tbuckley/cabot-search huggingface dataset:
Experimental research into the pathogenesis of cobalt/hard metal lung disease
Authors: D Lison, R Lauwerys, M Demedts, B Nemery
Journal: European Respiratory Journal (1996)

In recent years clinical, epidemiological and experimental evidence has accumulated indicating that cobalt metal particles, when inhaled in association with other agents such as metallic carbides (hard metals) or diamond dust, may produce an interstitial lung disease termed "hard metal disease" or "cobalt lung". This article summarizes the progress accomplished in our two laboratories to understand the pathogenesis of this disease. Gaps and weaknesses in our current knowledge have also been highlighted in order to suggest potential avenues for further research. Whilst animal models have proved useful for the demonstration of the toxic synergy between cobalt and carbides (e.g. tungsten carbide), most animal models have remained descriptive and have not provided information on the mechanism for this synergy. In particular, the bizarre multinucleated giant cells which are an important hallmark of the human disease, have not been reproduced consistently in experimental animals. Since cobalt is a known sensitizer, there may also be a need to develop experimental models to test the possible involvement of immunological mechanisms in the pathogenesis of the interstitial disease. In vitro systems including macrophage cell cultures and physico-chemical tests have been useful to investigate the mechanism underlying the toxic synergy. The recent finding that, in vitro, cobalt and metallic carbides interact with oxygen to produce toxic activated oxygen species opens a new avenue of research and may offer an alternative interpretation of the fact that only a limited proportion of exposed workers develop interstitial disease. Besides the possible involvement of immunological mechanisms, it may be speculated that individuals with a lower antioxidant defence are more susceptible to the toxic effect of activated oxygen species produced by cobalt-containing dusts from hard metal.
Remission in Depressed Geriatric Primary Care Patients: A Report From the PROSPECT Study
Authors: George S. Alexopoulos, Ira R. Katz, Martha L. Bruce, Moonseong Heo, Thomas Ten Have, Patrick Raue, Hillary R. Bogner, Herbert C. Schulberg, Benoit H. Mulsant, Charles F. Reynolds
Journal: American Journal of Psychiatry (2005)

This study compared time to first remission for elderly depressed patients in primary care for practices that implemented a care management model versus those providing usual care. In addition, it sought to identify risk factors for nonremission that could guide treatment planning and referral to care managers or specialists.Prevention of Suicide in Primary Care Elderly: Collaborative Trial (PROSPECT) data were analyzed. Participants were older patients (> or =60 years) selected following screening of 9,072 randomly identified primary care patients. The present analysis examined patients with major depression and a 24-item Hamilton Depression Rating Scale score of 18 or greater who were followed for at least 4 months (N=215). Primary care practices were randomly assigned to offer the PROSPECT intervention or usual care. The intervention consisted of services of trained care managers, who offered algorithm-based recommendations to physicians and helped patients with treatment adherence over 18 months.First remission occurred earlier and was more common among patients receiving the intervention than among those receiving usual care. For all patients, limitations in physical and emotional functions predicted poor remission rate. Patients experiencing hopelessness were more likely to achieve remission if treated in intervention practices. Similarly, the intervention was more effective in patients with low baseline anxiety.Longitudinal assessment of depression, hopelessness, anxiety, and physical and emotional functional limitations in depressed older primary care patients is critical. Patients with prominent symptoms or impairment in these areas may be candidates for care management or mental health care, since they are at risk for remaining depressed and disabled.
MRI biomarkers identify the differential response of glioblastoma multiforme to anti-angiogenic therapy
Authors: Shahrzad Jalali, Caroline Chung, Warren Foltz, Kelly Burrell, Sanjay Singh, Richard Hill, Gelareh Zadeh
Journal: Neuro-Oncology (2014)

Although anti-angiogenic therapy (AATx) holds great promise for treatment of malignant gliomas, its therapeutic efficacy is not well understood and can potentially increase the aggressive recurrence of gliomas. It is essential to establish sensitive, noninvasive biomarkers that can detect failure of AATx and tumor recurrence early so that timely adaptive therapy can be instituted. We investigated the efficacy of MRI biomarkers that can detect response to different classes of AATxs used alone or in combination with radiation. Murine intracranial glioma xenografts (NOD/SCID) were treated with sunitinib, VEGF-trap or B20 (a bevacizumab equivalent) alone or in combination with radiation. MRI images were acquired longitudinally before and after treatment, and various MRI parameters (apparent diffusion coefficient, T1w + contrast, dynamic contrast-enhanced [DCE], initial area under the contrast enhancement curve, and cerebral blood flow) were correlated to tumor cell proliferation, overall tumor growth, and tumor vascularity. Combinatorial therapies reduced tumor growth rate more efficiently than monotherapies. Apparent diffusion coefficient was an accurate measure of tumor cell density. Vascular endothelial growth factor (VEGF)-trap or B20, but not sunitinib, resulted in significant reduction or complete loss of contrast enhancement. This reduction was not due to a reduction in tumor growth or microvascular density, but rather was explained by a reduction in vessel permeability and perfusion. We established that contrast enhancement does not accurately reflect tumor volume or vascular density; however, DCE-derived parameters can be used as efficient noninvasive biomarkers of response to AATx. MRI parameters following therapy vary based on class of AATx. Validation of clinically relevant MRI parameters for individual AATx agents is necessary before incorporation into routine practice.
Dose-densified chemoimmunotherapy followed by systemic central nervous system prophylaxis for younger high-risk diffuse large B-cell/follicular grade 3 lymphoma patients: results of a phase II Nordic Lymphoma Group study
Authors: H. Holte, S. Leppä, M. Björkholm, Ø. Fluge, S. Jyrkkiö, J. Delabie, C. Sundström, M.-L. Karjalainen-Lindsberg, M. Erlanson, A. Kolstad, A. Fosså, B. Østenstad, E. Löfvenberg, M. Nordström, R. Janes, L.M. Pedersen, H. Anderson, M. Jerkeman, M. Eriksson
Journal: Annals of Oncology (2012)
Moving Human Embryonic Stem Cells from Legislature to Lab: Remaining Legal and Ethical Questions
Authors: Henry T Greely
Journal: PLoS Medicine (2006)

Research with human embryonic stem cells (hESCs) has been controversial, but in the seven years since their isolation by James Thomson [1], governments have largely answered, at least for now, the first-level questions about this research. We now know in most jurisdictions whether derivation of hESC lines will not be permitted from any embryos or whether it will be permitted from all embryos, only from embryos created as part of in vitro fertilization clinical services (IVF), or only from embryos not created by somatic cell nuclear transfer (SCNT). We also have learned where the various kinds of cell lines, if derived elsewhere, may be used, and whether public funding for the derivation or use of some or all of the lines will be possible. A set of second-level questions, revolving around the donors of cells and embryos used in this research, is also rapidly being answered.
Leuprolide Acetate Plus Aromatase Inhibition for Male Breast Cancer
Authors: Sharon H. Giordano, Gabriel N. Hortobagyi
Journal: Journal of Clinical Oncology (2006)

TO THE EDITOR: Approximately 1% of breast cancer occurs in male patients, yet little information is available on the optimal treatment of this disease. 1 Male patients with breast cancer are more likely than female patients to have tumors positive for estrogen and/or progesterone receptors. 2 However, the hormonal environment in male patients differs from that in female patients; thus hormone therapies that are effective in women may or may not be effective in male patients. In particular, the role of aromatase inhibitors in male patients is unclear. Preclinical data suggest that aromatase inhibitors maybelesseffectiveinmen.Inanimalmodels,chronicadministration of aromatase inhibitors was associated with significant increases in follicular stimulating hormone and testosterone and no change in levels of estradiol. 3 A possible explanation for this finding is that the increaseinfollicularstimulatinghormoneandtestosteronecouldlead to an increase in substrate for aromatization via a feedback loop. Aromataseinhibitorshavealsobeentestedinhealthymalevolunteers and resulted in a 50% decrease in estradiol but an increase in testosterone levels. 4 To our knowledge, seven cases of men with breast cancer treated with aromatase inhibitors have been reported in the literature. One series offive patients reported no responses, 5 and two case reports have documented responses to aromatase inhibitors. 6,7 We now wish to report two cases of male patients treated with a combinationofleuprolideacetateandaromataseinhibitors.Therationale
Asthma: epidemics and epidemiology.
Authors: D J Hendrick
Journal: Thorax (1989)

A recent editorial in Thorax challenged its readers with an interest in the aetiology of asthma to investigate potential causative agents in the environment using epidemiological methods.'The aetiology of scurvy, it was argued, was established readily enough from a recognition in population studies that the disease was associated with a lack of fresh fruit and vegetables.
Effect of Estrogen Therapy on Gallbladder Disease
Authors: Dominic J. Cirillo, Robert B. Wallace, Rebecca J. Rodabough, Philip Greenland, Andrea Z. LaCroix, Marian C. Limacher, Joseph C. Larson
Journal: JAMA (2005)

Context Estrogen therapy is thought to promote gallstone formation and cholecystitis but most data derive from observational studies rather than randomized trials.Objective To determine the effect of estrogen therapy in healthy postmenopausal women on gallbladder disease outcomes.Design, Setting, and Participants Two randomized, double-blind, placebocontrolled trials conducted at 40 US clinical centers.The volunteer sample was 22579 community-dwelling women aged 50 to 79 years without prior cholecystectomy.Intervention Women with hysterectomy were randomized to 0.625 mg/d of conjugated equine estrogens (CEE) or placebo (n=8376).Women without hysterectomy were randomized to estrogen plus progestin (E+P), given as CEE plus 2.5 mg/d of medroxyprogesterone acetate (n=14203). Main Outcome MeasuresParticipants reported hospitalizations for gallbladder diseases and gallbladder-related procedures, with events ascertained through medical record review.Cox proportional hazards regression was used to assess hazard ratios (HRs) and 95% confidence intervals (CIs) using intention-to-treat and time-to-event methods. ResultsThe CEE and the E+P groups were similar to their respective placebo groups at baseline.The mean follow-up times were 7.1 years and 5.6 years for the CEE and the E+P trials, respectively.The annual incidence rate for any gallbladder event was 78 events per 10000 person-years for the CEE group (vs 47/10000 person-years for placebo) and 55 per 10000 person-years for E+P (vs 35/10000 person-years for placebo).Both trials showed greater risk of any gallbladder disease or surgery with estrogen (CEE: HR, 1.67; 95% CI, 1.35-2.06;E+P: HR, 1.59; 95% CI, 1.28-1.97).Both trials indicated a higher risk for cholecystitis (CEE: HR, 1.80; 95% CI, 1.42-2.28;E+P: HR, 1.54; 95% CI 1.22-1.94);and for cholelithiasis (CEE: HR, 1.86; 95% CI, 1. 48-2.35;E+P: HR, 1.68; 95% CI, 1.34-2.11)for estrogen users.Also, women undergoing estrogen therapy were more likely to receive cholecystectomy (CEE: HR, 1.93; 95% CI, 1.52-2.44;E+P: HR, 1.67; 95% CI, 1.32-2.11),but not other biliary tract surgery (CEE: HR, 1.18; 95% CI, 0.68-2.04;E+P: HR, 1.49; 95% CI, 0.78-2.84).Conclusions These data suggest an increase in risk of biliary tract disease among postmenopausal women using estrogen therapy.The morbidity and cost associated with these outcomes may need to be considered in decisions regarding the use of estrogen therapy.
Low-Dose Aspirin for the Prevention of Atherothrombosis
Authors: Carlo Patrono, Luis A. García Rodríguez, Raffaele Landolfi, Colin Baigent
Journal: New England Journal of Medicine (2005)

This review considers the role of low-dose aspirin for the prevention of atherothrombosis, discussing the molecular mechanism of action of aspirin as well as clinical and epidemiologic studies of aspirin as an antiplatelet agent, with special emphasis on the benefits and risks in different patient populations.
Unstable Coronary Plaque and Its Relation to Coronary Calcium
Authors: Axel Schmermund, Raimund Erbel
Journal: Circulation (2001)

Coronary calcium is intimately associated with coronary atherosclerotic plaque development. The use of electron-beam computed tomography (EBCT) for accurate quantitative measurements has led to an increased interest in understanding the clinical importance of coronary calcium, particularly in terms of the ability to identify unstable coronary plaques that underlie the clinical acute coronary syndromes. Histopathologic studies have demonstrated that calcium is a frequent feature of ruptured plaques, but the presence or absence of calcium does not allow for reliable distinction between unstable versus stable plaques. This issue is complicated by the lack of a prospective definition for “unstable.” Plaque rupture is sometimes found in apparently healthy subjects and in patients with clinically stable disease. Coronary atherosclerosis is a coronary systemic disease process. Imaging of coronary calcium, although unable to identify a localized unstable plaque, potentially can identify the more clinically pertinent “unstable patient.” Almost all patients with a recent acute coronary syndrome have measurable coronary calcium because moderate-to-advanced coronary plaque disease is already present, although obstructive disease frequently is not. Prospective studies have demonstrated that extensive coronary calcium detected by EBCT is associated with a significantly increased incidence of subsequent myocardial infarction, need for revascularization, and coronary death. The incremental prognostic value of coronary calcium compared with that of risk factor assessment remains to be fully defined. The occurrence of an acute coronary syndrome is determined by many factors apart from the extent of atherosclerotic plaque disease. Large prospective trials in the general population are needed to define the subgroups that will benefit most from quantitative assessment of coronary calcium.
Adjuvant Chemotherapy in Older Patients With Stage III Colon Cancer: An Underused Lifesaving Treatment
Authors: Hyman B. Muss, Debra L. Bynum
Journal: Journal of Clinical Oncology (2012)

absolute 5-year improvement in survival for all patients of 7% favoring chemotherapy (64% for surgery alone v 71% for surgery and chemotherapy), and similar survival benefits were seen in the 506 patients in this data set who were older than 70 years of age. Moreover, there was no relationship between age and chemotherapy toxicity, including nausea and vomiting, stomatitis, and diarrhea; however, leucopenia was more common in older patients in two of the trials. A key goal of the Sanoff et al 4 analysis was to determine the value of oxaliplatin when added to fluoropyrimidine (fluorouracil [FU] or capecitabine) therapy. Of those patients who received chemotherapy, oxaliplatin was administered to 46%, 25%, and 7% of patients age 75 to 79, 80 to 84, and 85 years or older, respectively. There was a trend for improved survival with oxaliplatin (HR, 0.82; 95% CI, 0.51 to 1.33) that corresponded to an absolute 5% improvement in survival at 3 years compared with fluoropyrimidines alone; these results are similar to the HRs reported in the MOSAIC (Multicenter International Study of Oxaliplatin/FU/Leucovorin in the Adjuvant Treatment of Colon
Inhibition of calpains improves memory and synaptic transmission in a mouse model of Alzheimer disease
Authors: Fabrizio Trinchese, Mauro Fa’, Shumin Liu, Hong Zhang, Ariel Hidalgo, Stephen D. Schmidt, Hisako Yamaguchi, Narihiko Yoshii, Paul M. Mathews, Ralph A. Nixon, Ottavio Arancio
Journal: Journal of Clinical Investigation (2008)

Calpains are calcium-dependent enzymes that determine the fate of proteins through regulated proteolytic activity. Calpains have been linked to the modulation of memory and are key to the pathogenesis of Alzheimer disease (AD). When abnormally activated, calpains can also initiate degradation of proteins essential for neuronal survival. Here we show that calpain inhibition through E64, a cysteine protease inhibitor, and the highly specific calpain inhibitor BDA-410 restored normal synaptic function both in hippocampal cultures and in hippocampal slices from the APP/PS1 mouse, an animal model of AD. Calpain inhibition also improved spatial-working memory and associative fear memory in APP/PS1 mice. These beneficial effects of the calpain inhibitors were associated with restoration of normal phosphorylation levels of the transcription factor CREB and involved redistribution of the synaptic protein synapsin I. Thus, calpain inhibition may prove useful in the alleviation of memory loss in AD.
Calcium waves driven by “sensitization” wave-fronts
Authors: M KELLER, J KAO, M EGGER, E NIGGLI
Journal: Cardiovascular Research (2007)

Cellular Ca(2+) waves are understood as reaction-diffusion systems sustained by Ca(2+)-induced Ca(2+) release (CICR) from Ca(2+) stores. Given the recently discovered sensitization of Ca(2+) release channels (ryanodine receptors; RyRs) of the sarcoplasmic reticulum (SR) by luminal SR Ca(2+), waves could also be driven by RyR sensitization, mediated by SR overloading via Ca(2+) pump (SERCA), acting in tandem with CICR.Confocal imaging of the Ca(2+) indicator fluo-3 was combined with UV-flash photolysis of caged compounds and the whole-cell configuration of the patch clamp technique to carry out these experiments in isolated guinea pig ventricular cardiomyocytes.Upon sudden slowing of the SERCA in cardiomyocytes with a photoreleased inhibitor, waves indeed decelerated immediately. No secondary changes of Ca(2+) signaling or SR Ca(2+) content due to SERCA inhibition were observed in the short time-frame of these experiments.Our findings are consistent with Ca(2+) loading resulting in a zone of RyR 'sensitization' traveling within the SR, but inconsistent with CICR as the predominant mechanism driving the Ca(2+) waves. This alternative mode of RyR activation is essential to fully conceptualize cardiac arrhythmias triggered by spontaneous Ca(2+) release.
Long-term follow up after bronchoscopic lung volume reduction coil treatment
Authors: Jorine E. Hartman, Karin Klooster, Nick H.T. ten Hacken, Dirk-Jan Slebos
Journal: European Respiratory Journal (2014)

Background:  Bronchoscopic lung volume reduction coil (LVRC) treatment has shown to be clinically effective in patients with severe emphysema in the short term, but long term safety and efficacy has not been evaluated. We evaluated the LVRC treatment up to 3 year follow up (FU).   Methods:  38 patients with severe emphysema (median age 59 years, FEV 1  27%pred) who previously participated in our pilot LVRC trials, were voluntarily invited for a yearly visit. Safety was evaluated by chest-Xray and recording of adverse events. Efficacy by pulmonary function testing, 6MWD and questionnaires.   Results:  35 patients visited us after 1 year, 27 after 2 year and 22 after 3 year. We witnessed no coil migrations on the FU X-rays. At 1 year FU, all clinical outcomes were significantly improved compared to baseline. At 2 years FU, only RV%pred, mMRC and the SGRQ score were still significantly improved, with at 3 years FU only a significant improvement in mMRC score, with 40% of the patients reaching the 6MWD minimal important difference, and 59% for the SGRQ (table1).   Conclusion:  Follow-up of our very first pilot patients shows that LVRC treatment is safe in the long term, with especially no late pneumothoraces, coil migrations or unexpected adverse events. Clinical benefit declines over time with at 3 years still a significant number of patients responding for 6MWT, SGRQ and mMRC, not taking the expected disease related decline over time into account.
Increased circulating endothelial microparticles in COPD patients: a potential biomarker for COPD exacerbation susceptibility
Authors: Toru Takahashi, Seiichi Kobayashi, Naoya Fujino, Takaya Suzuki, Chiharu Ota, Mei He, Mitsuhiro Yamada, Satoshi Suzuki, Masaru Yanai, Shin Kurosawa, Mutsuo Yamaya, Hiroshi Kubo
Journal: Thorax (2012)

<h3>Rationale</h3> The influence of COPD exacerbation on the endothelium is not completely understood. Circulating endothelial microparticles (EMPs) are membrane vesicles in circulating blood that are shed by activated or apoptotic endothelial cells. <h3>Objective</h3> To compare EMP numbers in stable COPD patients with those during and after exacerbation. <h3>Methods</h3> We examined the EMP numbers in 80 stable COPD patients, 27 patients with exacerbated COPD, and 20 healthy non-COPD volunteers. EMPs were defined as CD144+ MPs (VE-cadherin EMPs), CD31+/CD41− MPs (PECAM EMPs), CD146 MPs (MCAM EMPs) and CD62E+ EMPs (E-selectin EMPs) as analysed by FACS. Von Willebrand factor (vWF) expression was utilised to identify the origins of the EMPs. <h3>Results</h3> VE-cadherin, PECAM and E-selectin EMP numbers were significantly higher in the stable COPD patients than in the non-COPD volunteers, and they were significantly higher in the patients with exacerbated COPD than in the stable COPD patients. The majority of these increased EMPs were vWF-negative, indicating a pulmonary capillary origin. Baseline E-selectin EMP levels were significantly higher in COPD patients who experienced frequent exacerbations than in those who did not have frequent exacerbations (p&lt;0.001). Twenty-eight days after the onset of exacerbation, E-selectin EMP levels returned to those observed in stable COPD patients, whereas PECAM EMP levels remained high. MCAM EMP numbers were not elevated in stable or exacerbated-COPD patients. <h3>Conclusions</h3> Endothelial damage, mainly in pulmonary capillaries, occurs during exacerbation and continues even after clinical symptoms disappear. Higher baseline E-selectin EMP levels may indicate COPD patients who are susceptible to exacerbation.