tbuckley/cabot-search huggingface dataset:
Live imaging reveals a biphasic mode of dissemination of Borrelia burgdorferi within ticks
Authors: Star M. Dunham-Ems, Melissa J. Caimano, Utpal Pal, Charles W. Wolgemuth, Christian H. Eggers, Anamaria Balic, Justin D. Radolf
Journal: Journal of Clinical Investigation (2009)

Lyme disease is caused by transmission of the spirochete Borrelia burgdorferi from ticks to humans. Although much is known about B. burgdorferi replication, the routes and mechanisms by which it disseminates within the tick remain unclear. To better understand this process, we imaged live, infectious B. burgdorferi expressing a stably integrated, constitutively expressed GFP reporter. Using isolated tick midguts and salivary glands, we observed B. burgdorferi progress through the feeding tick via what we believe to be a novel, biphasic mode of dissemination. In the first phase, replicating spirochetes, positioned at varying depths throughout the midgut at the onset of feeding, formed networks of nonmotile organisms that advanced toward the basolateral surface of the epithelium while adhering to differentiating, hypertrophying, and detaching epithelial cells. In the second phase of dissemination, the nonmotile spirochetes transitioned into motile organisms that penetrated the basement membrane and entered the hemocoel, then migrated to and entered the salivary glands. We designated the first phase of dissemination “adherence-mediated migration” and provided evidence that it involves the inhibition of spirochete motility by one or more diffusible factors elaborated by the feeding tick midgut. Our studies, which we believe are the first to relate the transmission dynamics of spirochetes to the complex morphological and developmental changes that the midgut and salivary glands undergo during engorgement, challenge the conventional viewpoint that dissemination of Lyme disease–causing spirochetes within ticks is exclusively motility driven.
Soluble mesothelin in effusions: a useful tool for the diagnosis of malignant mesothelioma
Authors: J. Creaney, D. Yeoman, L. K Naumoff, M. Hof, A. Segal, A. W. Musk, N. De Klerk, N. Horick, S. J Skates, B. W S Robinson
Journal: Thorax (2007)

<b>Background:</b> The diagnosis of malignant mesothelioma is frequently difficult, the most common differential diagnosis being reactive pleural conditions and metastatic adenocarcinoma. Soluble mesothelin levels in serum have recently been shown to be highly specific and moderately sensitive for mesothelioma. As most patients with mesothelioma present with exudative effusions of either the pleura or the peritoneum, a study was undertaken to determine if levels of mesothelin were raised in these fluids and if the increased levels could help to distinguish mesothelioma from other causes of exudative effusion. <b>Methods:</b> Pleural fluid was collected from 192 patients who presented to respiratory clinics (52 with malignant mesothelioma, 56 with non-mesotheliomatous malignancies and 84 with effusions of non-neoplastic origin). Peritoneal fluid was collected from 42 patients (7 with mesothelioma, 14 with non-mesotheliomatous malignancies and 21 with benign effusions). Mesothelin levels were determined in effusion and serum samples by ELISA. <b>Results:</b> Significantly higher levels of mesothelin were found in effusions of patients with mesothelioma; with a specificity of 98%, the assay had a sensitivity of 67% comparing patients with mesothelioma and those with effusions of non-neoplastic origin. In 7 out of 10 cases mesothelin levels were raised in the effusion collected 3 weeks to 10 months before the diagnosis of mesothelioma was made; in 4 out of 8 of these, mesothelin levels were increased in the effusion but not in the serum. <b>Conclusions:</b> Measurement of mesothelin concentrations in the pleural and/or peritoneal effusion of patients may aid in the differential diagnosis of mesothelioma in patients presenting with effusions.
Type 1 Diabetes Mellitus and Cardiovascular Disease: A Scientific Statement From the American Heart Association and American Diabetes Association
Authors: Sarah D. de Ferranti, Ian H. de Boer, Vivian Fonseca, Caroline S. Fox, Sherita Hill Golden, Carl J. Lavie, Sheela N. Magge, Nikolaus Marx, Darren K. McGuire, Trevor J. Orchard, Bernard Zinman, Robert H. Eckel
Journal: Diabetes Care (2014)

Despite the known higher risk of cardiovascular disease (CVD) in individuals with type 1 diabetes mellitus (T1DM), the pathophysiology underlying the relationship between cardiovascular events, CVD risk factors, and T1DM is not well understood. Management approaches to CVD reduction have been extrapolated in large part from experience in type 2 diabetes mellitus (T2DM), despite the longer duration of disease in T1DM than in T2DM and the important differences in the underlying pathophysiology. Furthermore, the phenotype of T1DM is changing. As a result of the findings of the Diabetes Control and Complications Trial (DCCT), which compared intensive glycemic control with usual care, and its follow-up observational study, Epidemiology of Diabetes Interventions and Complications (EDIC), intensive management of diabetes mellitus (DM) has become the standard of care and has led to increasing longevity. However, our understanding of CVD in T1DM comes in large part from the previous era of less intensive glycemic control. More intensive glycemic control is associated with significant risk of weight gain, which may be magnified by the obesity epidemic. There is growing interest in better understanding the adverse effects of glycemia, the prevalence and type of lipid abnormalities in T1DM, the prognostic role of albuminuria and renal insufficiency, and the role of blood pressure (BP) in CVD. Obesity-associated metabolic abnormalities such as the proinflammatory state likely modify CVD risk in T1DM; however, the effect may be different from what is seen in T2DM. These concepts, and how they may affect management, have not been fully explored.

The present review will focus on the importance of CVD in patients with T1DM. We will summarize recent observations of potential differences in the pathophysiology of T1DM compared with T2DM, particularly with regard to atherosclerosis. We will explore the implications of these concepts for treatment of CVD risk factors in patients with …
Therapeutic antagonists of microRNAs deplete leukemia-initiating cell activity
Authors: Chinavenmeni S. Velu, Aditya Chaubey, James D. Phelan, Shane R. Horman, Mark Wunderlich, Monica L. Guzman, Anil G. Jegga, Nancy J. Zeleznik-Le, Jianjun Chen, James C. Mulloy, Jose A. Cancelas, Craig T. Jordan, Bruce J. Aronow, Guido Marcucci, Balkrishen Bhat, Brian Gebelein, H. Leighton Grimes
Journal: Journal of Clinical Investigation (2013)

Acute myelogenous leukemia (AML) subtypes that result from oncogenic activation of homeobox (HOX) transcription factors are associated with poor prognosis. The HOXA9 transcription activator and growth factor independent 1 (GFI1) transcriptional repressor compete for occupancy at DNA-binding sites for the regulation of common target genes. We exploited this HOXA9 versus GFI1 antagonism to identify the genes encoding microRNA-21 and microRNA-196b as transcriptional targets of HOX-based leukemia oncoproteins. Therapeutic inhibition of microRNA-21 and microRNA-196b inhibited in vitro leukemic colony forming activity and depleted in vivo leukemia-initiating cell activity of HOX-based leukemias, which led to leukemia-free survival in a murine AML model and delayed disease onset in xenograft models. These data establish microRNA as functional effectors of endogenous HOXA9 and HOX-based leukemia oncoproteins, provide a concise in vivo platform to test RNA therapeutics, and suggest therapeutic value for microRNA antagonists in AML.
Bronchiolitis Obliterans Syndrome after Lung Transplantation and Health-related Quality of Life
Authors: JAN W. K. van den BERG, ALBERT GEERTSMA, WIM van der BIJ, GERARD H. KOËTER, WILLEM J. de BOER, DIRKJE S. POSTMA, ELS M. ten VERGERT
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

The present study was undertaken to assess the relationship between health-related quality of life (HRQOL) and bronchiolitis obliterans syndrome (BOS), as both represent important parameters of outcome after lung transplantation. HRQOL was measured both cross-sectionally and longitudinally by standardized patient self-administered questionnaires, including the Nottingham Health Profile, the State-trait Anxiety Inventory, the Zung Self-Rating Depression Scale, and the Index of Well-Being. Data were collected at 4 and 7 mo, and every 6 mo afterwards for as long as 49 mo post-transplantation. The number of patients who completed the questionnaires varied from 72 at 4 mo, to 27 at 49 mo after transplantation. Cross-sectionally, the patients with BOS reported persistently statistically significantly more restrictions on the dimensions energy and physical mobility of the Nottingham Health Profile compared with patients without BOS. Other domains, i.e., pain, sleep, social interaction, and emotional reactions, were not affected. Additionally, patients with BOS reported statistically significantly more depressive symptoms and anxiety 1 and 2 yr after transplantation. Results from the longitudinal analysis support these findings, although no change in depressive symptoms could be found after onset of BOS. This study suggests that all lung transplant recipients improve in HRQOL. The development of BOS, however, is associated with a significantly reduced HRQOL.
(1) Long-term Reversal of Hypogammaglobulinemia in two Common Variable Immunodeficiency (CVID) Patients after Discontinuation of Intravenous Immunoglobulin (IVIG)
Authors: P. Chirichella, J.P. Guo, B. McGoey, M. Michelis
Journal: Journal of Allergy and Clinical Immunology (2009)
Calcium buffering in coronary smooth muscle after chronic occlusion and exercise training
Authors: J Jones
Journal: Cardiovascular Research (2001)

Objective: Exercise promotes “sarcoplasmic reticulum (SR) Ca2+ unloading” in porcine coronary smooth muscle, resulting in decreased agonist-induced Ca2+ release. We studied Ca2+ handling in healthy, non-occluded right coronary artery cells from hearts chronically occluded at the circumflex artery. Methods: Myoplasmic free Ca2+ (Cam) was assessed with fura-2 in cells from sedentary (n=8) and aerobically exercise-trained (n=6) female Yucatan pigs after 6-month circumflex artery ameroid occlusion (OCC) and in cells from non-occluded, sedentary pigs (SED, n=5). First, Ca influx was induced by 80 mM KCl depolarization (priming step) followed by 5 mM caffeine to elicit maximal Ca2+ release and depletion. The SR was Ca-loaded again by depolarization and then exposed to caffeine after 2- or 11-min recovery to compare SR Ca2+ unloading. Results: Baseline Cam, caffeine-induced peak Cam, and depolarization-induced maximum Cam were decreased, and depolarization-induced time-to-half-maximum was increased in OCC vs. SED pigs, suggesting a tonic Ca2+ buffering (lowering) effect of occlusion. Exercise did not alter these effects. SR Ca2+ unloading occurred only in SED, as evidenced by decreased caffeine-induced Ca2+ release after 11 min of recovery, and was inhibited by low extracellular Na+. Conclusions: SR Ca2+ unloading can be demonstrated in coronary smooth muscle from sedentary pigs using a novel SR Ca2+ unloading protocol, and Ca2+ unloading partly depends on Na+–Ca2+ exchange activity. Furthermore, SR Ca2+ unloading in cells from non-occluded right coronary arteries of chronically circumflex-occluded pig hearts was not altered by exercise, perhaps due to enhanced tonic Ca2+ extrusion versus cells from normal, sedentary animals.
Randomized Phase II Study of Two Doses of Gefitinib in Hormone-Refractory Prostate Cancer: A Trial of the National Cancer Institute of Canada-Clinical Trials Group
Authors: C.M. Canil, M.J. Moore, E. Winquist, T. Baetz, M. Pollak, K.N. Chi, S. Berry, D.S. Ernst, L. Douglas, M. Brundage, B. Fisher, A. McKenna, L. Seymour
Journal: Journal of Clinical Oncology (2005)

Purpose Overexpression of the epidermal growth factor receptor has been demonstrated in advanced prostate cancer and is associated with a poor outcome. A multi-institutional, randomized, phase II study was undertaken by the National Cancer Institute of Canada-Clinical Trials Group to evaluate the efficacy and toxicity of two doses of oral gefitinib in patients with minimally symptomatic, hormone-refractory prostate cancer (HRPC). Patients and Methods Between July and November 2001, 40 patients with HRPC and increasing prostate-specific antigen (PSA) or progression in measurable disease who had not received prior chemotherapy were randomly assigned to 250 mg (n = 19) or 500 mg (n = 21) oral gefitinib daily continuously. The primary end points were PSA response rate and objective measurable response. Functional Assessment of Cancer Therapy Prostate Cancer Subscale (FACT-P) quality-of-life questionnaires were completed at baseline and during treatment. Results None of the patients demonstrated a PSA or objective measurable response. Five (14.3%) of 35 assessable patients had stable PSA (one patient at 250 mg and four patients at 500 mg), and five patients (14.3%) had a best response of stable disease (duration, 2.5 to 16.8 months). No significant effect on the rate of increase in PSA was seen. The most common drug-related nonhematologic toxicities observed were grade 1 to 2 diarrhea (250 mg, 65%; 500 mg, 56%), fatigue (250 mg, 29%; 500 mg, 33%), and grade 1 to 2 skin rash (250 mg, 24%; 500 mg, 39%). FACT-P scores decreased during treatment, indicating worsening of symptoms compared with baseline. Conclusion Gefitinib did not result in any responses in PSA or objective measurable disease at either dose level. Gefitinib has minimal single-agent activity in HRPC.
Critical factors for the prevention of low back pain in elite junior divers
Authors: Takaya Narita, Koji Kaneoka, Masahiro Takemura, Yoshihiro Sakata, Takamichi Nomura, Shumpei Miyakawa
Journal: British Journal of Sports Medicine (2013)

During competitive diving, divers jump up from 1 to 3 m springboards or 5 to 10 m platforms and dive into the water. The impact forces are very large in the water entry phase, and, as such, microtraumatic injuries are common due to the tremendous physical stress placed on the diver. Low-back pain (LBP) is the most frequently reported symptom in divers. This study aimed to extract possible risk factors related to LBP from physical and technical characteristics in Japanese elite junior divers.Eighty-three elite junior divers (42 men and 41 women) in Japan were included in this study. LBP was assessed by a questionnaire, interview and physical examination during a national training camp. Morphological data, physical fitness and diving skills were also evaluated. The factors related to LBP were extracted by using logistic-regression analysis and the forward-selection method (likelihood ratio).A total of 37.3% (31 reports) of back pain occurred in the lumbar region. Shoulder flexibility (OR 0.919; 95% CI 0.851 to 0.992) and age (OR 0.441; 95% CI 0.239 to 0.814) were recognised as factors related to LBP in male-elite junior divers, whereas only age (OR 0.536; 95% CI 0.335 to 0.856) was a factor in female-elite junior divers.Our results suggest that shoulder flexibility is important for preventing LBP in elite-male junior divers, since they require full shoulder flexion during the water entry phase. Limited shoulder flexibility could cause lumbar hyperextension when adjusting for the angle of water entry.
Effect of steroid pulse therapy on mixed connective tissue disease with pulmonary arterial hypertension
Authors: Y Kamata
Journal: Annals of the Rheumatic Diseases (2005)

Background: The human Mut-S-homolog-2 (MSH2) is part of the DNA mismatch repair system (MMR). Mutations in genes of the MMR are a predisposition to hereditary non-polyposis colorectal cancer (HNPCC). In women, MMR gene mutations may lead to primary endometrial cancer (EC). The important function of the MMR for the integrity of the DNA during replication makes it probable that the MMR might also be involved in the development and the course of sporadic carcinomas. Insufficient MMR activity or expression levels could be prognostic markers of the disease. Patients and Methods: Immunohistochemical analysis of MSH2 was performed in 86 tumor samples from patients with EC. Results: Compared to known tumor markers, namely estrogen and progesterone receptors, histopathological grading, TNM stage and FIGO classification, no significant correlation between MSH2 immunoreactivity and EC was found. Conclusion: MSH2 immunohistochemical analysis is not of prognostic value for endometrial carcinoma.
Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency
Authors: Bertrand Boisson, Emmanuel Laplantine, Carolina Prando, Silvia Giliani, Elisabeth Israelsson, Zhaohui Xu, Avinash Abhyankar, Laura Israël, Giraldina Trevejo-Nunez, Dusan Bogunovic, Alma-Martina Cepika, Donna MacDuff, Maya Chrabieh, Marjorie Hubeau, Fanny Bajolle, Marianne Debré, Evelina Mazzolari, Donatella Vairo, Fabrice Agou, Herbert W Virgin, Xavier Bossuyt, Caroline Rambaud, Fabio Facchetti, Damien Bonnet, Pierre Quartier, Jean-Christophe Fournet, Virginia Pascual, Damien Chaussabel, Luigi D Notarangelo, Anne Puel, Alain Israël, Jean-Laurent Casanova, Capucine Picard
Journal: Nature Immunology (2012)
BJSM social media contributes to health policy rethink: a physical activity success story in Hertfordshire
Authors: Richard Weiler, Christine Neyndorff
Journal: British Journal of Sports Medicine (2013)

Strategies to modernise the National Health Service (NHS) in England have brought about the development of local organisations called Health and Wellbeing (H&WB) boards through the Health and Social Care Act 2012. These boards were intended to become a forum where key leaders and stakeholders from health and care systems work together to improve the health and well-being of their local population and reduce health inequalities. Throughout England these boards have been drafting their strategies, largely ignoring the importance of physical activity in health and well-being. In the county of Hertfordshire, the initial draft priorities were released in 2012 and physical activity promotion was not included. Using a BJSM blog, BJSM online poll, Twitter and email, an attempt was made to generate as much interest and formal feedback as possible to the draft strategy, in order to ensure the inclusion of physical activity as a priority in the revised strategy.
Functional coordination of alternative splicing in the mammalian central nervous system
Authors: Matthew Fagnani, Yoseph Barash, Joanna Y Ip, Christine Misquitta, Qun Pan, Arneet L Saltzman, Ofer Shai, Leo Lee, Aviad Rozenhek, Naveed Mohammad, Sandrine Willaime-Morawek, Tomas Babak, Wen Zhang, Timothy R Hughes, Derek van der Kooy, Brendan J Frey, Benjamin J Blencowe
Journal: Genome biology (2007)

Abstract Background Alternative splicing (AS) functions to expand proteomic complexity and plays numerous important roles in gene regulation. However, the extent to which AS coordinates functions in a cell and tissue type specific manner is not known. Moreover, the sequence code that underlies cell and tissue type specific regulation of AS is poorly understood. Results Using quantitative AS microarray profiling, we have identified a large number of widely expressed mouse genes that contain single or coordinated pairs of alternative exons that are spliced in a tissue regulated fashion. The majority of these AS events display differential regulation in central nervous system (CNS) tissues. Approximately half of the corresponding genes have neural specific functions and operate in common processes and interconnected pathways. Differential regulation of AS in the CNS tissues correlates strongly with a set of mostly new motifs that are predominantly located in the intron and constitutive exon sequences neighboring CNS-regulated alternative exons. Different subsets of these motifs are correlated with either increased inclusion or increased exclusion of alternative exons in CNS tissues, relative to the other profiled tissues. Conclusion Our findings provide new evidence that specific cellular processes in the mammalian CNS are coordinated at the level of AS, and that a complex splicing code underlies CNS specific AS regulation. This code appears to comprise many new motifs, some of which are located in the constitutive exons neighboring regulated alternative exons. These data provide a basis for understanding the molecular mechanisms by which the tissue specific functions of widely expressed genes are coordinated at the level of AS.
Paradoxical effects of IFN-γ in graft-versus-host disease reflect promotion of lymphohematopoietic graft-versus-host reactions and inhibition of epithelial tissue injury
Authors: Hui Wang, Wannee Asavaroengchai, Beow Yong Yeap, Min-Guang Wang, Shumei Wang, Megan Sykes, Yong-Guang Yang
Journal: Blood (2009)
Dexfenfluramine and the oestrogen-metabolizing enzyme CYP1B1 in the development of pulmonary arterial hypertension
Authors: Yvonne Dempsie, Neil A. MacRitchie, Kevin White, Ian Morecroft, Audrey F. Wright, Margaret Nilsen, Lynn Loughlin, Kirsty M. Mair, Margaret R. MacLean
Journal: Cardiovascular Research (2013)

AimsPulmonary arterial hypertension (PAH) occurs more frequently in women than men. Oestrogen and the oestrogen-metabolising enzyme cytochrome P450 1B1 (CYP1B1) play a role in the development of PAH. Anorectic drugs such as dexfenfluramine (Dfen) have been associated with the development of PAH. Dfen mediates PAH via a serotonergic mechanism and we have shown serotonin to up-regulate expression of CYP1B1 in human pulmonary artery smooth muscle cells (PASMCs). Thus here we assess the role of CYP1B1 in the development of Dfen-induced PAH.
Results at 1 year of outpatient multidisciplinary pulmonary rehabilitation: a randomised controlled trial
Authors: T L Griffiths, M L Burr, I A Campbell, V Lewis-Jenkins, J Mullins, K Shiels, P J Turner-Lawlor, N Payne, R G Newcombe, A A Ionescu, J Thomas, J Tunbridge, A A Lonescu
Journal: The Lancet (2000)
Active inference and cognitive-emotional interactions in the brain
Authors: Giovanni Pezzulo, Laura Barca, Karl J. Friston
Journal: Behavioral and Brain Sciences (2015)

Abstract All organisms must integrate cognition, emotion, and motivation to guide action toward valuable (goal) states, as described by active inference. Within this framework, cognition, emotion, and motivation interact through the (Bayesian) fusion of exteroceptive, proprioceptive, and interoceptive signals, the precision-weighting of prediction errors, and the “affective tuning” of neuronal representations. Crucially, misregulation of these processes may have profound psychopathological consequences.
S38. Many reasons for combining immunotherapy with chemotherapy to enhance anti tumour response
Authors: A Dalgleish, D Fowler, A Gravett, R Allen, W Liu
Journal: Journal for ImmunoTherapy of Cancer (2014)

Meeting abstracts Chemotherapy and Immunotherapy were always considered incompatible in the treatment of cancer. However, analysis of sequential use has revealed that there may be significant additive potential if not synergistic, in enhancing the immune response to cancer. There are many reasons