tbuckley/cabot-search huggingface dataset:
VX-710 (Biricodar) Increases Drug Retention and Enhances Chemosensitivity in Resistant Cells Overexpressing P-Glycoprotein, Multidrug Resistance Protein, and Breast Cancer Resistance Protein
Authors: Hans Minderman, Kieran L. O’Loughlin, Lakshmi Pendyala, Maria R. Baer
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The pipecolinate derivative VX-710 (biricodar; Incel) is a clinically applicable modulator of P-glycoprotein (Pgp) and multidrug resistance protein (MRP-1); we studied its activity against the third multidrug resistance (MDR)-associated drug efflux protein, breast cancer resistance protein (BCRP). Experimental Design: VX-710 modulation of uptake, retention, and cytotoxicity of mitoxantrone, daunorubicin, doxorubicin, topotecan, and SN38 was studied in cell lines overexpressing Pgp, MRP-1 and wild-type (BCRPR482) and mutant (BCRPR482T) BCRP. Results: In 8226/Dox6 cells (Pgp), VX-710 increased mitoxantrone and daunorubicin uptake by 55 and 100%, respectively, increased their retention by 100 and 60%, respectively, and increased their cytotoxicity 3.1- and 6.9-fold, respectively. In HL60/Adr cells (MRP-1), VX-710 increased mitoxantrone and daunorubicin uptake by 43 and 130%, increased their retention by 90 and 60%, and increased their cytotoxicity 2.4- and 3.3-fold. In 8226/MR20 cells (BCRPR482), VX-710 increased mitoxantrone uptake and retention by 60 and 40%, respectively, and increased cytotoxicity 2.4-fold. VX-710 increased daunorubicin uptake and retention by only 10% in 8226/MR20 cells, consistent with the fact that daunorubicin is not a substrate for BCRPR482, but, nevertheless, it increased daunorubicin cytotoxicity 3.6-fold, and this increase was not associated with intracellular drug redistribution. VX-710 had little effect on uptake, retention, or cytotoxicity of mitoxantrone, daunorubicin, doxorubicin, topotecan, or SN38 in MCF7 AdVP3000 cells (BCRPR482T). Conclusions: VX-710 modulates Pgp, MRP-1, and BCRPR482, and has potential as a clinical broad-spectrum MDR modulator in malignancies such as the acute leukemias in which these proteins are expressed.
Do clinical guidelines improve general practice management and referral of infertile couples?
Authors: C Emslie, J Grimshaw, A Templeton
Journal: BMJ (1993)

OBJECTIVE--To evaluate guidelines for general practice management and referral of infertile couples. Guidelines were implemented with a disease specific reminder at the time of consultation (the guidelines were embedded within a structured infertility management sheet for each couple). DESIGN--Pragmatic randomised controlled trial. Participating practices were randomised to a group that received the guidelines and a control group. SETTING--82 general practices in Grampian region. SUBJECTS--100 couples referred by general practitioners receiving the guideline and 100 couples referred by control general practitioners. MAIN OUTCOME MEASURES--Whether the general practitioner had taken a full sexual history and examined and investigated both partners appropriately. RESULTS--Characteristics of patients referred by study and control general practitioners did not differ significantly at baseline. Compliance with the guidelines increased for all targeted activities. General practitioners in the study group were more likely to take a sexual history (for example, couples9 use of fertile period, 85% v 69%, p &lt; 0.01); examine both partners (female partner, 68% v 52%, p &lt; 0.05; male partner 39% v 13%, p &lt; 0.01); and investigate both partners (day 21 progesterone, 72% v 41%, p &lt; 0.001; semen analysis, 51% v 41%, p &gt; 0.05). Improvements were greater when general practitioners used the disease specific reminder. CONCLUSION--Receiving guidelines led to improvements in the process of care of infertile couples within general practice. This effect was enhanced when the guidelines were embedded in a structured infertility management sheet for each couple.
P291 Obstructive Sleep Apnoea Screening For Patients Undergoing Bronchoscopy - Is It Required?
Authors: V. Palissery, D. Ghosh, M. Elliott
Journal: Thorax (2014)

<h3>Introduction</h3> A recent meta-analysis shows obstructive sleep apnoea (OSA) increases the incidence of postoperative desaturation, respiratory failure, cardiac events, and ICU transfers (Kaw, R., <i>et al</i>, 2012). A study in gastrointestinal endoscopy showed no increased risk of cardiopulmonary complications in OSA screening positive patients (Mador, M. J., <i>et al</i>, 2012). There are no published studies in patients with OSA undergoing bronchoscopy, as far as we are aware. It has been suggested that patients should be screened for OSAS prior to endoscopy and bronchoscopy. <h3>Methods</h3> Nursing staff in the bronchoscopy suite used a validated OSA screening tool STOP-BANG score prior to the procedure. The physician performing the rpocedure was unaware of the score. The amount of sedation used during the procedure is recorded. Sedation score, Respiratory Rate (RR), Oxygen Sturation (SpO2) were documented 0,30,60,120 min post procedure. <h3>Results</h3> Procedures were performed in 57 patients; diagnostic bronchoscopy 28, EBUS 29. Twenty-three patients (40.3%) were identified high risk for OSA (STOP-BANG score 3 or above). The mean age was 64 +/- 15. Male 29 (50.8%). There was no statistically significant difference in: amount of sedation used (midazolam, fentanyl or both), lignocaine use, initial sedation score, RR, SpO2, between high and low risk group. (Table 1). There was no correlation between initial sedation score with STOP-BANG score. There was no evidence of deeper sedation, drop in RR or SpO2 noticed in the post procedure observation period in the high risk group. Median length of observation was same in both groups. There were no complications or emergency admissions. <h3>Conclusion</h3> In this small study there is no evidence of increased cardio respiratory complications in patients at high risk for OSA undergoing bronchoscopy under conscious sedation. <h3>References</h3> Kaw, R, <i>et al</i>. Meta-analysis of association between obstructive sleep apnoea and postoperative outcome. <i>Br J Anaesth</i> 2012;109(6):897-906 Mador, MJ, <i>et al</i>. D patients at risk of sleep apnea have an increased risk of cardio-respiratory complications during endoscopy procedures? <i>Sleep Breath</i> 2012;16(3):609-615
Metabolic Syndrome With and Without C-Reactive Protein as a Predictor of Coronary Heart Disease and Diabetes in the West of Scotland Coronary Prevention Study
Authors: Naveed Sattar, Allan Gaw, Olga Scherbakova, Ian Ford, Denis St.J. O’Reilly, Steven M. Haffner, Chris Isles, Peter W. Macfarlane, Chris J. Packard, Stuart M. Cobbe, James Shepherd
Journal: Circulation (2003)

The National Cholesterol Education Program (NCEP) recently proposed a simple definition for metabolic syndrome. Information on the prospective association of this definition for coronary heart disease (CHD) and type 2 diabetes is currently limited.We used a modified NCEP definition with body mass index in place of waist circumference. Baseline assessments in the West of Scotland Coronary Prevention Study were available for 6447 men to predict CHD risk and for 5974 men to predict incident diabetes over 4.9 years of follow-up. Mean LDL cholesterol was similar but C-reactive protein was higher (P<0.0001) in the 26% of men with the syndrome compared with those without. Metabolic syndrome increased the risk for a CHD event [univariate hazard ratio (HR)=1.76 (95% CI, 1.44 to 2.15)] and for diabetes [univariate HR=3.50 (95% CI 2.51 to 4.90)]. Metabolic syndrome continued to predict CHD events (HR=1.30, 95% CI, 1.00 to 1.67, P=0.045) in a multivariate model incorporating conventional risk factors. Men with 4 or 5 features of the syndrome had a 3.7-fold increase in risk for CHD and a 24.5-fold increase for diabetes compared with men with none (both P<0.0001). C-reactive protein enhanced prognostic information for both outcomes. With pravastatin, men with the syndrome had similar risk reduction for CHD as compared with those without (HR, 0.73 and 0.69; pravastatin versus placebo).A modified NCEP metabolic syndrome definition predicts CHD events, and, more strikingly, new-onset diabetes, and thus helps identify individuals who may receive particular benefit from lifestyle measures to prevent these diseases.
Hospitalization burden and survival among older glioblastoma patients
Authors: N. D. Arvold, Y. Wang, C. Zigler, D. Schrag, F. Dominici
Journal: Neuro-Oncology (2014)

Half of all glioblastoma patients are at least 65 years old. The frequency and duration of hospitalization from disease- and treatment-related morbidity in this population are unknown. We performed a retrospective cohort study among patients aged 65 years and older with glioblastoma diagnosed between 1999 and 2007 using SEER–Medicare linked data. Diagnoses and procedures were identified using administrative claims data. Logistic regression was performed to identify predictors of high hospitalization burden. Among the 5029 patients in the cohort, 52% were ages 65–74, and 52% were male. Twenty-six percent of patients underwent extensive resection, 72% received radiotherapy, and 18% received temozolomide. Median survival was 4.9 months. Among all patients, 21% were hospitalized at least 30 cumulative days between diagnosis and death, and 22% of all patients spent at least one-fourth of their remaining lives as inpatients. Higher comorbidity score (adjusted hazard ratio [AHR], 1.72; 95% CI, 1.42–2.07) and black race (AHR, 1.56; 95% CI, 1.11–2.18) were associated with an increased risk of being hospitalized for at least 25% of remaining life, whereas radiation (AHR, 0.49; 95% CI, 0.42–0.58), temozolomide (AHR, 0.31; 95% CI, 0.23–0.42), and extensive surgery (AHR, 0.83; 95% CI, 0.69–0.99) were associated with a decreased risk. These data highlight the burden of hospitalization faced by a large proportion of older glioblastoma patients. In the setting of short survival, strategies to reduce the amount of time these patients spend hospitalized are urgently needed, to help maintain quality of life at the end of life.
Emotion Dysregulation in Attention Deficit Hyperactivity Disorder
Authors: Philip Shaw, Argyris Stringaris, Joel Nigg, Ellen Leibenluft
Journal: American Journal of Psychiatry (2014)

Emotion dysregulation, a major contributor to impairment throughout life, is common in ADHD and may arise from deficits in orienting toward and processing emotional stimuli, implicating dysfunction within the prefrontal cortical network. Understanding the nature of the overlap between emotional dysregulation and ADHD can stimulate novel treatment approaches.
A critical role for the host mediator macrophage migration inhibitory factor in the pathogenesis of malarial anemia
Authors: Michael A. McDevitt, Jianlin Xie, Shanmugasundaram Ganapathy-Kanniappan, Jason Griffith, Aihua Liu, Courtney McDonald, Philip Thuma, Victor R. Gordeuk, Christine N. Metz, Robert Mitchell, Jeffrey Keefer, John David, Lin Leng, Richard Bucala
Journal: The Journal of Experimental Medicine (2006)

The pathogenesis of malarial anemia is multifactorial, and the mechanisms responsible for its high mortality are poorly understood. Studies indicate that host mediators produced during malaria infection may suppress erythroid progenitor development (Miller, K.L., J.C. Schooley, K.L. Smith, B. Kullgren, L.J. Mahlmann, and P.H. Silverman. 1989. Exp. Hematol. 17:379–385; Yap, G.S., and M.M. Stevenson. 1991. Ann. NY Acad. Sci. 628:279–281). We describe an intrinsic role for macrophage migration inhibitory factor (MIF) in the development of the anemic complications and bone marrow suppression that are associated with malaria infection. At concentrations found in the circulation of malaria-infected patients, MIF suppressed erythropoietin-dependent erythroid colony formation. MIF synergized with tumor necrosis factor and γ interferon, which are known antagonists of hematopoiesis, even when these cytokines were present in subinhibitory concentrations. MIF inhibited erythroid differentiation and hemoglobin production, and it antagonized the pattern of mitogen-activated protein kinase phosphorylation that normally occurs during erythroid progenitor differentiation. Infection of MIF knockout mice with Plasmodium chabaudi resulted in less severe anemia, improved erythroid progenitor development, and increased survival compared with wild-type controls. We also found that human mononuclear cells carrying highly expressed MIF alleles produced more MIF when stimulated with the malarial product hemozoin compared with cells carrying low expression MIF alleles. These data suggest that polymorphisms at the MIF locus may influence the levels of MIF produced in the innate response to malaria infection and the likelihood of anemic complications.
Aprotinin But Not ε-Aminocaproic Acid Decreases Interleukin-10 After Cardiac Surgery With Extracorporeal Circulation
Authors: Philip E. Greilich, Kuniyuki Okada, Paige Latham, Ramaswamy Ravi Kumar, Michael E. Jessen
Journal: Circulation (2001)

Extracorporeal circulation induces a systemic inflammatory response, which may adversely affect organ function. One manifestation of this response is increased fibrinolysis. Antifibrinolytic drugs such as aprotinin and epsilon-aminocaproic acid have been effective in reducing fibrinolysis and blood loss after extracorporeal circulation; however, the effects of antifibrinolytic drugs on proinflammatory and anti-inflammatory mediators are not known. This study examined the effects of aprotinin and epsilon-aminocaproic acid on plasma levels of proinflammatory [interleukin-6 (IL-6)] and anti-inflammatory [interleukin-10 (IL-10)] cytokines during and after extracorporeal circulation.Seventy-two patients undergoing coronary artery bypass grafting with extracorporeal circulation were randomly assigned in a double-blind study to receive high-dose aprotinin, epsilon-aminocaproic acid, or saline placebo. Plasma levels of IL-6 and IL-10 were measured at 5 time points before, during, and after extracorporeal circulation. In all 3 groups, both IL-6 and IL-10 rose significantly after institution of extracorporeal circulation and remained elevated through the first postoperative day. Compared with saline, aprotinin significantly reduced IL-10 (P=0.02) and peak IL-6 (P=0.02) after extracorporeal circulation. In contrast, none of the reductions in IL-6 and IL-10 by epsilon-aminocaproic acid achieved statistical significance. Both aprotinin and epsilon-aminocaproic acid decreased blood loss compared with saline, but there was no significant difference in the number of patients receiving blood products among the treatment groups.These data suggest that aprotinin and epsilon-aminocaproic acid differ in their effects on the inflammatory response to extracorporeal circulation. Aprotinin but not epsilon-aminocaproic acid appears to attenuate the rise in the proinflammatory and anti-inflammatory cytokines IL-6 and IL-10. Further studies will be required to determine if these cytokine alterations translate to changes in clinical outcomes.
3D co-culture of hematopoietic stem and progenitor cells and mesenchymal stem cells in collagen scaffolds as a model of the hematopoietic niche
Authors: Isabelle Leisten, Rafael Kramann, Mónica S. Ventura Ferreira, Manfred Bovi, Sabine Neuss, Patrick Ziegler, Wolfgang Wagner, Ruth Knüchel, Rebekka K. Schneider
Journal: Biomaterials (2011)
Prevalence of Symptoms of Posttraumatic Stress Disorder in German Professional Firefighters
Authors: Dieter Wagner, Markus Heinrichs, Ulrike Ehlert
Journal: American Journal of Psychiatry (1998)

This study investigated the prevalence of posttraumatic stress disorder (PTSD) and comorbid symptoms among professional firefighters in Germany and examined not only primary but also secondary traumatic stress disorder experienced by these firefighters who were exposed to the sufferings of others.To estimate the prevalence of trauma-related disorders, a representative group of 402 professional firefighters from the State of Rheinland-Pfalz in Germany was surveyed through use of the General Health Questionnaire, a PTSD Symptom Scale, a stress coping questionnaire, and a self-rating scale to assess bodily complaints.The current prevalence rate of PTSD symptoms among professional firefighters was 18.2%. About 27% of the recruited subjects had a mental disorder according to the General Health Questionnaire. Predictors for the extent of traumatic stress were longer job experience and the number of distressing missions during the last month. Traumatic stress also predicted psychiatric impairment beyond PTSD, such as depressive mood, psychosomatic complaints, social dysfunction, and substance abuse.The high prevalence of PTSD and other psychiatric impairments in firefighters indicates that they often fail to cope with primary and particularly secondary stress in their daily work. This problem, together with the individual psychological consequences and expenses related to work absenteeism and early retirement, seems to be very specific for the profession of firefighters. The present findings provide a better understanding of the relationship between secondary traumatic stress and PTSD in professional helpers and high-risk populations such as firefighters, emergency workers, and the police.
The Gamma Knife
Authors: W. Robert Hudgins
Journal: JAMA (1989)

<h3>To the Editor. —</h3> The November 4 letter by Dr Kjellberg<sup>1</sup>criticizing a previous letter comparing radiosurgery using the gamma knife with proton beam therapy was itself misleading. For instance, Dr Kjellberg belittled gamma knife therapy for arteriovenous malformations by equating it to previously unsuccessful treatment by conventional cobalt teletherapy. The gamma knife is an entirely new device, using 201 separately collimated cobalt sources for a single "surgical" treatment, and its well-documented results speak for themselves. Two years after gamma knife radio-surgery, 80% of arteriovenous malformations disappeared, as judged by strict angiographic criteria that included that there not even be an early filling vein, in a 97% follow-up of 159 patients.<sup>2</sup>However, 2 years after proton beam therapy, only 22% of arteriovenous malformations disappeared angiographically in the follow-up by Kjellberg et al<sup>3</sup>of "about" 57% of 260 patients. To justify these poorer results, Dr Kjellberg dismisses angiographic
The distribution of labeled albumin across the rabbit thoracic aorta in vivo.
Authors: R L Bratzler, G M Chisolm, C K Colton, K A Smith, D B Zilversmit, R S Lees
Journal: Circulation Research (1977)

125I-albumin was injected intravenously into normal conscious rabbits. The rabbits were killed after 10 minutes to 24 hours, and the descending thoracic aorta was excises immediately, opened longitudinally, rinsed, and frozen. Samples of frozen aorta were sectioned paralled to the intimal surface and washed with trichloroacetic acid (TCA) prior to counting. TCA-soluble tissue radioactivity slowly increased with time, suggesting that 125I was cleaved gradually from the labeled albumin within the aortic wall. At up to 4 hours, transmural concentration profiles of TCA-precipitable radioactivity had steep gradients near the intimal surface, moderate gradients near the medial-advential border, and were relatively falt in the middle of the media. After 24 hours, the steep intimal gradient had disappeared. Concentrations were otherwise comparable to those at 4 hours. The rate of accumulation of TCA-precipitable radioactivity was rapid initially (measurable concentrations were found throughout the media after only 10 minutes) and decreased with time. The results are consistent with entry of 125I-albumin into the media from both the luminal and adventitial sides. Approximate calculations indicate that the albumin mass transfer resistance associated with the intimal endothelium is about 1 order of magnitude greater than that associated with the media.
Colesevelam Improves Oral but Not Intravenous Glucose Tolerance by a Mechanism Independent of Insulin Sensitivity and β-Cell Function
Authors: Anna L. Marina, Kristina M. Utzschneider, Lorena A. Wright, Brenda K. Montgomery, Santica M. Marcovina, Steven E. Kahn
Journal: Diabetes Care (2012)

To determine the mechanism by which the bile acid sequestrant colesevelam improves glycemic control.We performed a frequently sampled intravenous glucose tolerance test (FSIGT) with minimal model analysis and a meal tolerance test (MTT) in 20 subjects with impaired fasting glucose (11 men, 9 women; mean age 60.7 ± 1.9 years, BMI 29.4 ± 0.9 kg/m(2)) in a single-blind study after 2 weeks of placebo treatment and 8 weeks of colesevelam 3.75 g daily. From these tests, insulin sensitivity, β-cell function, and glucose tolerance were determined, along with gastrointestinal peptide levels during the MTT.Fasting plasma glucose and HbA(1c) decreased with colesevelam (from 5.9 ± 0.1 to 5.7 ± 0.1 mmol/L, P < 0.05, and from 5.86 ± 0.06 to 5.76 ± 0.06%, P = 0.01, respectively), but fasting insulin did not change. Colesevelam had no effect on any FSIGT measures. In contrast, the MTT incremental area under the curve (iAUC) for both glucose (from 249.3 ± 28.5 to 198.8 ± 23.6 mmol/L · min, P < 0.01) and insulin (from 20,130 [13,542-35,292] to 13,086 [9,804-21,138] pmol/L · min, P < 0.05) decreased with colesevelam. However, the ratio of iAUC insulin to iAUC glucose was not changed. iAUC for cholecystokinin (CCK) increased (from 43.2 [0-130.1] to 127.1 [47.2-295.2] pmol/L · min, P < 0.01), while iAUC for fibroblast growth factor 19 decreased (from 11,185 [1,346-17,661] to 2,093 [673-6,707] pg/mL · min, P < 0.01) with colesevelam. However, iAUC for glucagon, glucose-dependent insulinotropic peptide, and glucagon-like peptide 1 did not change.Colesevelam improves oral but not intravenous glucose tolerance without changing insulin sensitivity, β-cell function, or incretins. This effect may be at least partially explained by the colesevelam-induced increase in CCK.