tbuckley/cabot-search huggingface dataset:
Vessel wall, not platelet, P2Y12 potentiates early atherogenesis
Authors: L. E. West, T. Steiner, H. M. Judge, S. E. Francis, R. F. Storey
Journal: Cardiovascular Research (2014)

Platelets have a fundamental role in atherothrombosis, but their role in early atherogenesis is unclear. The P2Y12 receptor is responsible for amplifying and sustaining platelet activation and P2Y12 inhibition is crucial in modulating the vessel wall response to injury. We therefore examined the role of platelet vs. vessel wall P2Y12 in early atherogenesis and considered the use of P2Y12 antagonists ticagrelor and clopidogrel in modulating this process. ApoE−/− and ApoE−/−P2Y12−/− male mice underwent bone marrow transplantation and were fed a western diet for 4 weeks before assessing atherosclerotic burden. Compared with ApoE−/− controls, platelet P2Y12 deficiency profoundly reduced platelet reactivity but had no effect on atheroma formation, whereas vessel wall P2Y12 deficiency significantly attenuated atheroma in the aortic sinus and brachiocephalic artery (both P < 0.001). ApoE−/− and ApoE−/−P2Y12−/− male mice fed western diet plus either twice-daily doses of ticagrelor (100 mg/kg) or daily clopidogrel (20 mg/kg) for 4 weeks exhibited no significant reduction in atheroma compared with control mice fed mannitol. Attenuated P-selectin expression confirmed platelet P2Y12 inhibition in drug-treated mice. Despite its major contribution to platelet reactivity, platelet P2Y12 has no effect on early atheroma formation, whereas vessel wall P2Y12 is important in this process. Ticagrelor and clopidogrel effectively reduced platelet reactivity but were unable to inhibit early atherogenesis, demonstrating that these P2Y12 inhibitors may not be effective in preventing early disease.
Deep vein thrombosis and air travel: record linkage study
Authors: C W Kelman
Journal: BMJ (2003)

<h3>Abstract</h3> <b>Objective</b> To investigate the time relations between long haul air travel and venous thromboembolism. <b>Design</b> Record linkage study using the case crossover approach. <b>Setting</b> Western Australia. <b>Participants</b> 5408 patients admitted to hospital with venous thromboembolism and matched with data for arrivals of international flights during 1981-99. <b>Results</b> The risk of venous thromboembolism is increased for only two weeks after a long haul flight; 46 Australian citizens and 200 non-Australian citizens had an episode of venous thromboembolism during this so called hazard period. The relative risk during this period for Australian citizens was 4.17 (95% confidence interval, 2.94 to 5.40), with 76% of cases (n = 35)attributable to the preceding flight. A “healthy traveller” effect was observed, particularly for Australian citizens. <b>Conclusions</b> The annual risk of venous thromboembolism is increased by 12% if one long haul flight is taken yearly. The average risk of death from flight related venous thromboembolism is small compared with that from motor vehicle crashes and injuries at work. The individual risk of death from flight related venous thromboembolism for people with certain pre-existing medical conditions is, however, likely to be greater than the average risk of 1 per 2 million for passengers arriving from a flight. Airlines and health authorities should continue to advise passengers on how to minimise risk.
The link between female infertility and cancer: epidemiology and possible aetiologies
Authors: D Meirow
Journal: Human Reproduction Update (1996)

Infertility has been suggested as a risk factor for various gynaecological cancers. Data analyses show that among infertile women, those with anovulation or polycystic ovarian syndrome (PCOS) have an increased risk of cancer. Clinical and laboratory data such as anthropometric measurements, endogenous hormones and growth factors may explain mechanisms which link tumorogenesis or tumour promotion to infertility. The possible association between ovulation induction and cancer is discussed both on theoretical grounds and based on epidemiological data. We conclude that according to epidemiological studies, laboratory data and on theoretical grounds, infertile patients have an increased lifetime risk of gynaecological cancer. The risk of cancer should be evaluated further for each sub-population of infertile patients. Thus, more adequate means of monitoring these patients will become available. These data are necessary for a further evaluation of the possible cancer risks of infertility treatments.
William John Oldfield Box
Authors: J. Strong
Journal: BMJ (2002)

Former consultant radiologist Stratford upon Avon, Leominster, and Warwick (b 1924; q Edinburgh 1946; FRCR), d 25 October 2002.

He worked in surgical posts in Chertsey, Harrow, Exeter, and West Africa. He held the surgical fellowship at both Edinburgh and London but then decided to train as a radiologist at University College London. He then took up a consultant post at Stratford, Leominster, and Warwick until his retirement in 1989. A skilled cabinet maker, he enjoyed making beautiful pieces of furniture in his workshop. He leaves a wife; and three children.
Fever-Like Temperatures Affect Neutrophil NF-κB Signaling, Apoptosis, and ANCA-Antigen Expression
Authors: Ralph Kettritz, Mira Choi, Birgit Salanova, Maren Wellner, Susanne Rolle, Friedrich C. Luft
Journal: Journal of the American Society of Nephrology (2006)

The neutrophil is pivotal to ANCA vasculitis pathogenesis. Fever frequently complicates ANCA diseases. This study investigated the effects of short-term heat exposure on apoptosis in neutrophils that were treated with LPS, GM-CSF, IL-8, and dexamethasone. All compounds delayed apoptosis. Heat abrogated the apoptosis-delaying effect of LPS without affecting constitutive apoptosis or delayed apoptosis by GM-CSF, IL-8, or dexamethasone. The heat effect was dose dependent over the 39 to 42 degrees C range. NF-kappaB but not extracellular signal-regulated kinase, p38 mitogen-activated protein kinase (MAPK), or phosphatidylinositol 3-kinase/Akt controlled LPS-delayed apoptosis. Furthermore, LPS-induced IkappaBalpha degradation, DNA binding, and NF-kappaB-dependent gene transcription activation were abrogated by short-term heat. When core temperatures were raised to 40.5 degrees C for 30 min in mice, LPS-induced neutrophil NF-kappaB activation also was prevented. Short-term heat removed heat-shock protein 90 from the IkappaB kinase complex, resulting in failure of LPS-induced IkappaB kinase activation. Despite delayed apoptosis, ANCA antigen expression was increased in LPS-treated neutrophils. ANCA antigen increase was prevented by p38 MAPK inhibition and by heat exposure. Heat exposure did not inhibit LPS-induced p38 MAPK phosphorylation. Instead, apoptosis-mediated p38 MAPK degradation was accelerated, thereby decreasing the p38 MAPK that was available for LPS-mediated ANCA antigen upregulation. These data suggest that fever-like temperatures modulate neutrophil behavior in this disease.
A 12-Month Phase 3 Study of Pasireotide in Cushing's Disease
Authors: Annamaria Colao, Stephan Petersenn, John Newell-Price, James W. Findling, Feng Gu, Mario Maldonado, Ulrike Schoenherr, None Dipl.-Biol., David Mills, Luiz Roberto Salgado, Beverly M.K. Biller
Journal: New England Journal of Medicine (2012)

Cushing's disease is associated with high morbidity and mortality. Pasireotide, a potential therapy, has a unique, broad somatostatin-receptor-binding profile, with high binding affinity for somatostatin-receptor subtype 5.In this double-blind, phase 3 study, we randomly assigned 162 adults with Cushing's disease and a urinary free cortisol level of at least 1.5 times the upper limit of the normal range to receive subcutaneous pasireotide at a dose of 600 μg (82 patients) or 900 μg (80 patients) twice daily. Patients with urinary free cortisol not exceeding 2 times the upper limit of the normal range and not exceeding the baseline level at month 3 continued to receive their randomly assigned dose; all others received an additional 300 μg twice daily. The primary end point was a urinary free cortisol level at or below the upper limit of the normal range at month 6 without an increased dose. Open-label treatment continued through month 12.Twelve of the 82 patients in the 600-μg group and 21 of the 80 patients in the 900-μg group met the primary end point. The median urinary free cortisol level decreased by approximately 50% by month 2 and remained stable in both groups. A normal urinary free cortisol level was achieved more frequently in patients with baseline levels not exceeding 5 times the upper limit of the normal range than in patients with higher baseline levels. Serum and salivary cortisol and plasma corticotropin levels decreased, and clinical signs and symptoms of Cushing's disease diminished. Pasireotide was associated with hyperglycemia-related adverse events in 118 of 162 patients; other adverse events were similar to those associated with other somatostatin analogues. Despite declines in cortisol levels, blood glucose and glycated hemoglobin levels increased soon after treatment initiation and then stabilized; treatment with a glucose-lowering medication was initiated in 74 of 162 patients.The significant decrease in cortisol levels in patients with Cushing's disease who received pasireotide supports its potential use as a targeted treatment for corticotropin-secreting pituitary adenomas. (Funded by Novartis Pharma; ClinicalTrials.gov number, NCT00434148.).
When small is better: volume reduction in severe emphysema
Authors: Erik Folch, Gunnar Hillerdal
Journal: European Respiratory Journal (2015)

Severe emphysema radically diminishes quality of life. The disease is a result of destruction of lung parenchyma and is most commonly associated with cigarette smoke exposure or the congenital absence of α1-antitrypsin. The elastic fibres of the lung, which in a healthy state strive to retract the lungs, are particularly affected. The inward force determined by these fibres is balanced by the chest wall, which strives to push outwards. The result is a finely balanced system where only minimal work is needed in quiet breathing. Emphysema results in a loss of elasticity of the lungs, and thus the inward traction, while the outward force of the thorax remains unopposed, resulting in lung hyperinflation. Further, the small airways, that in normal lungs are kept open and wide by the elastic recoil from the lung parenchyma [1, 2], will have predilection for collapse due to the diminished elasticity of emphysema. Thus, even mild exertion may result in dynamic hyperinflation with air trapping adding to the increased work of breathing. In the 1950s it was shown that removal of emphysematous regions of the lung could considerably enhance lung function and quality of life by improving the total elasticity of the lungs [1]. If successful, residual volume is diminished, small airways collapse is reduced, and the chest will be less hyperinflated allowing the respiratory muscles to work more efficiently. What are our options for lung volume reduction treatment in patients with severe emphysema? <http://ow.ly/PgQLV>
Migration of Children and Impact on Depression in Older Parents in Rural Thailand, Southeast Asia
Authors: Melanie Abas, Kanchana Tangchonlatip, Sureeporn Punpuing, Tawanchai Jirapramukpitak, Niphon Darawuttimaprakorn, Martin Prince, Clare Flach
Journal: JAMA Psychiatry (2012)

CONTEXT Migration is feared to be associated with abandonment and depression in older parents "left behind" in rural areas of low- and middle-income countries. OBJECTIVE To test for prospective associations between (1) out-migration of all children and subsequent depression in parents and (2) having a child move back and an improvement in parents' depression. DESIGN A cohort study with a 1-year follow-up. SETTING A population-based study nested in a demographic surveillance site of 100 villages in rural Thailand. Most out-migration is to the capital city. PARTICIPANTS A stratified random sample of 1111 parents 60 years and older (1 per household) drawn from all 100 villages, of whom 960 (86%) provided depression data at follow-up. MAIN OUTCOME MEASURES Scoring 6 or more on the Thai version of the EURO-D depression scale at follow-up. RESULTS Depression prevalence was 22%. At baseline, 155 (16%) had all their children migrated from the district and 806 (84%) had at least 1 child living in the district. Having all children out-migrated at baseline, compared with having none or some children out-migrated, predicted a smaller odds of depression, after controlling for baseline sociodemographic and health measures (odds ratio [OR], 0.43; 95% CI, 0.20-0.92). Having a child move back in the study year was associated with greater odds of depression at follow-up when adjusted for baseline measures (OR, 1.75; 95% CI, 1.04-2.94), although this was no longer significant after adjusting for changes in disability and marital status since baseline (OR, 1.72; 95% CI, 0.99-2.98). CONCLUSIONS Contrary to our hypothesis, parents whose children are not migrants may be at greater risk of depression than those with migrant children. More understanding is needed about the risks for depression in older rural populations and about the effectiveness of interventions.
Sex differences in the association between body mass index and total hip or knee joint replacement resulting from osteoarthritis
Authors: J Franklin, T Ingvarsson, M Englund, L S Lohmander
Journal: Annals of the Rheumatic Diseases (2008)

Objective: To examine the association between body mass index (BMI) and osteoarthritis (OA) leading to total hip (THR) or knee (TKR) joint replacement. Methods: Case–control study design. All patients still living in Iceland who had had a THR or TKR resulting from OA before the end of 2002 were invited to participate. First-degree relatives of participating patients served as controls. A total of 1473 patients (872 women) and 1103 controls (599 women), all born between 1910 and 1939 and who had answered a questionnaire including questions about height and weight, were analysed. A randomly selected sample, representative of the Icelandic population, was used as a secondary control group. Results: The OR, adjusted for age, occupation and presence of hand OA, for having a THR was 1.1 (95% CI 0.9 to 1.5) for overweight men and 1.7 (95% CI 1.0 to 2.9) for obese men. The OR for having a TKR was 1.7 (95% CI 1.1 to 2.6) for overweight men and 5.3 (95% CI 2.8 to 10.1) for obese men. The OR for having a THR was 1.0 (95% CI 0.8 to 1.3) for overweight women and 1.0 (95% CI 0.6 to 1.5) for obese women. The OR for having a TKR was 1.6 (95% CI 1.1 to 2.2) for overweight women and 4.0 (95% CI 2.6 to 6.1) for obese women. Conclusion: This study supports a positive association between high BMI and TKR in both sexes, but for THR the association with BMI seems to be weaker, and possibly negligible for women.
An Unexpectedly Large Polyclonal Repertoire of HPV-Specific T Cells Is Poised for Action in Patients with Cervical Cancer
Authors: Peggy J. de Vos van Steenwijk, Moniek Heusinkveld, Tamara H. Ramwadhdoebe, Margriet J. Löwik, Jeanette M. van der Hulst, Renske Goedemans, Sytse J. Piersma, Gemma G. Kenter, Sjoerd H. van der Burg
Journal: Cancer Research (2010)

Abstract The diversity and extent of the local tumor-specific T-cell response in a given individual is largely unknown. We have performed an in-depth study of the local T-cell repertoire in a selected group of patients with cervical cancer, by systematic analyses of the proportion, breadth, and polarization of human papillomavirus (HPV) E6/E7-specific T cells within the total population of tumor-infiltrating lymphocytes (TIL) and tumor-draining lymph node cells (TDLNC). Isolated T cells were stimulated with sets of overlapping E6 and E7 peptides and analyzed by multiparameter flow cytometry with respect to activation, cytokine production, and T-cell receptor Vβ usage. HPV-specific CD4+ and CD8+ T-cell responses were detected in TIL and TDLNC and their relative contribution varied between &amp;lt;1% and 66% of all T cells. In general, these HPV-specific responses were surprisingly broad, aimed at multiple E6 and E7 epitopes and involved multiple dominant and subdominant T-cell receptor Vβs per single peptide-epitope. In most patients, only few IFNγ-producing T cells were found and the amount of IFNγ produced was low, suggesting that these are poised T cells, rendered functionally inactive within the tumor environment. Importantly, stimulation of the TIL and TDLNC with cognate antigen in the presence of commonly used Toll-like receptor ligands significantly enhanced the effector T-cell function. In conclusion, our study suggests that within a given patient with HPV-specific immunity many different tumor-specific CD4+ and CD8+ T cells are locally present and poised for action. This vast existing local T-cell population is awaiting proper stimulation and can be exploited for the immunotherapy of cancer. Cancer Res; 70(7); 2707–17
Pharmacotherapy of Childhood Obesity
Authors: Michael Freemark
Journal: Diabetes Care (2007)

This review provides a comparative analysis of the benefits of lifestyle intervention and pharmacotherapy in adults and children using previously published meta-analyses, as well as new data published within the past 2 years. The manuscript critically summarizes the potential risks of various established (orlistat, sibutramine, and metformin) and new (rimonabant) pharmacologic agents and presents a conceptual approach to selection of patients for pharmacotherapy, tailored drug selection, and timing of intervention.

Forty-five years after an amphetamine was approved for the treatment of obesity in adults, an expert in the field characterized a new therapeutic formulation as being effective and long-lasting, posing “little risk” (1). Four years later, others (2) “confirmed the weight-reducing efficacy and good tolerability” of the drug and noted that adverse effects were “generally mild and transient.” The drug in question was dexfenfluramine, which was removed from the commercial market 18 months after its subsequent U.S. Food and Drug Administration approval owing to the development of valvular heart disease and primary pulmonary hypertension in a subset of patients (3,4).

This experience and many others (5) have forced us to think long and hard before making sweeping recommendations about the use of behavior-modifying drugs for the treatment of obesity.

Yet, the pediatric community confronts a serious problem: the surge of metabolic complications in obese adolescents, including impaired glucose tolerance (IGT) and type 2 diabetes, hypertension, dyslipidemia, ovarian hyperandrogenism, hepatic steatosis, and sleep apnea (6). Two recent studies highlight the concern. First (7), despite regular lifestyle counseling in a university-based clinic, one-third of obese teenagers with profound insulin resistance and IGT developed type 2 diabetes during a follow-up period of 21 months. Second (8), among Pima-Indian children and adolescents with type 2 diabetes, the rate of development of end-stage renal disease was proportional to the duration of diabetes, …
Interaction of Endothelial Nitric Oxide and Angiotensin in the Circulation
Authors: Noboru Toda, Kazuhide Ayajiki, Tomio Okamura
Journal: Pharmacological Reviews (2007)

Discovery of the unexpected intercellular messenger and transmitter nitric oxide (NO) was the highlight of highly competitive investigations to identify the nature of endothelium-derived relaxing factor. This labile, gaseous molecule plays obligatory roles as one of the most promising physiological regulators in cardiovascular function. Its biological effects include vasodilatation, increased regional blood perfusion, lowering of systemic blood pressure, and antithrombosis and anti-atherosclerosis effects, which counteract the vascular actions of endogenous angiotensin (ANG) II. Interactions of these vasodilator and vasoconstrictor substances in the circulation have been a topic that has drawn the special interest of both cardiovascular researchers and clinicians. Therapeutic agents that inhibit the synthesis and action of ANG II are widely accepted to be essential in treating circulatory and metabolic dysfunctions, including hypertension and diabetes mellitus, and increased availability of NO is one of the most important pharmacological mechanisms underlying their beneficial actions. ANG II provokes vascular actions through various receptor subtypes (AT<sub>1</sub>, AT<sub>2</sub>, and AT<sub>4</sub>), which are differently involved in NO synthesis and actions. ANG II and its derivatives, ANG III, ANG IV, and ANG-(1-7), alter vascular contractility with different mechanisms of action in relation to NO. This review article summarizes information concerning advances in research on interactions between NO and ANG in reference to ANG receptor subtypes, radical oxygen species, particularly superoxide anions, ANG-converting enzyme inhibitors, and ANG receptor blockers in patients with cardiovascular disease, healthy individuals, and experimental animals. Interactions of ANG and endothelium-derived relaxing factor other than NO, such as prostaglandin I<sub>2</sub> and endothelium-derived hyperpolarizing factor, are also described.
Domestic aeroallergen exposures among infants in an English town
Authors: W Atkinson, J Harris, P Mills, S Moffat, C White, O Lynch, M Jones, P Cullinan, AJ Newman Taylor
Journal: European Respiratory Journal (1999)

A multicentre, prospective cohort study of childhood asthma was established in three European countries; the purpose of the project is the examination of factors which modify the relationship between allergen exposure in infant life and subsequent atopy and asthma. Dust samples were collected from the homes of 643 infants in a single town in the UK (the first cohort) and assayed for house dust mites (Der p 1) and cat allergen (Fel d 1) concentrations by enzyme-linked immunosorbent assay. A questionnaire with potential relevance to the development of atopy and asthma was completed. A wide variation in exposure to both allergens was observed. Carpeted, double-glazed or damp living rooms, and those sampled in the winter months, had higher levels of Der p 1, but these features did not predict Fel d 1 concentrations. Measures of high home occupancy were positively related to Der p 1 concentrations; and inversely with levels of Fel d 1, a finding which could not be explained by cat ownership. Homes in which one or more persons smoked had significantly lower concentrations of Der p 1, but not Fel d 1. There were no consistent differences in allergen levels between homes where one or more parent or sibling was either atopic or asthmatic. These findings indicate complex interactions among domestic, behavioural and seasonal factors and early allergen exposure in British children.
Hepatitis B virus-specific T-cell reactivity during adefovir dipivoxil (ADV) treatment: a multicentre, controlled study
Authors: Helen Cooksley, S. Chokshi, H. Wedemeyer, P. Andreone, R. Gilson, T. Warnes, S. Paganin, F. Zoulim, Anant Jain, Craig James, Craig Gibbs, John Fry, Carol Brosgart, N. Naoumov
Journal: Journal of Hepatology (2002)