tbuckley/cabot-search huggingface dataset:
Influence on general practitioners of teaching undergraduates: qualitative study of London general practitioner teachers
Authors: S. Hartley, F. Macfarlane, M. Gantley, E. Murray
Journal: BMJ (1999)

Objective: To examine the perceived effect of teaching clinical skills and associated teacher training programmes on general practitioners' morale and clinical practice. Design: Qualitative semistructured interview study. Setting: General practices throughout north London. Subjects: 30 general practitioners who taught clinical skills were asked about the effect of teaching and teacher training on their morale, confidence in clinical and teaching skills, and clinical practice. Results: The main theme was a positive effect on morale. Within teacher training this was attributed to developing peer and professional support; improved teaching skills; and revision of clinical knowledge and skills Within teaching this was attributed to a broadening of horizons; contact with enthusiastic students; increased time with patients; improved clinical practice; improved teaching skills; and an improved image of the practice. Problems with teaching were due to external factors such as lack of time and space and anxieties about adequacy of clinical cover while teaching. Conclusions: Teaching clinical skills can have a positive effect on the morale of general practitioner teachers as a result of contact with students and peers, as long as logistic and funding issues are adequately dealt with. #### Key messages
CD4+ T cells are trigger and target of the glucocorticoid response that prevents lethal immunopathology in toxoplasma infection
Authors: David G. Kugler, Paul R. Mittelstadt, Jonathan D. Ashwell, Alan Sher, Dragana Jankovic
Journal: The Journal of Experimental Medicine (2013)

Synthetic glucocorticoids (GCs) are commonly used in the treatment of inflammatory diseases, but the role of endogenous GCs in the regulation of host-protective immune responses is poorly understood. Here we show that GCs are induced during acute Toxoplasma gondii infection and directly control the T cell response to the parasite. When infected with toxoplasma, mice that selectively lack GC receptor (GR) expression in T cells (GRlck-Cre) rapidly succumb to infection despite displaying parasite burdens indistinguishable from control animals and unaltered levels of the innate cytokines IL-12 and IL-27. Mortality in the GRlck-Cre mice was associated with immunopathology and hyperactive Th1 cell function as revealed by enhanced IFN-γ and TNF production in vivo. Unexpectedly, these CD4+ T lymphocytes also overexpressed IL-10. Importantly, CD4+ T cell depletion in wild-type or GRlck-Cre mice led to ablation of the GC response to infection. Moreover, in toxoplasma-infected RAG−/− animals, adoptive transfer of CD4+ T lymphocytes was required for GC induction. These findings establish a novel IL-10–independent immunomodulatory circuit in which CD4+ T cells trigger a GC response that in turn dampens their own effector function. In the case of T. gondii infection, this self-regulatory pathway is critical for preventing collateral tissue damage and promoting host survival.
Nuclear remodelling: a consequence of nucleocytoplasmic traffic run amok?
Authors: Julie Bossuyt
Journal: Cardiovascular Research (2014)

This editorial refers to ‘Nuclear pore rearrangements and nuclear trafficking in cardiomyocytes from rat and human failing hearts’ by M.N. Chahine et al. , pp. 31–43, this issue. 

An intriguing new study by Chahine et al. 1 finds that alterations in nuclear architecture and transport machinery (leading to increased export and decreased import) manifest early on, during hypertrophy development, in both a rat infarct model and human failing hearts. Moreover, it finds that general blockade of the increased nuclear export traffic can prevent or even reverse both the nuclear remodelling and hypertrophic changes. This article forwards the interesting notion that failure of the nuclear import/export pathways themselves is at the basis of the nuclear remodelling process during heart failure development.

Cardiac remodelling is a hallmark of heart failure characterized at the myocyte level by cellular hypertrophy and reactivation of a fetal gene program. Studies examining the molecular mechanisms underlying the transcriptional reprogramming typically focus on the interwoven signalling cascades that culminate in the nucleus …
Annual Ambient Black Carbon Associated with Shorter Telomeres in Elderly Men: Veterans Affairs Normative Aging Study
Authors: John McCracken, Andrea Baccarelli, Mirjam Hoxha, Laura Dioni, Steve Melly, Brent Coull, Helen Suh, Pantel Vokonas, Joel Schwartz
Journal: Environmental Health Perspectives (2010)

BackgroundTelomere length reflects biological age and is inversely associated with risk of cardiovascular disease (CVD). Ambient air pollution is associated with CVD, but its effect on telomere length is unknown.ObjectiveWe investigated whether ambient black carbon (BC), a marker for traffic-related particles, is associated with telomere length in the Normative Aging Study (NAS).MethodsAmong 165 never-smoking men from the NAS, leukocyte telomere length (LTL) was measured repeatedly approximately every 3 years from 1999 through 2006 using quantitative real-time polymerase chain reaction (qRT-PCR). BC concentration at their residences during the year before each LTL measurement was estimated based on a spatiotemporal model calibrated with BC measurements from 82 locations within the study area.ResultsThe median [interquartile range (IQR)] annual moving-average BC concentration was 0.32 (0.20–0.45) μg/m3. LTL, expressed as population-standardized ratio of telomere repeat to single-copy gene copy numbers, had a geometric mean (geometric SD) of 1.25 (1.42). We used linear mixed-effects models including random subject intercepts and adjusted for several potential confounders. We used inverse probability of response weighting to adjust for potential selection bias due to loss to follow-up. An IQR increase in annual BC (0.25 μg/m3) was associated with a 7.6% decrease (95% confidence interval, −12.8 to −2.1) in LTL. We found evidence of effect modification, with a stronger association among subjects ≥ 75 years of age compared with younger participants (p = 0.050) and statin medications appearing protective of the effects of BC on LTL (p = 0.050).ConclusionsTelomere attrition, linked to biological aging, may be associated with long-term exposures to airborne particles, particularly those rich in BC, which are primarily related to automobile traffic.
A Gower Maneuver: The American Society for Bioethics and Humanities' Resolution of the "Taking Stands" Debate
Authors: Armand H. Matheny Antommaria
Journal: The American Journal of Bioethics (2004)

The American Society for Bioethics and Humanities debated for several years about whether it should adopt positions and, if so, on what range of issues. The membership recently approved an amendment to its bylaws permitting the Society to adopt positions on matters related to academic freedom and professionalism but not on substantive moral and policy issues. This resolution is problematic for a number of reasons, including the lack of a categorical difference between these types of claims and the Society's inability to speak on behalf of patients and research subjects. The implementation of the amendment also raises several issues. The Society will need to refrain from speaking too specifically and to articulate the responsibilities of its members. If the Society fails to address these concerns, it runs the risk of denigrating its public image and that of the profession.
Use of regularly scheduled albuterol treatment in asthma: genotype-stratified, randomised, placebo-controlled cross-over trial
Authors: Elliot Israel, Vernon M Chinchilli, Jean G Ford, Homer A Boushey, Reuben Cherniack, Timothy J Craig, Aaron Deykin, Joanne K Fagan, John V Fahy, James Fish, Monica Kraft, Susan J Kunselman, Stephen C Lazarus, Robert F Lemanske, Stephen B Liggett, Richard J Martin, Nandita Mitra, Stephen P Peters, Eric Silverman, Christine A Sorkness, Stanley J Szefler, Michael E Wechsler, Scott T Weiss, Jeffrey M Drazen
Journal: The Lancet (2004)
Loss of Tuberous Sclerosis Complex-2 Function and Activation of Mammalian Target of Rapamycin Signaling in Endometrial Carcinoma
Authors: Karen H. Lu, Weiguo Wu, Bhuvanesh Dave, Brian M. Slomovitz, Thomas W. Burke, Mark F. Munsell, Russell R. Broaddus, Cheryl Lyn Walker
Journal: Clinical Cancer Research (2008)

Abstract Purpose: The involvement of phosphatase and tensin homologue deleted on chromosome ten (PTEN) in endometrial carcinoma has implicated phosphatidylinositol 3-kinase signaling and mammalian target of rapamycin (mTOR) activation in this disease. Understanding the extent of mTOR involvement and the mechanism responsible for activation is important, as mTOR inhibitors are currently being evaluated in clinical trials for endometrial carcinoma. Although tuberous sclerosis complex 2 (TSC2) is the “gatekeeper” for mTOR activation, little is known about defects in the TSC2 tumor suppressor or signaling pathways that regulate TSC2, such as LKB1/AMP-activated protein kinase, in the development of endometrial carcinoma. Experimental Design: We determined the frequency of mTOR activation in endometrial carcinoma (primary tumors and cell lines) and investigated PTEN, LKB1, and TSC2 defects as underlying cause(s) of mTOR activation, and determined the ability of rapamycin to reverse these signaling defects in endometrial carcinoma cells. Results: Activation of mTOR was a consistent feature in endometrial carcinomas and cell lines. In addition to PTEN, loss of TSC2 and LKB1 expression occurred in a significant fraction of primary tumors (13% and 21%, respectively). In tumors that retained TSC2 expression, phosphorylation of tuberin at S939 was observed with a high frequency, indicating that mTOR repression by TSC2 had been relieved via AKT phosphorylation of this tumor suppressor. In PTEN-null and LKB1-null endometrial carcinoma cell lines with functional inactivation of TSC2, phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin and LY294002 were able to inhibit AKT and mTOR signaling and reverse TSC2 phosphorylation. In contrast, although rapamycin inhibited mTOR signaling, it did not relieve phosphorylation of TSC2 at S939. Conclusions: Inactivation of TSC2 via loss of expression or phosphorylation occurred frequently in endometrial carcinoma to activate mTOR signaling. High-frequency mTOR activation supports mTOR as a rational therapeutic target for endometrial carcinoma. However, whereas rapamycin and its analogues may be efficacious at inhibiting mTOR activity, these drugs do not reverse the functional inactivation of TSC2 that occurs in these tumors.
Inositol Hexaphosphate Suppresses Growth and Induces Apoptosis in Prostate Carcinoma Cells in Culture and Nude Mouse Xenograft: PI3K-Akt Pathway as Potential Target
Authors: Mallikarjuna Gu, Srirupa Roy, Komal Raina, Chapla Agarwal, Rajesh Agarwal
Journal: Cancer Research (2009)

Abstract Constitutive activation of phosphoinositide 3-kinase (PI3K)-Akt pathway transmits growth-regulatory signals that play a central role in promoting survival, proliferation, and angiogenesis in human prostate cancer cells. Here, we assessed the efficacy of inositol hexaphosphate (IP6) against invasive human prostate cancer PC-3 and C4-2B cells and regulation of PI3K-Akt pathway. IP6 treatment of cells suppressed proliferation, induced apoptosis along with caspase-3 and poly(ADP-ribose) polymerase (PARP) cleavage, and inhibited constitutive activation of Akt and its upstream regulators PI3K, phosphoinositide-dependent kinase-1 and integrin-linked kinase-1 (ILK1). Downstream of Akt, IP6 inhibited the phosphorylation of glycogen synthase kinase-3α/β at Ser21/9 and consequently reduced cyclin D1 expression. Efficacy studies employing PC-3 tumor xenograft growth in nude mice showed that 2% (w/v) IP6 feeding in drinking water inhibits tumor growth and weight by 52% to 59% (P &amp;lt; 0.001). Immunohistochemical analysis of xenografts showed that IP6 significantly reduces the expression of molecules associated with cell survival/proliferation (ILK1, phosphorylated Akt, cyclin D1, and proliferating cell nuclear antigen) and angiogenesis (platelet endothelial cell adhesion molecule-1 or CD31, vascular endothelial growth factor, endothelial nitric oxide synthase, and hypoxia-inducible factor-1α) together with an increase in apoptotic markers (cleaved caspase-3 and PARP). These findings suggest that, by targeting the PI3K-ILK1-Akt pathway, IP6 suppresses cell survival, proliferation, and angiogenesis but induces death in prostate cancer cells, which might have translational potential in preventing and controlling the growth of advanced and aggressive prostate cancer for which conventional chemotherapy is not effective. [Cancer Res 2009;69(24):9465–72]
Collagen type III alpha I is a gastro-oesophageal reflux disease susceptibility gene and a male risk factor for hiatus hernia
Authors: B. Asling, J. Jirholt, P. Hammond, M. Knutsson, A. Walentinsson, G. Davidson, L. Agreus, A. Lehmann, M. Lagerstrom-Fermer
Journal: Gut (2009)

<h3>Background and objectives:</h3> Gastro-oesophageal reflux disease (GORD) is a common gastrointestinal disorder with a genetic component. Our aim was to identify genetic factors associated with GORD. <h3>Patients and methods:</h3> Four separate patient cohorts were analysed using a step-wise approach. (1) Whole genome linkage analysis was performed in 36 families. (2) Candidate genes were tested for GORD association in a trio cohort. (3) Genetic association was replicated in a case–control cohort. We also investigated genetic association to hiatus hernia (HH). (4) Protein expression was analysed in oesophageal biopsies. <h3>Results:</h3> A region on chromosome 2, containing collagen type III alpha 1 (COL3A1), was identified (LOD = 3.3) in families with dominant transmission of GORD, stratified for hiatus hernia (HH). COL3A1 showed significant association with GORD in an independent paediatric trio cohort (p<sub>corr</sub> = 0.003). The association was male specific (p<sub>corr</sub> = 0.018). The COL3A1 association was replicated in an independent adult case control cohort (p<sub>corr</sub> = 0.022). Moreover, male specific association to HH (p<sub>corr</sub> = 0.019) was found for a SNP not associated to GORD. Collagen type III protein was more abundant in oesophageal biopsies from male patients with GORD (p = 0.03). <h3>Conclusion:</h3> COL3A1 is a disease-associated gene in both paediatric and adult GORD. Furthermore, we show that COL3A1 is genetically associated with HH in adult males. The GORD- and HH-associated alleles are different, indicating two separate mechanisms leading to disease. Our data provides new insight into GORD aetiology, identifying a connective tissue component and indicating a tissue remodelling mechanism in GORD. Our results implicate gender differences in the genetic risk for both for GORD and HH.
Human L-ferritin deficiency is characterized by idiopathic generalized seizures and atypical restless leg syndrome
Authors: Anna Cozzi, Paolo Santambrogio, Daniela Privitera, Vania Broccoli, Luisa Ida Rotundo, Barbara Garavaglia, Rudolf Benz, Sandro Altamura, Jeroen S. Goede, Martina U. Muckenthaler, Sonia Levi
Journal: The Journal of Experimental Medicine (2013)

The ubiquitously expressed iron storage protein ferritin plays a central role in maintaining cellular iron homeostasis. Cytosolic ferritins are composed of heavy (H) and light (L) subunits that co-assemble into a hollow spherical shell with an internal cavity where iron is stored. The ferroxidase activity of the ferritin H chain is critical to store iron in its Fe3+ oxidation state, while the L chain shows iron nucleation properties. We describe a unique case of a 23-yr-old female patient affected by a homozygous loss of function mutation in the L-ferritin gene, idiopathic generalized seizures, and atypical restless leg syndrome (RLS). We show that L chain ferritin is undetectable in primary fibroblasts from the patient, and thus ferritin consists only of H chains. Increased iron incorporation into the FtH homopolymer leads to reduced cellular iron availability, diminished levels of cytosolic catalase, SOD1 protein levels, enhanced ROS production and higher levels of oxidized proteins. Importantly, key phenotypic features observed in fibroblasts are also mirrored in reprogrammed neurons from the patient’s fibroblasts. Our results demonstrate for the first time the pathophysiological consequences of L-ferritin deficiency in a human and help to define the concept for a new disease entity hallmarked by idiopathic generalized seizure and atypical RLS.
Antiviral Cd8+ T Cell Responses in Neonatal Mice
Authors: Janice M. Moser, John D. Altman, Aron E. Lukacher
Journal: The Journal of Experimental Medicine (2001)

Polyoma virus is a potent oncogenic pathogen when inoculated into newborn mice of particular H-2k strains. Using Dk tetramers containing the dominant antipolyoma CD8+ T cell epitope, middle T protein (MT)389–397, and intracellular interferon γ staining, we enumerated MT389-specific CD8+ T cells in infected neonates having opposite susceptibilities to polyoma virus–induced tumors. In resistant mice, MT389-specific CD8+ T cells dramatically expanded during acute infection in neonates to a frequency rivaling that in adults; furthermore, in both neonatal and adult mice, this antipolyoma CD8+ T cell response exhibited nearly identical T cell receptor (TCR) functional avidities and TCR functional fingerprints. Susceptible mice mounted an MT389-specific CD8+ T cell response of only fourfold lower magnitude than resistant mice; but, in clear contrast to resistant mice, these CD8+ T cells lacked ex vivo MT389-specific cytotoxic activity. However, MT389-specific CD8+ T cells in resistant and susceptible mice expressed similar TCR avidities, perforin levels, and surface type O-glycan levels indicative of mature CD8+ T cell effectors. Upon in vitro restimulation with infected antigen-presenting cells, CD8+ T cells from acutely infected susceptible neonates acquired strong MT389-specific cytotoxicity. These findings indicate that polyoma-specific CD8+ T cells are armed with, but restrained from deploying, their cytotoxic effector function in mice susceptible to polyoma virus tumorigenesis.
Innate immunity defines the capacity of antiviral T cells to limit persistent infection
Authors: Daniel M. Andrews, Marie J. Estcourt, Christopher E. Andoniou, Matthew E. Wikstrom, Andrea Khong, Valentina Voigt, Peter Fleming, Hyacinth Tabarias, Geoffrey R. Hill, Robbert G. van der Most, Anthony A. Scalzo, Mark J. Smyth, Mariapia A. Degli-Esposti
Journal: The Journal of Experimental Medicine (2010)

Effective immunity requires the coordinated activation of innate and adaptive immune responses. Natural killer (NK) cells are central innate immune effectors, but can also affect the generation of acquired immune responses to viruses and malignancies. How NK cells influence the efficacy of adaptive immunity, however, is poorly understood. Here, we show that NK cells negatively regulate the duration and effectiveness of virus-specific CD4+ and CD8+ T cell responses by limiting exposure of T cells to infected antigen-presenting cells. This impacts the quality of T cell responses and the ability to limit viral persistence. Our studies provide unexpected insights into novel interplays between innate and adaptive immune effectors, and define the critical requirements for efficient control of viral persistence.
Dermal fluid translocation is an important determinant of the diurnal variation in human skin thickness
Authors: K. Tsukahara, Y. Takema, S. Moriwaki, T. Fujimura, G. Imokawa
Journal: British Journal of Dermatology (2001)

Ultrasonography has been used as a non-invasive approach to measure skin thickness. To date there have been no studies on diurnal variations in skin thickness.To evaluate diurnal variations in skin thickness and to compare these with corresponding echogenicity and skin elasticity.Measurements by ultrasonography B-mode and by Cutometer SEM 575 were carried out in the morning and in the afternoon on 20 men and 20 women (mean age 30 years) on three areas of the face (forehead, corner of the eye and cheek), the forearm and the upper arm, and the flank, thigh and calf.From the morning to the afternoon, the skin thickness in both sexes significantly decreased on three areas of the face, the forearm and the upper arm, but significantly increased on the thigh and calf. In parallel, the echogenicity significantly increased from the morning to the afternoon on the three areas of the face, the forearm and the upper arm, but decreased significantly on the thigh and calf. Measurements of mechanical properties at four sites demonstrated that from the morning to the afternoon, the major parameters of skin elasticity Ue* and Uf* increased significantly in both sexes on two areas of the face and slightly on the forearm, but decreased significantly on the calf.The diurnal profiles of skin thickness and skin elasticity in the upper half of the body are the reverse of those in the lower half of the body. These findings suggest that shifts of dermal fluid from the face to the leg by gravity during the day cause the diurnal variation in skin thickness.
R-wave amplitude variations during acute experimental myocardial ischemia: an inadequate index for changes in intracardiac volume.
Authors: D David, M Naito, C C Chen, E L Michelson, J Morganroth, M Schaffenburg
Journal: Circulation (1981)

The role of intracardiac volume in controlling electrocardiographic R-wave amplitude changes during acute myocardial ischemia was studied in 24 open-chest dogs. The R-wave amplitude in surface ECG leads 2, V5 and Frank X, Y and Z leads were correlated with hemodynamic, echocardiographic and angiographic changes in a 5-minute circumflex coronary artery ligation and reperfusion model. After coronary ligation, left ventricular end-diastolic diameter and volume increased progressively above control, reached a peak and plateau at 120--130 seconds after ligation and did not return to control levels until more than 5 minutes after release of the occlusion. In contrast, the R-wave amplitude showed a biphasic response to acute ischemia, reaching a nadir (sigma R = 18.2% below control) at 30 seconds after coronary ligation and only subsequently increased to reach a peak (sigma R = 52% above control) at 150 seconds after ligation. In addition, R-wave amplitude returned immediately to control levels within 10 seconds after reperfusion. In six other dogs, both venae cavae were occluded for a 30-second period, beginning 180 seconds after coronary ligation. Although intracardiac volume decreased markedly, R-wave amplitudes increased even more. Thus, the demonstration of discordance between alterations in intracardiac volume and R-wave amplitude in these studies suggests that factors other than intracardiac volume determine R-wave amplitude changes in the course of acute myocardial ischemia.
Proteoglycans on bone marrow endothelial cells bind and present SDF-1 towards hematopoietic progenitor cells
Authors: T Netelenbos, J van den Born, F L Kessler, S Zweegman, P A Merle, J W van Oostveen, J J Zwaginga, P C Huijgens, A M Dräger
Journal: Leukemia (2003)
Myelodysplastic syndrome and acute myeloid leukemia after autotransplantation for lymphoma: a multicenter case-control study
Authors: Catherine Metayer, Rochelle E. Curtis, Julie Vose, Kathleen A. Sobocinski, Mary M. Horowitz, Smita Bhatia, Joseph W. Fay, Cesar O. Freytes, Steven C. Goldstein, Roger H. Herzig, Armand Keating, Carol B. Miller, Thomas J. Nevill, Andrew L. Pecora, Douglas J. Rizzo, Stephanie F. Williams, Chin Yang Li, Lois B. Travis, Daniel J. Weisdorf
Journal: Blood (2002)