infusion rate of 0.5 mg/kg/min is safe, logical, and the current policy at our institution.
Accuracy of thermistors and thermocouples as flow-measuring devices for detecting hypopnoeas
Authors: R Farre, JM Montserrat, M Rotger, E Ballester, D Navajas
Journal: European Respiratory Journal (1998)

The aim of this work was to assess the accuracy of thermistors/thermocouples as devices for detecting hypopnoeas in sleep studies. Conventional thermistor/thermocouples were studied with a respiratory model allowing the simulation of inspiratory (22 degrees C) and expiratory (37 degrees C) flows. The thermistor signal (V'th) was compared with a pneumotachograph (V'th): 1) for sinusoidal and square-wave airflows (+/-0.05 to +/-0.8 L.s(-1), 10-20 breaths.min(-1) (bpm)); 2) when changing the distance from the thermistor to the nose (0-20 mm); and 3) when doubling the section of the nostrils. The thermistor was strongly nonlinear and flow reductions (hypopnoeas) were underestimated: a 50% reduction in V' (+/-0.5 L.s(-1), 15 bpm, sinusoidal) resulted in only an 18% reduction in V'th. V'th depended considerably on the airflow pattern: for V'=+/-0.5 L.s(-1), V'th increased by 100% from sinusoidal (20 bpm) to square-wave (10 bpm). For V'=+/-0.5 L.s(-1), 15 bpm, sinusoidal flow, V'th increased by 79% when the distance thermistor-nose varied from 20-0 mm, and V'th decreased by 37% when doubling the nose section. We concluded that thermistor/thermocouples are inaccurate flow-measuring devices when used at the airflow conditions typical of sleep studies. Their use for quantifying hypopnoeas may lead to considerable underdetection of these respiratory events.
Recent advances in the genetics of language impairment
Authors: Dianne F Newbury, Simon E Fisher, Anthony P Monaco
Journal: Genome Medicine (2010)

Specific language impairment (SLI) is defined as an unexpected and persistent impairment in language ability despite adequate opportunity and intelligence and in the absence of any explanatory medical conditions. This condition is highly heritable and affects between 5% and 8% of pre-school children. Over the past few years, investigations have begun to uncover genetic factors that may contribute to susceptibility to language impairment. So far, variants in four specific genes have been associated with spoken language disorders - forkhead box P2 (FOXP2) and contactin-associated protein-like 2 (CNTNAP2) on chromosome7 and calcium-transporting ATPase 2C2 (ATP2C2) and c-MAF inducing protein (CMIP) on chromosome 16. Here, we describe the different ways in which these genes were identified as candidates for language impairment. We discuss how characterization of these genes, and the pathways in which they are involved, may enhance our understanding of language disorders and improve our understanding of the biological foundations of language acquisition.
Ghrelin Gene Products and the Regulation of Food Intake and Gut Motility
Authors: Chih-Yen Chen, Akihiro Asakawa, Mineko Fujimiya, Shou-Dong Lee, Akio Inui
Journal: Pharmacological Reviews (2009)

A breakthrough using "reverse pharmacology" identified and characterized acyl ghrelin from the stomach as the endogenous cognate ligand for the growth hormone (GH) secretagogue receptor (GHS-R) 1a. The unique post-translational modification of <i>O</i>-<i>n</i>-octanoylation at serine 3 is the first in peptide discovery history and is essential for GH-releasing ability. Des-acyl ghrelin, lacking <i>O</i>-<i>n</i>-octanoylation at serine 3, is also produced in the stomach and remains the major molecular form secreted into the circulation. The third ghrelin gene product, obestatin, a novel 23-amino acid peptide identified from rat stomach, was found by comparative genomic analysis. Three ghrelin gene products actively participate in modulating appetite, adipogenesis, gut motility, glucose metabolism, cell proliferation, immune, sleep, memory, anxiety, cognition, and stress. Knockdown or knockout of acyl ghrelin and/or GHS-R1a, and overexpression of des-acyl ghrelin show benefits in the therapy of obesity and metabolic syndrome. By contrast, agonism of acyl ghrelin and/or GHS-R1a could combat human anorexia-cachexia, including anorexia nervosa, chronic heart failure, chronic obstructive pulmonary disease, liver cirrhosis, chronic kidney disease, burn, and postsurgery recovery, as well as restore gut dysmotility, such as diabetic or neurogenic gastroparesis, and postoperative ileus. The ghrelin acyl-modifying enzyme, ghrelin <i>O</i>-Acyltransferase (GOAT), which attaches octanoate to serine-3 of ghrelin, has been identified and characterized also from the stomach. To date, ghrelin is the only protein to be octanylated, and inhibition of GOAT may have effects only on the stomach and is unlikely to affect the synthesis of other proteins. GOAT may provide a critical molecular target in developing novel therapeutics for obesity and type 2 diabetes.
Statin therapy and clinical outcomes in myocardial infarction patients complicated by acute heart failure: insights from the EPHESUS trial
Authors: Daniela Dobre, Patrick Rossignol, Jan Murin, Alexander Parkhomenko, Zohra Lamiral, Henry Krum, Dirk J. van Veldhuisen, Bertram Pitt, Faiez Zannad
Journal: European Journal of Heart Failure (2012)
Immunoglobulin Heavy Chain Variable Region Gene Replacement as a Mechanism for Receptor Revision in Rheumatoid Arthritis Synovial Tissue B Lymphocytes
Authors: Kenji Itoh, Eric Meffre, Emilia Albesiano, Andrew Farber, David Dines, Peter Stein, Stanley E. Asnis, Richard A. Furie, Rita I. Jain, Nicholas Chiorazzi
Journal: The Journal of Experimental Medicine (2000)

Mature B cells can alter their antibody repertoires by several mechanisms, including immunoglobulin heavy chain variable region (VH) replacement. This process changes the antigen combining site by replacing a portion of the original VH/diversity/heavy chain joining region (VHDJH) rearrangement with a corresponding portion of a new VH segment. This exchange can involve cryptic heptamer-like sequences embedded in the coding regions of VH genes. While studying the B lymphocytes that expand in the synovial tissues of patients with rheumatoid arthritis (RA), clones with VHDJH variants that were apparently generated by VH replacement were identified with surprising frequency (∼8%). Examples of multiple independent VH replacement events occurring in distinct progeny clones were also identified. These secondary VH rearrangements were documented at both the cDNA and genomic DNA levels and involved several heptamer-like sequences at four distinct locations within VH (three sites in framework region 3 and one in complementarity determining region 2). The identification of blunt-ended double-stranded DNA breaks at the embedded heptamers and the demonstration of recombinase activating gene (RAG) expression suggested that these rearrangements could occur in the synovial tissues, presumably in pseudo-germinal centers, and that they could be mediated by RAG in a recognition signal sequence–specific manner. The presence of VH mutations in the clones that had undergone replacement indicated that these B cells were immunocompetent and could receive and respond to diversification signals. A relationship between these secondary VH gene rearrangements and the autoimmunity characteristic of RA should be considered.
Cas S 8, the Lipid Transfer Protein from Chestnut Seeds, is a Major Allergen in Chestnut Allergic Patients without Associated Latex Allergy, but not in those with the Latex-Fruit Syndrome
Authors: C. Blanco, R. Sánchez-Monge, M. Recas, G. López-Torrejón, J. Cumplido, J. Figueroa, T. Carrillo, G. Salcedo
Journal: Journal of Allergy and Clinical Immunology (2006)
MORPHOLOGICAL AND FUNCTIONAL STUDIES OF FETAL THYMUS TRANSPLANTS IN MICE
Authors: W. D. Biggar, Osias Stutman, Robert A. Good
Journal: The Journal of Experimental Medicine (1972)

The fetal thymus at 13 days of gestation withstands transplantation and develops normally under the renal capsule of a syngenic host. Distinct differences were observed between the fetal thymus grafts and grafts from neonatal or adult thymus donors. The fetal thymus graft did not undergo the rapid and severe necrosis observed when adult thymus was grafted. Furthermore, when thymuses were transplanted into allogenic recipients, rejection was delayed. The fetal thymus was as effective as the adult thymus in restoring syngenic neonatally thymectomized mice and far superior to adult thymus when grafted into allogenic recipients. These observations seem relevant to clinical efforts to restore immunocompetence in patients with congenital absence of the thymus.
Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial
Authors: Yung-Jue Bang, Young-Woo Kim, Han-Kwang Yang, Hyun Cheol Chung, Young-Kyu Park, Kyung Hee Lee, Keun-Wook Lee, Yong Ho Kim, Sang-Ik Noh, Jae Yong Cho, Young Jae Mok, Yeul Hong Kim, Jiafu Ji, Ta-Sen Yeh, Peter Button, Florin Sirzén, Sung Hoon Noh
Journal: The Lancet (2012)
First TV advert for abortion services prompts anger
Authors: A. O'Dowd
Journal: BMJ (2010)

Plans to screen the UK’s first television advertisement for abortion services next week have prompted anger from various organisations.

The advert for advice on unplanned pregnancy and abortion from Marie Stopes International is designed to raise awareness of sexual health and help women make informed choices, said the organisation.

Various anti-abortion groups, however, have protested strongly, and one is looking into the possibility of legal action to prevent the advert from being screened.

The advert campaign called “Are you late?” deals with women who have missed their period and directs people facing an unplanned pregnancy to Marie Stopes International’s 24 hour helpline. The first of a campaign, it is scheduled to …
Renal tubular events following passage from the supine to the standing position in patients with compensated liver cirrhosis: loss of tubuloglomerular feedback
Authors: G Sansoe
Journal: Gut (2002)

Patients with preascitic liver cirrhosis display significant renal sodium retention in the upright posture and an exaggerated natriuresis during recumbency. To date, intrarenal sodium handling in these patients has not been studied using lithium clearance and fractional excretion techniques during recumbency and orthostatism.Ten patients with preascitic (Child-Pugh A) liver cirrhosis and 10 healthy subjects underwent the following measurements during recumbency and then after four hours of standing: (a) active renin and aldosterone plasma levels; and (b) renal clearance of creatinine, sodium, potassium, and lithium (an index of fluid delivery to the loop of Henle).Unlike the control group, in the upright posture patients had significantly lower values of lithium clearance and fractional excretion compared with recumbency (21.6 (8.6) v 30.5 (10.2) ml/min (p<0.03) and 12.8 (4.4)% v 20.8 (4.9)% (p<0.01), respectively). Our patients showed maintenance of the glomerular-tubular balance-that is, the correlation between creatinine clearance and proximal tubular reabsorption of fluid-during both recumbency and in the upright posture (r=0.96, p<0.001; r=0.97, p<0.001, respectively). In contrast, patients displayed tubuloglomerular feedback only in the supine position. This was demonstrated by the observation of a negative correlation between lithium fractional excretion (a measure of the fractional delivery of sodium to the distal nephron) and filtered sodium load only in recumbency (r=-0.73; p< 0.03) and not during standing (r=0.22; p> 0.05).This study suggests that both the reduction in fluid and sodium delivery to the distal nephron and loss of tubuloglomerular feedback (the mechanism increasing glomerular filtration rate when the distal tubule is reached by a reduced sodium load) contribute towards the tendency to sodium retention in compensated cirrhosis during prolonged upright posture.
Asthma deaths: what now?
Authors: M. L. Levy, R. Winter
Journal: Thorax (2015)

It is almost 50 years since the first UK studies identified potentially preventable factors in the majority of asthma deaths.1 Those first reports led to the development of national asthma guidelines, intended to radically improve management. Since the 1980s, asthma care in the UK has shifted from secondary to primary care,2 linked to enhanced asthma nurse training and involvement. With the development of new doctor–patient partnerships in the form of personalised self-management plans and newer drugs with innovative delivery systems, improving asthma care in the future seemed a certainty. And yet, from 1992, the only ongoing inquiry into asthma death in the East of England fuelled background concern that preventable death was still a major issue.3 That concern was highlighted by the National Atlas of Variation in Healthcare for Respiratory Disease,4 published in September 2012, which showed great variation in almost every facet of asthma care delivery across the UK.

The National Review of Asthma Deaths (NRAD) was a confidential enquiry that investigated in detail 900 deaths of people of all ages who had died in 2012 with an ICD-10 code J459, where the underlying cause of death was classified as asthma. It was the first national study by the Clinical Effectiveness and Evaluation Unit at the Royal College of Physicians (RCP) to span both primary and secondary care, thus providing comprehensive information about asthma death. On World Asthma Day 2014, 24 years after the publication of the first UK guideline, the NRAD report, ‘Why asthma still kills’,5 stated asthma care was poor in most cases investigated and concluded that the vast majority of asthma deaths in the UK remain potentially preventable.

In all age groups, NRAD identified errors in primary and secondary care: in making the diagnosis of asthma; in the identification of risk factors (leading …
Inflammatory Cortical Demyelination in Early Multiple Sclerosis
Authors: Claudia F. Lucchinetti, Bogdan F.G. Popescu, Reem F. Bunyan, Natalia M. Moll, Shanu F. Roemer, Hans Lassmann, Wolfgang Brück, Joseph E. Parisi, Bernd W. Scheithauer, Caterina Giannini, Stephen D. Weigand, Jay Mandrekar, Richard M. Ransohoff
Journal: New England Journal of Medicine (2011)

Cortical disease has emerged as a critical aspect of the pathogenesis of multiple sclerosis, being associated with disease progression and cognitive impairment. Most studies of cortical lesions have focused on autopsy findings in patients with long-standing, chronic, progressive multiple sclerosis, and the noninflammatory nature of these lesions has been emphasized. Magnetic resonance imaging studies indicate that cortical damage occurs early in the disease.We evaluated the prevalence and character of demyelinating cortical lesions in patients with multiple sclerosis. Cortical tissues were obtained in passing during biopsy sampling of white-matter lesions. In most cases, biopsy was done with the use of stereotactic procedures to diagnose suspected tumors. Patients with sufficient cortex (138 of 563 patients screened) were evaluated for cortical demyelination. Using immunohistochemistry, we characterized cortical lesions with respect to demyelinating activity, inflammatory infiltrates, the presence of meningeal inflammation, and a topographic association between cortical demyelination and meningeal inflammation. Diagnoses were ascertained in a subgroup of 77 patients (56%) at the last follow-up visit (at a median of 3.5 years).Cortical demyelination was present in 53 patients (38%) (104 lesions and 222 tissue blocks) and was absent in 85 patients (121 tissue blocks). Twenty-five patients with cortical demyelination had definite multiple sclerosis (81% of 31 patients who underwent long-term follow-up), as did 33 patients without cortical demyelination (72% of 46 patients who underwent long-term follow-up). In representative tissues, 58 of 71 lesions (82%) showed CD3+ T-cell infiltrates, and 32 of 78 lesions (41%) showed macrophage-associated demyelination. Meningeal inflammation was topographically associated with cortical demyelination in patients who had sufficient meningeal tissue for study.In this cohort of patients with early-stage multiple sclerosis, cortical demyelinating lesions were frequent, inflammatory, and strongly associated with meningeal inflammation. (Funded by the National Multiple Sclerosis Society and the National Institutes of Health.).
Market-access agreements for anti-cancer drugs
Authors: Katelijne van de Vooren, Alessandro Curto, Nick Freemantle, Livio Garattini
Journal: Journal of the Royal Society of Medicine (2014)

Newly marketed pharmaceuticals command increasingly high prices, particularly in oncology where single treatment cycles can be very costly, even though data at market approval are usually inadequate to describe thoroughly their effectiveness and cost-effectiveness. Both manufacturers and payers have shown interest in solutions to achieve rapid access for patients – known as ‘market-access agreements’. Although the literature offers a variety of definitions, these agreements can be roughly grouped under two main types: financial-based and performance-based. Financial-based schemes focus on the budget impact of a new drug and usually consist of price/dose discounts. Performancebased schemes involve collecting clinical evidence once a new drug has been marketed in a healthcare system and lead to payment only for patients responding to therapy, an objective which is methodologically and practically challenging while not without political appeal. The underlying strategy is to help reduce the likelihood of payers adopting technologies that turn out not to be cost-effective, while at the same time helping manufacturers increase market access time and take profit. Market-access agreements can also be considered an opportunistic way for manufacturers to keep official prices high such as maintaining a common European price, while granting health authorities confidential rebates, thus preventing parallel trade and undermining effective external reference pricing. The English and Italian health services have been the first countries to introduce market-access agreements on specific drugs. These contracts are now called Managed Entry Agreements (MEA) in Italy and Patient Access Schemes (PAS) in England and Wales. We focus on the area of oncology, where many new drugs are costly and fall under these arrangements. Italy
The Restless Engram: Consolidations Never End
Authors: Yadin Dudai
Journal: Annual Review of Neuroscience (2012)

Memory consolidation is the hypothetical process in which an item in memory is transformed into a long-term form. It is commonly addressed at two complementary levels of description and analysis: the cellular/synaptic level (synaptic consolidation) and the brain systems level (systems consolidation). This article focuses on selected recent advances in consolidation research, including the reconsolidation of long-term memory items, the brain mechanisms of transformation of the content and of cue-dependency of memory items over time, as well as the role of rest and sleep in consolidating and shaping memories. Taken together, the picture that emerges is of dynamic engrams that are formed, modified, and remodified over time at the systems level by using synaptic consolidation mechanisms as subroutines. This implies that, contrary to interpretations that have dominated neuroscience for a while, but similar to long-standing cognitive concepts, consolidation of at least some items in long-term memory may never really come to an end.