tbuckley/cabot-search huggingface dataset:
Treatment of small cell lung cancer patients
Authors: S. Zöchbauer-Müller, R. Pirker, H. Huber
Journal: Annals of Oncology (1999)

Small cell lung cancers, comprising approximately 20% of lung cancers, are rapidly growing and disseminating carcinomas which are initially chemosensitive but acquire drug resistance during the course of disease. Thus, outcome is poor with median survival of 10-16 months for patients with limited and 7-11 months for patients with extensive disease. Polychemotherapy with established drugs (platins, etoposide, anthracyclines, cyclophosphamide, ifosfamide and Vinca alkaloids) plays the major role in the treatment of this disease and results in overall response rates between 80%-95% for limited disease and 60%-80% for extensive disease. Dose-intensified chemotherapy and high-dose chemotherapy with peripheral blood progenitor cell support were tested in several trials but their exact impact on outcome remains to be determined. New drugs including the taxanes (paclitaxel, docetaxel), the topoisomerase I inhibitors (topotecan, irinotecan), vinorelbine and gemcitabine are currently evaluated in clinical trials. In limited disease, thoracic radiotherapy improves survival and prophylactic cranial irradiation should be administered to those with a reasonable chance of cure.
Endogenous Muscle Atrophy F-Box Mediates Pressure Overload–Induced Cardiac Hypertrophy Through Regulation of Nuclear Factor-κB
Authors: Soichiro Usui, Yasuhiro Maejima, Jayashree Pain, Chull Hong, Jaeyeaon Cho, Ji Yeon Park, Daniela Zablocki, Bin Tian, David J. Glass, Junichi Sadoshima
Journal: Circulation Research (2011)

Overexpression of muscle atrophy F-box (MAFbx/atrogin-1), an E3 ubiquitin ligase, induces proteasomal degradation in cardiomyocytes. The role of endogenous MAFbx in regulating cardiac hypertrophy and failure remains unclear.We investigated the role of MAFbx in regulating cardiac hypertrophy and function in response to pressure overload. Transverse aortic constriction (TAC) was applied to MAFbx knockout (KO) and wild-type (WT) mice.Expression of MAFbx in WT mice was significantly increased by TAC. TAC-induced increases in cardiac hypertrophy were significantly smaller in MAFbx KO than in WT mice. There was significantly less lung congestion and interstitial fibrosis in MAFbx KO than in WT mice. MAFbx KO also inhibited β-adrenergic cardiac hypertrophy. DNA microarray analysis revealed that activation of genes associated with the transcription factor binding site for the nuclear factor-κB family were inhibited in MAFbx KO mice compared with WT mice after TAC. Although the levels of IκB-α were significantly decreased after TAC in WT mice, they were increased in MAFbx KO mice. MAFbx regulates ubiquitination and proteasomal degradation of IκB-α in cardiomyocytes. In primary cultured rat cardiomyocytes, phenylephrine-induced activation of nuclear factor-κB and hypertrophy were significantly suppressed by MAFbx knockdown but were partially rescued by overexpression of nuclear factor-κB p65.MAFbx plays an essential role in mediating cardiac hypertrophy in response to pressure overload. Downregulation of MAFbx inhibits cardiac hypertrophy in part through stabilization of IκB-α and inactivation of nuclear factor-κB. Taken together, inhibition of MAFbx attenuates pathological hypertrophy, thereby protecting the heart from progression into heart failure.
Inhibition of Reflex Vasoconstriction after Experimental Coronary Embolization in the Dog
Authors: DANIEL B. TOUBES, MICHAEL J. BRODY
Journal: Circulation Research (1970)

The possibility that failure of vascular resistance to increase contributes to hypotension after myocardial infarction was examined in the hindlimbs of dogs following embolization of the coronary arteries. Vascular resistance did not change significantly during sustained severe hypotension after embolization in either the intact hindlimb or in simultaneously autoperfused innervated and denervated hindlimbs using constant flow. In nonembolized animals, an immediate large increase in hindlimb vascular resistance occurred when equivalent hypotension was produced by stimulation of the distal end of the sectioned vagus nerve. Lack of such response during hypotension after embolization suggested that inhibition of reflex vasoconstriction had occcurred. Bilateral cervical vagotomy allowed normal reflex vasoconstriction to proceed during hypotension after infarction. These data indicate that (1) since vascular resistance is unchanged in both innervated and denervated hindlimbs, normal neurogenic vascular tone is sustained during hypotension after myocardial infarction and (2) the baroreceptor reflex, which normally promotes vasoconstriction during hypotension, is inhibited reflexly following myocardial infarction, probably by activation of cardiac vagal afferents.
Evolution of nicotinic acetylcholine receptor subunits
Authors: K. Tsunoyama, T. Gojobori
Journal: Molecular Biology and Evolution (1998)

A phylogenetic tree of a gene family of nicotinic acetylcholine receptor subunits was constructed using 84 nucleotide sequences of receptor subunits from 18 different species in order to elucidate the evolutionary origin of receptor subunits. The tree constructed showed that the common ancestor of all subunits may have appeared first in the nervous system. Moreover, we suggest that the alpha 1 subunits in the muscle system originated from the common ancestor of alpha 2, alpha 3, alpha 4, alpha 5, alpha 6, and beta 3 in the nervous system, whereas the beta 1, gamma, delta, and epsilon subunits in the muscle system shared a common ancestor with the beta 2 and beta 4 subunits in the nervous system. Using the ratio (f) of the number of nonsynonymous substitutions to that of synonymous substitutions, we predicted the functional importance of subunits. We found that the alpha 1 and alpha 7 subunits had the lowest f values in the muscle and nervous systems, respectively, indicating that very strong functional constraints work on these subunits. This is consistent with the fact that the alpha 1 subunit has sites binding to the ligand, and the alpha 7-containing receptor regulates the release of the transmitter. Moreover, the window analysis of the f values showed that strong functional constraints work on the so-called M2 region in all five types of muscle subunits. Thus, the window analysis of the f values is useful for evaluating the degree of functional constraints in not only the entire gene region, but also the within-gene subregion.
Intrinsic Constraint on Plasmablast Growth and Extrinsic Limits of Plasma Cell Survival
Authors: Daniel M.-Y. Sze, Kai-Michael Toellner, Carola García de Vinuesa, Dale R. Taylor, Ian C.M. MacLennan
Journal: The Journal of Experimental Medicine (2000)

B cells recruited into splenic antibody responses grow exponentially, either in extrafollicular foci as plasmablasts, or in follicles where they form germinal centers. Both responses yield plasma cells. Although many splenic plasma cells survive <3 d, some live much longer. This study shows that early plasma cell death relates to a finite capacity of the spleen to sustain plasma cells rather than a life span endowed by the cell's origin or the quality of antibody it produces. Antibody responses were compared where the peak numbers of plasma cells in spleen sections varied between 100 and 5,000 cells/mm(2). In each response, plasmablast clones divided some five times, with the peak numbers of plasma cells produced relating directly to the number of B cells recruited into the response. The spleen seems to have the capacity to sustain between 20 and 100 plasma cells/mm(2). When this number is exceeded, there is a loss of excess cells. Immunoglobulin variable region gene sequencing, and 5-bromo-2'-deoxyuridine pulse-chase studies indicate that long-lived splenic plasma cells are a mixture of cells derived from the extrafollicular and germinal center responses and cells derived from virgin and memory B cells. Only a proportion has switched immunoglobulin class.
Effects of interleukin (IL)-17A and IL-17F in human rheumatoid arthritis synoviocytes
Authors: A. Hot, P. Miossec
Journal: Annals of the Rheumatic Diseases (2011)

Rheumatoid arthritis (RA) is a chronic inflammatory disease where the contribution of T cells is now supported by clinical results. Among the cytokines produced by T cells, interleukin (IL)-17A (previously known as IL-17) and IL-17F constitute the signature cytokines of the newly described Th17 T helper cell subset. While the effects of IL-17A on RA synoviocytes been well described, those of IL-17F remain less studied. The present review describes the effects of IL-17A and IL-17F on synoviocytes and their contribution to RA pathogenesis. Although IL-17F is less active than IL-17A when used alone, IL-17A and IL-17F induce in synoviocytes a rather similar expression pattern in the presence of tumour necrosis factor α. They enhance their response by stabilising mRNA of cytokines and enhancing receptor expression. They increase the migration, chemokine gene expression and invasiveness of synoviocytes. They contribute to disease chronicity by inhibiting synoviocyte apoptosis. Finally, they enhance metalloprotease secretion leading to cartilage damage. These properties support the combined inhibition of IL-17A and -F to control RA inflammation and joint destruction.
The Admissibility of Behavioral Science Evidence in the Courtroom: The Translation of Legal to Scientific Concepts and Back
Authors: David Faust, Paul W. Grimm, David C. Ahern, Mark Sokolik
Journal: Annual Review of Clinical Psychology (2010)

Starting with the Daubert case, courtroom rules and guides regulating the admissibility of scientific evidence have undergone major revisions over the past 10 to 15 years. We review these changes and current legal rules and guides, in particular their impact on the admission of behavioral sciences evidence and testimony. We examine commonly intended meanings, conceptualizations, and language use relating to science and the admission of evidence within the legal system and their relation to more familiar terms and concepts within the behavioral sciences, identifying points of continuity and discontinuity. We then review illustrative legal cases involving challenges to the admission of psychological and psychiatric evidence and their implications for mental health professionals. Finally, we offer a framework for conceptualizing and prioritizing key legal criteria for determining admissibility and appraising standing on these factors within the mental health field. Increased mutual understanding between psychology and law should further enhance productive interfaces between the disciplines and add to the many instances in which the proper use of science in the courtroom has facilitated fair resolution of legal conflicts.
Margin Clearance and Outcome in Resected Pancreatic Cancer
Authors: David K. Chang, Amber L. Johns, Neil D. Merrett, Anthony J. Gill, Emily K. Colvin, Christopher J. Scarlett, Nam Q. Nguyen, Rupert W.L. Leong, Peter H. Cosman, Mark I. Kelly, Robert L. Sutherland, Susan M. Henshall, James G. Kench, Andrew V. Biankin
Journal: Journal of Clinical Oncology (2009)

Current adjuvant therapies for pancreatic cancer (PC) are inconsistently used and only modestly effective. Because a high proportion of patients who undergo resection for PC likely harbor occult metastatic disease, any adjuvant trials assessing therapies such as radiotherapy directed at locoregional disease are significantly underpowered. Stratification based on the probability (and volume) of residual locoregional disease could play an important role in the design of future clinical trials assessing adjuvant radiotherapy.We assessed the relationships between margin involvement, the proximity to operative resection margins and outcome in a cohort of 365 patients who underwent operative resection for PC.Microscopic involvement of a resection margin by tumor was associated with a poor prognosis. Stratifying the minimum clearance of resection margins by 0.5-mm increments demonstrated that although median survival was no different to clear margins based on these definitions, it was not until the resection margin was clear by more than 1.5 mm that optimal long-term survival was achieved.These data demonstrate that a margin clearance of more than 1.5 mm is important for long-term survival in a subgroup of patients. More aggressive therapeutic approaches that target locoregional disease such as radiotherapy may be beneficial in patients with close surgical margins. Stratification of patients for entry onto future clinical trials based on this criterion may identify those patients who benefit from adjuvant radiotherapy.
Dysphagia and an oesophageal stricture; not always cancer
Authors: K J Woittiez, W R ten Hove, J T M van der Heyden
Journal: Gut (2008)

A 48-year-old Caucasian male was referred to the hospital because of dysphagia. Medical history included a pleuritis and alcohol abuse. For 6 months he had been suffering from pain and regurgitation after ingestion of solid food. He reported a 6 kg weight loss in the past 6 months.

Physical examination showed no abnormalities, and …
Bullying victimisation and risk of self harm in early adolescence: longitudinal cohort study
Authors: H. L. Fisher, T. E. Moffitt, R. M. Houts, D. W. Belsky, L. Arseneault, A. Caspi
Journal: BMJ (2012)

<b>Objectives</b> To test whether frequent bullying victimisation in childhood increases the likelihood of self harming in early adolescence, and to identify which bullied children are at highest risk of self harm. <b>Design</b> The Environmental Risk (E-Risk) longitudinal study of a nationally representative UK cohort of 1116 twin pairs born in 1994-95 (2232 children). <b>Setting</b> England and Wales, United Kingdom. <b>Participants</b> Children assessed at 5, 7, 10, and 12 years of age. <b>Main outcome measures</b> Relative risks of children’s self harming behaviour in the six months before their 12th birthday. <b>Results</b> Self harm data were available for 2141 children. Among children aged 12 who had self harmed (2.9%; n=62), more than half were victims of frequent bullying (56%; n=35). Exposure to frequent bullying predicted higher rates of self harm even after children’s pre-morbid emotional and behavioural problems, low IQ, and family environmental risks were taken into account (bullying victimisation reported by mother: adjusted relative risk 1.92, 95% confidence interval 1.18 to 3.12; bullying victimisation reported by child: 2.44, 1.36 to 4.40). Victimised twins were more likely to self harm than were their non-victimised twin sibling (bullying victimisation reported by mother: 13/162 <i>v</i> 3/162, ratio=4.3, 95% confidence interval 1.3 to 14.0; bullying victimisation reported by child: 12/144 <i>v</i> 7/144, ratio=1.7, 0.71 to 4.1). Compared with bullied children who did not self harm, bullied children who self harmed were distinguished by a family history of attempted/completed suicide, concurrent mental health problems, and a history of physical maltreatment by an adult. <b>Conclusions</b> Prevention of non-suicidal self injury in young adolescents should focus on helping bullied children to cope more appropriately with their distress. Programmes should target children who have additional mental health problems, have a family history of attempted/completed suicide, or have been maltreated by an adult.
ADAPTIVE SERVO-VENTILATION IMPROVES CARDIAC SYMPATHETIC NERVE ACTIVITY IN PATIENTS WITH HEART FAILURE BY EVALUATION OF 11C-HYDROXYEPHEDRINE POSITRON EMISSION TOMOGRAPHY
Authors: Shiro Yamada, Mamoru Sakakibara, Kiwamu Kamiya, Naoya Asakawa, Takashi Yoshitani, Satoshi Yamada, Keiichiro Yoshinaga, Hiroyuki Tsutsui
Journal: Journal of the American College of Cardiology (2014)
The effectiveness of a neuromuscular prevention strategy to reduce injuries in youth soccer: a cluster-randomised controlled trial
Authors: C A Emery, W H Meeuwisse
Journal: British Journal of Sports Medicine (2010)

Background Soccer is a leading sport for participation and injury in youth. Objective To examine the effectiveness of a neuromuscular prevention strategy in reducing injury in youth soccer players. Design Cluster-randomised controlled trial. Setting Calgary soccer clubs (male or female, U13–U18, tier 1–2, indoor soccer). Participants Eighty-two soccer teams were approached for recruitment. Players from 60 teams completed the study (32 training (n=380), 28 control (n=364)). Intervention The training programme was a soccer-specific neuromuscular training programme including dynamic stretching, eccentric strength, agility, jumping and balance (including a home-based balance training programme using a wobble board). The control programme was a standardised warm-up (static and dynamic stretching and aerobic components) and a home-based stretching programme. Main outcome measures Previously validated injury surveillance included injury assessment by a study therapist. The injury definition was soccer injury resulting in medical attention and/or removal from a session and/or time loss. Results The injury rate in the training group was 2.08 injuries/1000 player-hours, and in the control group 3.35 injuries/1000 player-hours. Based on Poisson regression analysis, adjusted for clustering by team and covariates, the incidence rate ratios (IRR) for all injuries and acute onset injury were 0.62 (95% CI 0.39 to 0.99) and 0.57 (95% CI 0.35 to 0.91). Point estimates also suggest protection of lower extremity, ankle and knee sprain injuries (IRR=0.68 (95% CI 0.42 to 1.11), IRR=0.5 (95% CI 0.24 to 1.04) and IRR=0.38 (95% CI 0.08 to 1.75)). Conclusions A neuromuscular training programme is protective of all injuries and acute onset injury in youth soccer players.
Clinical features and functional significance of the P369S/R408Q variant in pyrin, the familial Mediterranean fever protein
Authors: J. G. Ryan, S. L. Masters, M. G. Booty, N. Habal, J. D. Alexander, B. K. Barham, E. F. Remmers, K. S. Barron, D. L. Kastner, I. Aksentijevich
Journal: Annals of the Rheumatic Diseases (2009)

<h3>Objectives</h3> Familial Mediterranean fever (FMF) is caused by mutations in <i>MEFV</i>, which encodes pyrin. The nature of substitutions P369S and R408Q in exon 3 remains unclear. Exon 3 encoding pyrin9s B-box domain is necessary for interactions with proline serine threonine phosphatase interacting protein 1 (PSTPIP1). The aim was to characterise the phenotype of patients with these substitutions and to determine their functional significance. <h3>Methods</h3> A database of genetic tests undertaken at the US National Institutes of Health was interrogated. Symptoms and signs were classified according to Tel-Hashomer criteria. Coimmunoprecipitation techniques were employed to determine the variants9 effects on pyrin/PSTPIP1 interactions. <h3>Results</h3> A total of 40 symptomatic and 4 asymptomatic family members with these substitutions were identified. P369S and R408Q were found in cis, and cosegregated in all patients sequenced. Clinical details were available on 22 patients. In all, 5 patients had symptoms and signs fulfilling a clinical diagnosis of FMF, and 15 received colchicine. In patients not achieving the criteria, trials of anti-tumour necrosis factor (TNF) agents resulted in partial or no benefit; resolution of symptoms was noted in those receiving anakinra. The carrier frequency was higher in the patient cohort than in controls but was not statistically significant. Coimmunoprecipitation studies demonstrated that these pyrin variants did not affect binding to PSTPIP1. <h3>Conclusions</h3> P369S/R408Q substitutions are associated with a highly variable phenotype, and are infrequently associated with typical FMF symptoms, however a trial of colchicine is warranted in all. Functional and modelling studies suggest that these substitutions do not significantly affect pyrin9s interaction with PSTPIP1. This study highlights the need for caution in interpreting genetic tests in patients with atypical symptoms.
Membrane Fas Ligand Kills Human Peripheral Blood T Lymphocytes, and Soluble Fas Ligand Blocks the Killing
Authors: Takashi Suda, Hideo Hashimoto, Masato Tanaka, Takahiro Ochi, Shigekazu Nagata
Journal: The Journal of Experimental Medicine (1997)

It has been believed that the Fas expressed on human peripheral blood T cells (PBT) is nonfunctional, because these cells are insensitive to agonistic anti-Fas/Apo-1 mAbs that efficiently kill in vitro–activated T cells and many Fas-expressing cell lines. Here, we demonstrate that membrane-bound Fas ligand (FasL) kills both fresh and in vitro–activated PBT, indicating that the Fas expressed on fresh PBT is functional. In contrast, soluble FasL kills only the latter. Naive T cells in umbilical cord blood do not express Fas, but can be induced to express Fas by IFN-γ or by a combination of IL-2 and anti-CD28 mAb, after which they acquire sensitivity to membrane but not to soluble FasL. Soluble FasL inhibited the killing of fresh PBT by membrane FasL. These results indicate that the shedding of FasL from the membrane is a mechanism for downregulating at least part of its killing activity.
Experts call for patient safety in preregistration training to be explicit
Authors: A. O'Dowd
Journal: BMJ (2009)

Patient safety is implicit rather than explicit in medical training and needs to be clarified for students and their educators, MPs have been told.

A researcher and expert on good clinical practice told MPs on the parliamentary health select committee as part of their inquiry into patient safety that the safety of patients had to become an integral part of everything that clinicians did in their work.

At an evidence session on Thursday 22 January, the committee asked whether patient safety was sufficiently taken into account in clinical education and training.

Pauline Pearson, deputy director of the Centre …
Psychological services in hospices in the UK and Republic ofIreland
Authors: A. Price, M. Hotopf, I. J. Higginson, B. Monroe, M. Henderson
Journal: Journal of the Royal Society of Medicine (2006)

To evaluate the level of psychological services available to patients and staff in hospices.Questionnaire analysis.Hospices in the UK and Republic of Ireland.224 hospices.The availability of professional psychological support for those with advanced disease.Responses were received from 166 hospices (74%). Only 50 hospices (30%) have access to a psychiatrist, whilst 68 (41%) have access to a clinical psychologist and 92 (45%) have neither. Only 21 hospices (12%) have service level agreements with local mental health trusts. Counsellors, complementary therapists and spiritual advisors such as chaplains were more plentiful.Delivery of the NICE guidelines, especially tier four, may be compromised by limited availability of specialist services. This has implications for the psychological assessment of applicants for voluntary euthanasia under an Assisted Dying Act.