tbuckley/cabot-search huggingface dataset:
Distinct Clinical Characteristics of C9orf72 Expansion Carriers Compared With GRN, MAPT, and Nonmutation Carriers in a Flanders-Belgian FTLD Cohort
Authors: Tim Van Langenhove, Julie van der Zee, Ilse Gijselinck, Sebastiaan Engelborghs, Rik Vandenberghe, Mathieu Vandenbulcke, Jan De Bleecker, Anne Sieben, Jan Versijpt, Adrian Ivanoiu, Olivier Deryck, Christiana Willems, Lubina Dillen, Stéphanie Philtjens, Githa Maes, Veerle Bäumer, Marleen Van Den Broeck, Maria Mattheijssens, Karin Peeters, Jean-Jacques Martin, Alex Michotte, Patrick Santens, Peter De Jonghe, Patrick Cras, Peter P. De Deyn, Marc Cruts, Christine Van Broeckhoven
Journal: JAMA Neurology (2013)

To characterize patients with frontotemporal lobar degeneration (FTLD) with a repeat expansion mutation in the gene C9orf72, and to determine whether there are differences in the clinical presentation compared with FTLD carriers of a mutation in GRN or MAPT or with patients with FTLD without mutation.Patient series.Dementia clinics in Flanders, Belgium.Two hundred seventy-five genetically and phenotypically thoroughly characterized patients with FTLD.Clinical and demographic characteristics of 26 C9orf72 expansion carriers compared with patients with a GRN or MAPT mutation, as well as patients with familial and sporadic FTLD without mutation.C9orf72 expansion carriers developed FTLD at an early age (average, 55.3 years; range, 42-69 years), significantly earlier than in GRN mutation carriers or patients with FTLD without mutation. Mean survival (6.2 years; range, 1.5-17.0 years) was similar to other patient groups. Most developed behavioral variant frontotemporal dementia (85%), with disinhibited behavior as the prominent feature. Concomitant amyotrophic lateral sclerosis is a strong distinguishing feature for C9orf72 -associated FTLD. However, in most patients (73%), amyotrophic lateral sclerosis symptoms were absent. Compared with C9orf72 expansion carriers, nonfluent aphasia and limb apraxia were significantly more common in GRN mutation carriers.C9orf72 -associated FTLD most often presents with early-onset behavioral variant frontotemporal dementia with disinhibition as the prominent feature, with or without amyotrophic lateral sclerosis. Based on the observed genotype-phenotype correlations between the different FTLD syndromes and different genetic causes, we propose a decision tree to guide clinical genetic testing in patients clinically diagnosed as having FTLD.
Burkholderia cepacia: another twist and a further threat
Authors: A K WEBB, J R GOVAN
Journal: Thorax (1998)

Patients with cystic fibrosis present a continuum of complex medical problems to their carers. It is for this reason that cystic fibrosis care is best delivered by a multidisciplinary team from recognised paediatric and adult cystic fibrosis centres. The consequences of this practice are that, over time, patients are better nourished with a slow decline in respiratory function.1The ultimate benefit of better care is increased survival.2 Despite this greater knowledge and better management, cystic fibrosis as a disease repeatedly produces unpleasant novel management problems; the recent descriptions of a six fold increase in the incidence of digestive tract cancer and the remarkably high prevalence of osteoporosis are typical examples of the cystic fibrosis Pandora’s box.3 4 

The current stigma of acquiring Burkholderia cepacia are both medical and social. The medical consequences of acquiring B cepacia may be accelerated lung disease, more intense treatment requirements, and doubt about suitability for transplantation due to a greater mortality following surgery with some strains.5The social consequences are segregation from other patients with cystic fibrosis in hospital, in social settings, and a ban from attending cystic fibrosis conferences or holiday schemes. It is not surprising that patients with cystic fibrosis infected by B cepacia have felt isolated by their peers and have done their best to organise their own social groups.

The current strict infection control measures which are currently recommended to reduce B cepacia acquisition are restrictive enough but …
An implantable microdevice to perform high-throughput in vivo drug sensitivity testing in tumors
Authors: Oliver Jonas, Heather M. Landry, Jason E. Fuller, John T. Santini, Jose Baselga, Robert I. Tepper, Michael J. Cima, Robert Langer
Journal: Science Translational Medicine (2015)

An implantable microdevice is demonstrated to release microdoses of multiple drugs into confined regions of tumors and allows for assessment of each drug’s efficacy to identify optimal therapy.
Reckoning with risk: learning to live with uncertainty: G Gigerenzer. Allen Lane Penguin Press Penguin Books Ltd, 2002, pound14.99, pp 310. ISBN 0713995122
Authors: D Humphries
Journal: British Journal of Sports Medicine (2003)

Gerd Gigerenzer has a passion for improving statistical numeracy which is rarely encountered in the normally dry statistics texts. He has researched and published extensively on how doctors and other professionals interpret risks and convey that information to their patients. He has also shown how clinicians' understanding of …
Prospective Multicenter Comparison of Models to Predict Four or More Involved Axillary Lymph Nodes in Patients With Breast Cancer With One to Three Metastatic Sentinel Lymph Nodes
Authors: Gabrielle Werkoff, Eric Lambaudie, Eric Fondrinier, Jean Levêque, Frédéric Marchal, Michèle Uzan, Emmanuel Barranger, François Guillemin, Emile Daraï, Serge Uzan, Gilles Houvenaeghel, Roman Rouzier, Charles Coutant
Journal: Journal of Clinical Oncology (2009)

Three models have been developed to predict four or more involved axillary lymph nodes (ALNs) in patients with breast cancer with one to three involved sentinel lymph nodes (SLNs). Two scores were developed by Chagpar et al (Louisville scores excluding or including method of detection), and a nomogram was developed by Katz et al. The purpose of our investigation was to compare these models in a prospective, multicenter study.Our study involved a cohort of 536 patients having one to three involved SLNs who underwent ALN dissection. We evaluated the area under the receiver operating characteristic curve (AUC), calibration (for the Katz nomogram only), false-negative (FN) rate, and clinical utility of the three models. Results were compared with the optimal logistic regression (OLR) model that was developed from the validation cohort.Among the 536 patients, 57 patients (10.6%) had > or = four involved ALNs. The AUC for the Katz nomogram was 0.84 (95% CI, 0.81 to 0.86). The Louisville score excluding method of detection was 0.75 (95% CI, 0.72 to 0.78). The Louisville score including method of detection was 0.77 (95% CI, 0.74 to 0.79). The FN rates were 2.5% (eight of 321 patients), 1.8% (two of 109 patients), and 0% (zero of 27 patients) for the Katz nomogram and the Louisville scores excluding and including method of detection, respectively. The Katz nomogram was well calibrated. Optimism-corrected bootstrap estimate AUC of the OLR model was 0.86. Using this result as a reasonable target for an external model, the performance of the Katz nomogram was remarkable.We validated the three models for their use in clinical practice. The Katz nomogram outperformed the two other models.
GPCR Interacting Proteins (GIPs) in the Nervous System: Roles in Physiology and Pathologies
Authors: Joël Bockaert, Julie Perroy, Carine Bécamel, Philippe Marin, Laurent Fagni
Journal: The Annual Review of Pharmacology and Toxicology (2010)

G protein-coupled receptors (GPCRs) are key transmembrane recognition molecules for regulatory signals such as light, odors, taste hormones, and neurotransmitters. In addition to activating guanine nucleotide binding proteins (G proteins), GPCRs associate with a variety of GPCR-interacting proteins (GIPs). GIPs contain structural interacting domains that allow the formation of large functional complexes involved in G protein-dependent and -independent signaling. At the cellular level, other functions of GIPs include targeting of GPCRs to subcellular compartments and their trafficking to and from the plasma membrane. Recently, roles of GPCR-GIP interactions in central nervous system physiology and pathologies have been revealed. Here, we highlight the role of GIPs in some important neurological and psychiatric disorders, as well as their potential for the future development of therapeutic drugs.
“Essential noise” – enhancing variability of informational constraints benefits movement control: a comment on Waddington and Adams (2003): Figure 1
Authors: K Davids, R Shuttleworth, C Button, I Renshaw, P Glazier
Journal: British Journal of Sports Medicine (2004)

This commentary proposes a dynamical systems perspective to re-interpret data from a group of international soccer players demonstrating that wearing textured insoles in soccer boots enhanced tactile information from the sole of the foot and increased movement discrimination capacity in ankle inversion sensitivity tests to levels similar to those in barefoot conditions. Theoretical arguments on the functional role of variability induced in the sensorimotor system by textured insoles, acting as a form of “essential noise” to enhance the accuracy of foot positioning are presented. It seems that, far from interfering with motor performance, variability can actually enhance perception of information to support motor performance. The addition of intermittent, intermediate levels of noise in a perceptual motor context may benefit performers by helping them to pick up information signals from background structure. Movement system variability is conceived as noise induced resonance benefiting the pick up of information to regulate behaviour. Variability can be functional in practical programmes to offset negative effects of losses in sensory sensitivity through ageing, disease, illness, or injury
Dynamic T cell migration program provides resident memory within intestinal epithelium
Authors: David Masopust, Daniel Choo, Vaiva Vezys, E. John Wherry, Jaikumar Duraiswamy, Rama Akondy, Jun Wang, Kerry A. Casey, Daniel L. Barber, Kim S. Kawamura, Kathryn A. Fraser, Richard J. Webby, Volker Brinkmann, Eugene C. Butcher, Kenneth A. Newell, Rafi Ahmed
Journal: The Journal of Experimental Medicine (2010)

Migration to intestinal mucosa putatively depends on local activation because gastrointestinal lymphoid tissue induces expression of intestinal homing molecules, whereas skin-draining lymph nodes do not. This paradigm is difficult to reconcile with reports of intestinal T cell responses after alternative routes of immunization. We reconcile this discrepancy by demonstrating that activation within spleen results in intermediate induction of homing potential to the intestinal mucosa. We further demonstrate that memory T cells within small intestine epithelium do not routinely recirculate with memory T cells in other tissues, and we provide evidence that homing is similarly dynamic in humans after subcutaneous live yellow fever vaccine immunization. These data explain why systemic immunization routes induce local cell-mediated immunity within the intestine and indicate that this tissue must be seeded with memory T cell precursors shortly after activation.
Interleukin 4–Producing Cd4 T Cells Arise from Different Precursors Depending on the Conditions of Antigen Exposure in Vivo
Authors: Gilles Foucras, Laurent Gapin, Christiane Coureau, Jean M. Kanellopoulos, Jean-Charles Guéry
Journal: The Journal of Experimental Medicine (2000)

The precursor origin of T helper (Th) cell subsets in vivo has been difficult to study and remains poorly investigated. We have previously shown that chronic administration of soluble protein antigen induces selective development of antigen-specific CD4 Th2 cells in genetically predisposed mouse strains. To analyze the origin of effector T cells in this model, we designed a competitive polymerase chain reaction–based approach to track public BV-J rearrangement expressed by CD4 T cells specific for hen egg white lysozyme (HEL) in BALB/c mice. We show that public T cell clones are predominantly associated with type 1 or 2 effector Th cells recovered after primary immunization in complete or incomplete Freund's adjuvant, respectively. Conversely, continuous administration of soluble antigen, which induces strong memory Th2 response, is associated with a dose-dependent reduction of public clone size by a mechanism resembling clonal anergy. Thus, soluble HEL–induced Th2 cells do not express the public complementarity determining region 3 motifs characteristic of immunogenic challenge in the presence of adjuvant. These results demonstrate that there are multiple pathways of induction of Th2 responses depending on the condition of antigen exposure in vivo, i.e., clonal immune deviation versus recruitment of a different pool of precursor cells.
Carboplatin Substitution for Cisplatin in the Treatment of Ovarian Carcinoma-- A Word of Caution
Authors: W. P. McGuire, M. D. Abeloff
Journal: JNCI Journal of the National Cancer Institute (1989)

After cisplatin was identified as the first of an important new class of compounds (organoplatinum compounds) with a broad spectrum of antitumor efficacy, a large number of analogs were developed with the hope that one or more would have equivalent antitumor activity without the two adverse effects that made dose escalation and long-term dosing with cisplatin a problem, i.e., renal tubular damage and peripheral neurotoxicity
Primary spontaneous pneumothorax: Seasonal influence?
Authors: Marta Fradinho, Cristina Cristóvão, Fernando Nogueira
Journal: European Respiratory Journal (2013)

Introduction: Primary spontaneous pneumothorax (PSP) arises in persons without risk/triggering factors or respiratory disease, between 18 and 40 years old, tall, thin, smokers with a male/female ratio of 6:1. Atmospheric pressure, humidity, temperature and seasonal variation have been studied as causes of PSP. Results are controversial. Some studies say most pneumothorax apears in winter months. Objective: Characterization and evaluation of patients admitted for PSP and evaluation of seasonal frequency. Material/methods: Retrospective study of patients admitted in the Pulmonology service of Center Hospital of West Lisbon (Hospital Egas Moniz) with PSP from 2008 to 2012. Analyzed parameters: gender, age, predisposing factors, seasonal variation, days of hospitalization, complications and destination after discharge. Results: Were admitted 69 patients with PSP (86% male and 14% female). Mean age was 32 ±17,6 years (16-93 years). Most patients had between 20 and 40 years old (68%). Twenty-four didn’t have any risk/triggering factor and 45 had smoking habits, height or previous episodes of pneumothorax as predisposing factor. Thirty percent were admitted in the warm months, but the difference to colder months was minimal. Fifty eight percent had no complications during hospitalization, 8 patients had bronchopleural fistula and 8 persistent pneumothorax, requiring transfer to Cardiothoracic Surgery service and surgical intervention. Mean of hospitalization days was 8±7,4 days (2- 44 days), being 5 or less days in 51% of patients. Conclusion: PSP occurs without risk factors or triggers and there may be predisposing factors. It is controversial whether this entity has a seasonal variation and more research is needed.
Experimental arthritis in CC chemokine receptor 2–null mice closely mimics severe human rheumatoid arthritis
Authors: Marlon P. Quinones, Sunil K. Ahuja, Fabio Jimenez, Jason Schaefer, Edgar Garavito, Arun Rao, George Chenaux, Robert L. Reddick, William A. Kuziel, Seema S. Ahuja
Journal: Journal of Clinical Investigation (2004)

The prevailing paradigm is that in human rheumatoid arthritis (RA), the accumulation of monocytes and T cells in the joint, mediated in part by such CC chemokine receptors (CCRs) as CCR2 and CCR5, respectively, plays a central role in disease pathogenesis. To further validate this paradigm, we conducted proof-of-principle studies and tested the hypothesis that gene inactivation of Ccr2 or Ccr5 will ameliorate experimental RA. Contrary to our expectations, we found that in two well-established murine models of experimental RA, CCR2 expression in the hematopoietic cell compartment served as a negative regulator of autoantibody production as well as arthritic disease onset, severity, and resolution. In contrast, the RA phenotype in Ccr5-null mice was similar to that of WT mice. Remarkably, the collagen-induced arthritis phenotype of Ccr2–/– mice mimicked closely that of severe human RA, including production of rheumatoid factor, enhanced T cell production, and monocyte/macrophage accumulation in the joints. Our findings demonstrate an essential protective role of CCR2 expression in RA, indicate the existence of alternative receptors responsible for monocyte/macrophage accumulation to inflamed joints, and emphasize the need to clarify carefully the complex effects of the chemokine system in RA before they can be considered as therapeutic targets.
Interplay between regulatory T cells and PD-1 in modulating T cell exhaustion and viral control during chronic LCMV infection
Authors: Pablo Penaloza-MacMaster, Alice O. Kamphorst, Andreas Wieland, Koichi Araki, Smita S. Iyer, Erin E. West, Leigh O’Mara, Shu Yang, Bogumila T. Konieczny, Arlene H. Sharpe, Gordon J. Freeman, Alexander Y. Rudensky, Rafi Ahmed
Journal: The Journal of Experimental Medicine (2014)

Regulatory T (T reg) cells are critical for preventing autoimmunity mediated by self-reactive T cells, but their role in modulating immune responses during chronic viral infection is not well defined. To address this question and to investigate a role for T reg cells in exhaustion of virus-specific CD8 T cells, we depleted T reg cells in mice chronically infected with lymphocytic choriomeningitis virus (LCMV). T reg cell ablation resulted in 10–100-fold expansion of functional LCMV-specific CD8 T cells. Rescue of exhausted CD8 T cells was dependent on cognate antigen, B7 costimulation, and conventional CD4 T cells. Despite the striking recovery of LCMV-specific CD8 T cell responses, T reg cell depletion failed to diminish viral load. Interestingly, T reg cell ablation triggered up-regulation of the molecule programmed cell death ligand-1 (PD-L1), which upon binding PD-1 on T cells delivers inhibitory signals. Increased PD-L1 expression was observed especially on LCMV-infected cells, and combining T reg cell depletion with PD-L1 blockade resulted in a significant reduction in viral titers, which was more pronounced than that upon PD-L1 blockade alone. These results suggest that T reg cells effectively maintain CD8 T cell exhaustion, but blockade of the PD-1 inhibitory pathway is critical for elimination of infected cells.
Southwest Oncology Group study S0413: a phase II trial of lapatinib (GW572016) as first-line therapy in patients with advanced or metastatic gastric cancer
Authors: S. Iqbal, B. Goldman, C.M. Fenoglio-Preiser, H.J. Lenz, W. Zhang, K.D. Danenberg, S.I. Shibata, C.D. Blanke
Journal: Annals of Oncology (2011)

BackgroundLapatinib (GW572016) is a dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2/ErbB2), which are reported as overexpressed in 15%–45% of gastric cancers, making them potential targets.Patients and methodsThe primary objective of this study was to assess response rate. Secondary objectives included overall survival (OS), toxicity, and the relationship of EGFR, ErbB2, and markers of angiogenesis with clinical outcome. Lapatinib was administered to chemonaive metastatic gastric cancer patients at a dose of 1500 mg orally daily for 28 days.ResultsThe study enrolled 47 patients from February 2005 until May 2006. Four patients (9%) had a confirmed partial response (PR), 1 (2%) had an unconfirmed PR, and 10 (23%) had stable disease. Median (95% confidence interval) time to treatment failure was 1.9 (1.6–3.1) months and OS was 4.8 (3.2–7.4) months. Significant adverse events: one grade 4 cardiac ischemia/infarction, one grade 4 fatigue, and one grade 4 emesis. One treatment-related death was due to central nervous system ischemia. An exploratory analysis of markers revealed gene expression of HER2, interleukin (IL)-8 and genomic polymorphisms IL-8, and vascular endothelial growth factor correlated with OS.ConclusionsLapatinib is well tolerated, with modest single-agent activity in advanced/metastatic gastric cancer patients. Potential molecular correlatives were identified which warrant further validation.
<i>Pseudomonas aeruginosa</i>quorum sensing molecules correlate with clinical status in cystic fibrosis
Authors: Helen L. Barr, Nigel Halliday, Miguel Cámara, David A. Barrett, Paul Williams, Douglas L. Forrester, Rebecca Simms, Alan R. Smyth, David Honeybourne, Joanna L. Whitehouse, Edward F. Nash, Jane Dewar, Andrew Clayton, Alan J. Knox, Andrew W. Fogarty
Journal: European Respiratory Journal (2015)

Pseudomonas aeruginosa produces quorum sensing signal molecules that are potential biomarkers for infection. A prospective study of 60 cystic fibrosis patients with chronic P. aeruginosa, who required intravenous antibiotics for pulmonary exacerbations, was undertaken. Clinical measurements and biological samples were obtained at the start and end of the treatment period. Additional data were available for 29 of these patients when they were clinically stable. Cross-sectionally, quorum sensing signal molecules were detectable in the sputum, plasma and urine of 86%, 75% and 83% patients, respectively. They were positively correlated between the three biofluids. Positive correlations were observed for most quorum sensing signal molecules in sputum, plasma and urine, with quantitative measures of pulmonary P. aeruginosa load at the start of a pulmonary exacerbation. Plasma concentrations of 2-nonyl-4-hydroxy-quinoline (NHQ) were significantly higher at the start of a pulmonary exacerbation compared to clinical stability (p&lt;0.01). Following the administration of systemic antibiotics, plasma 2-heptyl-4-hydroxyquinoline (p=0.02) and NHQ concentrations (p&lt;0.01) decreased significantly. In conclusion, quorum sensing signal molecules are detectable in cystic fibrosis patients with pulmonary P. aeruginosa infection and are positively correlated with quantitative measures of P. aeruginosa . NHQ correlates with clinical status and has potential as a novel biomarker for P. aeruginosa infection.
The detrimental role of angiotensin receptor agonistic autoantibodies in intrauterine growth restriction seen in preeclampsia
Authors: Roxanna A. Irani, Yujin Zhang, Sean C. Blackwell, Cissy Chenyi Zhou, Susan M. Ramin, Rodney E. Kellems, Yang Xia
Journal: The Journal of Experimental Medicine (2009)

Growth-restricted fetuses are at risk for a variety of lifelong medical conditions. Preeclampsia, a life-threatening hypertensive disorder of pregnancy, is associated with fetuses who suffer from intrauterine growth restriction (IUGR). Recently, emerging evidence indicates that preeclamptic women harbor AT1 receptor agonistic autoantibodies (AT1-AAs) that contribute to the disease features. However, the exact role of AT1-AAs in IUGR and the underlying mechanisms have not been identified. We report that these autoantibodies are present in the cord blood of women with preeclampsia and retain the ability to activate AT1 receptors. Using an autoantibody-induced animal model of preeclampsia, we show that AT1-AAs cross the mouse placenta, enter fetal circulation, and lead to small fetuses with organ growth retardation. AT1-AAs also induce apoptosis in the placentas of pregnant mice, human villous explants, and human trophoblast cells. Finally, autoantibody-induced IUGR and placental apoptosis are diminished by either losartan or an autoantibody-neutralizing peptide. Thus, these studies identify AT1-AA as a novel causative factor of preeclampsia-associated IUGR and offer two possible underlying mechanisms: a direct detrimental effect on fetal development by crossing the placenta and entering fetal circulation, and indirectly through AT1-AA–induced placental damage. Our findings highlight AT1-AAs as important therapeutic targets.