tbuckley/cabot-search huggingface dataset:
Estrogen, cognition and female ageing
Authors: Andrea Riccardo Genazzani, Nicola Pluchino, Stefano Luisi, Michele Luisi
Journal: Human Reproduction Update (2006)

Starting from fetal life, estrogens are crucial in determining central gender dimorphism, and an estrogen-induced synaptic plasticity is well evident during puberty and seasonal changes as well as during the ovarian cycle. Estrogens act on the central nervous system (CNS) both through genomic mechanisms, modulating synthesis, release and metabolism of neurotransmitters, neuropeptides and neurosteroids, and through non-genomic mechanisms, influencing electrical excitability, synaptic function and morphological features. Therefore, estrogen's neuroactive effects are multifaceted and encompass a system that ranges from the chemical to the biochemical to the genomic mechanisms, protecting against a wide range of neurotoxic insults. Clinical evidences show that, during the climacteric period, estrogen withdrawal in the limbic system gives rise to modifications in mood, behaviour and cognition and that estrogen administration is able to improve mood and cognitive efficiency in post-menopause. Many biological mechanisms support the hypothesis that estrogens might protect against Alzheimer's disease (AD) by influencing neurotransmission, increasing cerebral blood flow, modulating growth proteins associated with axonal elongation and blunting the neurotoxic effects of beta-amyloid. On the contrary, clinical studies of estrogen replacement therapy (ERT) and cognitive function have reported controversial results, indicating a lack of efficacy of estrogens on cognition in post-menopausal women aged >or=65 years. These findings suggest the presence of a critical period for HRT-related neuroprotection and underlie the potential importance of early initiation of therapy for cognitive benefit. In this review, we shall first describe the multiple effects of steroids in the nervous system, which may be significant in the ageing process. A critical update of HRT use in women and a discussion of possible prospectives for steroid use are subsequently proposed.
An Off-the-Shelf Instant Contact Casting Device for the Management of Diabetic Foot Ulcers
Authors: Alberto Piaggesi, Silvia Macchiarini, Loredana Rizzo, Francesca Palumbo, Anna Tedeschi, Laura Ambrosini Nobili, Elisa Leporati, Vincenzo Scire, Ilaria Teobaldi, Stefano Del Prato
Journal: Diabetes Care (2007)

This study was designed to test the safety, effectiveness, and costs of off-loading with a novel, off-the-shelf irremovable device in the management of diabetic foot ulceration (DFU).We prospectively evaluated off-loading of neuropathic plantar ulcers in 40 diabetic outpatients attending our diabetic foot clinic and compared healing rates at the 12-week follow-up, number and severity of adverse events, healing time, costs and applicability of the device, and patients' satisfaction between those randomly assigned to total contact casting (TCC; group A) or to the Optima Diab walker (group B). Deep or infected ulcers were excluded.No difference between groups A and B was observed in healing rates at 12 weeks (95 vs. 85%), healing time (6.5 +/- 4.4 vs. 6.7 +/- 3.4 weeks), and number of adverse events (six versus four). Treatment was significantly less expensive in group B, which showed a mean reduction of costs of 78% compared with group A (P < 0.001). Practicability was more favorable in group B, with a reduction of 77 and 58% of the time required for application and removal of the devices, respectively (P < 0.001). Patients' satisfaction with the treatment was higher in group B (P < 0.01).The Optima Diab walker is as safe and effective as TCC in the management of DFU, but its lower costs and better applicability may be of help in spreading the practice of off-loading among the centers that manage the diabetic foot.
Activation of the Aryl Hydrocarbon Receptor AhR Promotes Retinoic Acid–Induced Differentiation of Myeloblastic Leukemia Cells by Restricting Expression of the Stem Cell Transcription Factor Oct4
Authors: Rodica P. Bunaciu, Andrew Yen
Journal: Cancer Research (2011)

Retinoic acid (RA) is used to treat leukemia and other cancers through its ability to promote cancer cell differentiation. Strategies to enhance the anticancer effects of RA could deepen and broaden its beneficial therapeutic applications. In this study, we describe a receptor cross-talk system that addresses this issue. RA effects are mediated by RAR/RXR receptors that we show are modified by interactions with the aryl hydrocarbon receptor (AhR), a protein functioning both as a transcription factor and a ligand-dependent adaptor in an ubiquitin ligase complex. RAR/RXR and AhR pathways cross-talk at the levels of ligand-receptor and also receptor-promoter interactions. Here, we assessed the role of AhR during RA-induced differentiation and a hypothesized convergence at Oct4, a transcription factor believed to maintain stem cell characteristics. RA upregulated AhR and downregulated Oct4 during differentiation of HL-60 promyelocytic leukemia cells. AhR overexpression in stable transfectants downregulated Oct4 and also decreased ALDH1 activity, another stem cell-associated factor, enhancing RA-induced differentiation as indicated by cell differentiation markers associated with early (CD38 and CD11b) and late (neutrophilic respiratory burst) responses. AhR overexpression also increased levels of activated Raf1, which is known to help propel RA-induced differentiation. RNA interference-mediated knockdown of Oct4 enhanced RA-induced differentiation and G(0) cell-cycle arrest relative to parental cells. Consistent with the hypothesized importance of Oct4 downregulation for differentiation, parental cells rendered resistant to RA by biweekly high RA exposure displayed elevated Oct4 levels that failed to be downregulated. Together, our results suggested that therapeutic effects of RA-induced leukemia differentiation depend on AhR and its ability to downregulate the stem cell factor Oct4.
Donagh Declan O'Brien
Journal: BMJ (2006)

​FormerFormer military surgeon Royal Army Medical Corps (b 1923; q University College Dublin 1946; LM, MBE, OStJ), died from secondary lung cancer on 14 March 2006.




Figure 1




As surgeon and commanding officer of the British Military Hospital, Berlin, Declan was involved in Rudolph Hess's health care. In Musgrove Park Hospital, Belfast, he operated on soldiers and victims of the violence from both sides of the sectarian divide, and his final posting was to the main receiving hospital for casualties of the Falklands War. After retirement he became chief medical officer of the British Red Cross and worked for various benevolent organisations. He was also president of the BMA's Bromley division. Predeceased by his wife, Georgina, in 2001, he leaves six children.
Neoadjuvant chemotherapy for osteosarcoma of the extremities with metastases at presentation: recent experience at the Rizzoli Institute in 57 patients treated with cisplatin, doxorubicin, and a high dose of methotrexate and ifosfamide
Authors: G. Bacci, A. Briccoli, M. Rocca, S. Ferrari, D. Donati, A. Longhi, F. Bertoni, P. Bacchini, S. Giacomini, C. Forni, M. Manfrini, S. Galletti
Journal: Annals of Oncology (2003)
Chronic Bile Duct Injury Associated with Fibrotic Matrix Microenvironment Provokes Cholangiocarcinoma in p53-Deficient Mice
Authors: Paraskevi A. Farazi, Michael Zeisberg, Jonathan Glickman, Yan Zhang, Raghu Kalluri, Ronald A. DePinho
Journal: Cancer Research (2006)

Intrahepatic cholangiocarcinoma (CCA) is a lethal malignancy of the biliary epithelium associated with p53 mutations, bile duct injury, inflammation, and fibrosis. Here, to validate these processes in CCA, we developed a liver cirrhosis model driven by chronic intermittent toxin exposure, which provokes bile duct injury/necrosis and proliferation, fibroblast recruitment, and progressive extracellular matrix (ECM) changes. Fibrotic changes in the matrix microenvironment, typified by increased type I and III collagens and fibroblast recruitment, were shown to stimulate biliary epithelium hyperplasia with subsequent progression to malignant intrahepatic CCA only in mice harboring a p53 mutant allele. These murine CCAs bear histologic and genetic features of human intrahepatic CCA, including dense peritumoral fibrosis, increased inducible nitric oxide synthase, nitrotyrosine, and cyclooxygenase-2 expression, c-Met activation, cErbB2 overexpression, down-regulation of membrane-associated E-cadherin, and p53 codon 248 mutation. Thus, p53 deficiency, chronic bile duct injury/proliferation, and the fibrotic matrix microenvironment cooperate to induce intrahepatic CCA, highlighting the key role of the ECM microenvironment in this common liver cancer.
Imiquimod clears tumors in mice independent of adaptive immunity by converting pDCs into tumor-killing effector cells
Authors: Barbara Drobits, Martin Holcmann, Nicole Amberg, Melissa Swiecki, Roland Grundtner, Martina Hammer, Marco Colonna, Maria Sibilia
Journal: Journal of Clinical Investigation (2012)

Imiquimod is a synthetic compound with antitumor properties; a 5% cream formulation is successfully used to treat skin tumors. The antitumor effect of imiquimod is multifactorial, although its ability to modulate immune responses by triggering TLR7/8 is thought to be key. Among the immune cells suggested to be involved are plasmacytoid DCs (pDCs). However, a direct contribution of pDCs to tumor killing in vivo and the mechanism of their recruitment to imiquimod-treated sites have never been demonstrated. Using a mouse model of melanoma, we have now demonstrated that pDCs can directly clear tumors without the need for the adaptive immune system. Topical imiquimod treatment led to TLR7-dependent and IFN-α/β receptor 1-dependent (IFNAR1-dependent) upregulation of expression of the chemokine CCL2 in mast cells. This was essential to induce skin inflammation and for the recruitment of pDCs to the skin. The recruited pDCs were CD8α+ and induced tumor regression in a TLR7/MyD88- and IFNAR1-dependent manner. Lack of TLR7 and IFNAR1 or depletion of pDCs or CD8α+ cells from tumor-bearing mice completely abolished the effect of imiquimod. TLR7 was essential for imiquimod-stimulated pDCs to produce IFN-α/β, which led to TRAIL and granzyme B secretion by pDCs via IFNAR1 signaling. Blocking these cytolytic molecules impaired pDC-mediated tumor killing. Our results demonstrate that imiquimod treatment leads to CCL2-dependent recruitment of pDCs and their transformation into a subset of killer DCs able to directly eliminate tumor cells.
Chemokine receptor mutant CX3CR1-M280 has impaired adhesive function and correlates with protection from cardiovascular disease in humans
Authors: David H. McDermott, Alan M. Fong, Qiong Yang, Joan M. Sechler, L. Adrienne Cupples, Maya N. Merrell, Peter W.F. Wilson, Ralph B. D’Agostino, Christopher J. O’Donnell, Dhavalkumar D. Patel, Philip M. Murphy
Journal: Journal of Clinical Investigation (2003)

The chemokine receptor CX3CR1 is a proinflammatory leukocyte receptor specific for the chemokine fractalkine (FKN or CX3CL1). In two retrospective studies, CX3CR1 has been implicated in the pathogenesis of atherosclerotic cardiovascular disease (CVD) based on statistical association of a common receptor variant named CX3CR1-M280 with lower prevalence of atherosclerosis, coronary endothelial dysfunction, and acute coronary syndromes. However, the general significance of CX3CR1-M280 and its putative mechanism of action have not previously been defined. Here we show that FKN-dependent cell-cell adhesion under conditions of physiologic shear is severely reduced in cells expressing CX3CR1-M280. This was associated with marked reduction in the kinetics of FKN binding as well as reduced FKN-induced chemotaxis of primary leukocytes from donors homozygous for CX3CR1-M280. We also show that CX3CR1-M280 is independently associated with a lower risk of CVD (adjusted odds ratio, 0.60, P = 0.008) in the Offspring Cohort of the Framingham Heart Study, a long-term prospective study of the risks and natural history of this disease. These data provide mechanism-based and consistent epidemiologic evidence that CX3CR1 may be involved in the pathogenesis of CVD in humans, possibly by supporting leukocyte entry into the coronary artery wall. Moreover, they suggest that CX3CR1-M280 is a genetic risk factor for CVD.
Sport category is an important determinant of cardiac adaptation: an MRI study
Authors: Tim Luijkx, Maarten J Cramer, Niek H J Prakken, Constantinus F Buckens, Arend Mosterd, Rienk Rienks, Frank J G Backx, Willem P Th M Mali, Birgitta K Velthuis
Journal: British Journal of Sports Medicine (2012)

Physiological cardiac adaptation in athletes is influenced by body surface area, gender, age, training intensity and sport type. This study assesses the influence of sport category and provides a physiological reference for sport category and gender.Three hundred and eighty-one subjects (mean age 25±5 years, range 18 to 39 years; 61% men) underwent cardiac MRI and ECG: 114 healthy non-athletes (≤3 training h/week) and 267 healthy elite athletes (mean 17±6.6 training h/week). Athletes performed low-dynamic high-static (LD-HS, n=42), high-dynamic low-static (HD-LS, n=144) or high-dynamic high-static sports (HD-HS, n=81).Left ventricular (LV) end-diastolic volume (EDV) index (ml/m(2)) for non-athletes/LD-HS/HD-LS/HD-HS, respectively, was 101/107/122/129 in men and 90/103/106/111 in women. LV end-diastolic mass (EDM) index (g/m(2)) for non-athletes/LD-HS/HD-LS/HD-HS was, respectively, 47/49/57/69 for men and 34/38/42/51 for women. Left or right ventricular EDV ratios were alike in all groups. LV EDV/EDM ratios were similar in non-athletes/LD-HS/HD-LS athletes, and only lower in HD-HS athletes, disproving selective ventricular wall thickening in LD-HS athletes. Multivariate linear regression demonstrated HD-LS and HD-HS sport category coefficients (p<0.01) larger than those of training hours, gender and age (LV EDV/EDM coefficients for sport category LD-HS 6/0.75, HD-LS 16/7, HD-HS 21/17). ECG abnormalities were most frequent in HD-HS athletes and in male subjects.This study demonstrates a balanced cardiac adaptation with preserved ratios of LV/right ventricular volume (in all sport categories) and LV volume/wall mass (in LD-HS and HD-LS sports). Sport category has a strong impact on cardiac adaptation. HD-HS sports show the largest changes, whereas LD-HS sports show dimensions similar to non-athletes.
Salt sensitivity in hypertension
Authors: V M Campese, F Karubian
Journal: Journal of the American Society of Nephrology (1991)

The role of dietary sodium in the pathogenesis of essential hypertension has stimulated a great deal of interest and investigation in recent years. There are epidemiologic studies in the literature that suggest a link between dietary sodium intake and the prevalence of hypertension. However, not all patients are prone to the development of hypertension in response to dietary sodium. Therefore, a distinction between salt sensitivity and salt-resistant essential hypertension has evolved from this observation. The mechanisms which related dietary sodium to the pathogenesis of essential hypertension are not clearly defined, although it appears that inborn errors of renal sodium handling, along with certain components of the sympathetic nervous system, may be involved. Furthermore, intracellular sodium and its transport mechanisms have been implicated in the pathogenesis of hypertension associated with dietary sodium. Finally, there appears to be a correlation between dietary sodium, salt sensitivity, and the progression of renal disease. That is to say, patients with salt-sensitive essential hypertension appear to demonstrate a more relentless course to end-stage renal disease. This tendency may be related to deranged hemodynamic adaptation of the renal circulation in response to dietary sodium intake and the resulting rise in systemic blood pressure. The mechanism for this derangement of renal hemodynamic adaptation in salt-sensitive hypertensives remains to be determined.
Towards a feasible model for shared decision making: focus group study with general practice registrars
Authors: G. Elwyn, A. Edwards, R. Gwyn, R. Grol
Journal: BMJ (1999)

<h3>Abstract</h3> <b>Objectives:</b> To explore the views of general practice registrars about involving patients in decisions and to assess the feasibility of using the shared decision making model by means of simulated general practice consultations. <b>Design:</b> Qualitative study based on focus group interviews. <b>Setting:</b> General practice vocational training schemes in south Wales. <b>Participants:</b> 39 general practice registrars and eight course organisers (acting as observers) attended four sessions; three simulated patients attended each time. <b>Method:</b> After an introduction to the principles and suggested stages of shared decision making the registrars conducted and observed a series of consultations about choices of treatment with simulated patients using verbal, numerical, and graphical data formats. Reactions were elicited by using focus group interviews after each consultation and content analysis undertaken. <b>Results:</b> Registrars in general practice report not being trained in the skills required to involve patients in clinical decisions. They had a wide range of opinions about "involving patients in decisions," ranging from protective paternalism ("doctor knows best"), through enlightened self interest (lightening the load), to the potential rewards of a more egalitarian relationship with patients. The work points to three contextual precursors for the process: the availability of reliable information, appropriate timing of the decision making process, and the readiness of patients to accept an active role in their own management. <b>Conclusions:</b> Sharing decisions entails sharing the uncertainties about the outcomes of medical processes and involves exposing the fact that data are often unavailable or not known; this can cause anxiety to both patient and clinician. Movement towards further patient involvement will depend on both the skills and the attitudes of professionals, and this work shows the steps that need to be taken if further progress is to be made in this direction. <h3>Key messages</h3> Involvement of patients in decisions about their treatment or care is increasingly advocated Registrars in general practice report not receiving training in the skills needed for successful involvement of patients in decision making Attitudes towards involving patients range from being highly positive to being more circumspect Moves towards enhancing patient involvement in decision making will depend on developing both skills and attitudes of professionals
A portable forced oscillation device for respiratory home monitoring
Authors: J. Rigau, R. Farré, J. Roca, S. Marco, A. Herms, D. Navajas
Journal: European Respiratory Journal (2002)

The increase in the prevalence of chronic respiratory diseases has resulted in a rise in health services provided at home. The forced oscillation technique (FOT) proves to be a useful tool when it is desired to assess lung function noninvasively, and particularly for patients in whom spirometry cannot be applied. As no portable FOT device is currently available, the aim of this study was to design and test a portable FOT system for ambulatory and home care applications. The system devised is based on a microprocessor, which allows online computation of respiratory resistance ( R rs ) and reactance ( X rs ) and reliability indices. The portable device was compared with a conventional FOT system by using signals from 14 patients with chronic respiratory disease. This device has the same computation capabilities and flexibility as conventional FOT systems and meets the requirements for home application. R rs (14.2±6.0 cmH 2 O·s·L −1 , mean±sd) and X rs (−5.3±2.7 cmH 2 O·s·L −1 ) measured at 5 Hz by the portable system virtually coincided with those computed with the reference conventional FOT system: mean differences±sd were 0.074±0.025 and 0.005±0.009 cmH 2 O·s·L −1 , respectively. This portable forced oscillation technique device could be a useful tool for monitoring respiratory mechanics in ambulatory and home care applications.
HLA Class I Antigen Processing Machinery Component Expression and Intratumoral T-Cell Infiltrate as Independent Prognostic Markers in Ovarian Carcinoma
Authors: Liz Y. Han, Mavis S. Fletcher, Diana L. Urbauer, Peter Mueller, Charles N. Landen, Aparna A. Kamat, Yvonne G. Lin, William M. Merritt, Whitney A. Spannuth, Michael T. Deavers, Koen De Geest, David M. Gershenson, Susan K. Lutgendorf, Soldano Ferrone, Anil K. Sood
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Defects in the antigen processing machinery (APM) may provide tumor cells with a mechanism to escape immune recognition. The purpose of this study is to determine the clinical significance of APM component down-regulation and tumor-infiltrating T cells in ovarian carcinoma. Experimental Design: After institutional review board approval, tumor samples from 150 patients with invasive epithelial ovarian cancers were examined for TAP1, TAP2, tapasin, HLA class I heavy chain (HLA-HC), β2 microglobulin, and T-cell (CD3+ and CD8+) tumor infiltration using immunohistochemistry. Results: The majority of tumors had either heterogeneous or positive expression of TAP1, TAP2, HLA-HC, and β2 microglobulin (66.7%, 73.3%, 70.7%, and 63.3%, respectively), except tapasin for which 58% of the tumors lacked expression. Furthermore, 67% and 88% of the lesions possessed intratumoral and peritumoral CD3+ or CD8+ cells, respectively. The majority of APM component expression examined was significantly associated with both intratumoral and peritumoral T-cell infiltration (P &amp;lt; 0.05). The expression of APM components and the presence of intratumoral T-cell infiltrates were significantly associated with improved survival (all P ≤ 0.01); however, peritumoral T-cell infiltrates did not significantly affect survival (P = 0.33). APM component down-regulation (P &amp;lt; 0.001), lack of intratumoral T-cell infiltrates (P = 0.03), and suboptimal cytoreduction (P &amp;lt; 0.001) were independent prognostic markers for death from ovarian carcinoma. Conclusion: The negative effect of APM component down-regulation by itself and in combination with absent intratumoral T-cell infiltration on the survival of patients with ovarian carcinoma implies a role for immune escape in addition to immunosurveillance in the clinical course of disease.
Evidence supporting a role for active oxygen species in asbestos-induced toxicity and lung disease.
Authors: B T Mossman, J P Marsh
Journal: Environmental Health Perspectives (1989)

Asbestos is an important occupational and environmental toxicant that affects several cell types in the respiratory tract. In an effort to understand how asbestos causes cell injury and/or altered proliferation and differentiation of cells, this laboratory has focused on reactive oxygen species as mediators of asbestos-induced biological effects. A compendium of experimental results reported by this laboratory and others supports this hypothesis. For example, scavengers of reactive oxygen metabolites and iron chelators (i.e., desferroxamine) prevent cytotoxicity after addition of asbestos to a variety of cell lines and macrophages in vitro. DNA strand breakage associated with toxicity of crocidolite asbestos in C3H10T 1/2 cells also is ameliorated with use of desferroxamine. All types of asbestos cause lipid peroxidation in mammalian cells and artificial membranes, a phenomenon that can be prevented by removal of catalytic iron. Last, asbestos causes generation of active oxygen species after interaction with leukocytes or by reduction of oxygen on the surface of the fibers.