tbuckley/cabot-search huggingface dataset:
Autophagy: Basic Principles and Relevance to Disease
Authors: Mondira Kundu, Craig B. Thompson
Journal: Annual Review of Pathology Mechanisms of Disease (2008)

Autophagy is a process by which cytoplasmic components are sequestered in double membrane vesicles and degraded upon fusion with lysosomal compartments. In yeast, autophagy is activated in response to changes in the extracellular milieu. Depending upon the stimulus, autophagy can degrade cytoplasmic contents nonspecifically or can target the degradation of specific cellular components. Both of these have been adopted in higher eukaryotes and account for the expanding role of autophagy in various cellular processes, as well as contribute to the variation in cellular outcomes after induction of autophagy. In some cases, autophagy appears to be an adaptive response, whereas under other circumstances it is involved in cell death. In mammals, autophagy has been implicated in either the pathogenesis or response to a wide variety of diseases, including neurodegenerative disease, chronic bacterial and viral infections, atherosclerosis, and cancer. As the basic molecular pathways that regulate autophagy are elucidated, the relationship of autophagy to the pathogenesis of various disease states emerges.
The Terrible Choice: Re-Evaluating Hospice Eligibility Criteria for Cancer
Authors: David J. Casarett, Jessica M. Fishman, Hien L. Lu, Peter J. O'Dwyer, Frances K. Barg, Mary D. Naylor, David A. Asch
Journal: Journal of Clinical Oncology (2008)

To be eligible for the Medicare Hospice Benefit, cancer patients with a life expectancy of 6 months or less must give up curative treatment. Our goal was to determine whether willingness to make this choice identifies patients with greater need for hospice services.Three hundred patients with cancer and 171 family members were recruited from six oncology practices. Respondents completed conjoint interviews in which their perceived need for five hospice services was calculated from the choices they made among combinations of services. Patients' preferences for treatment were measured, and patients were followed for 6 months or until death.Thirty-eight patients (13%) said they would not want cancer treatment even if it offered an almost 100% chance of 6-month survival. These patients, who would have been eligible for hospice, did not have greater perceived need for hospice services compared with other patients (n = 262; mean, 1.75 v 1.98; Wilcoxon rank sum test, P = .46), nor did their family members (mean, 1.95 v 2.04; Wilcoxon rank sum test, P = .80). Instead, independent predictors of patients' perceived need for hospice services included African American ethnicity, less social support, worse functional status, and a greater burden of psychological symptoms. For families, predictors included caregiver burden, worse self-reported health, working outside the home, and caring for a patient with worse functional status.The requirement that patients forgo life-sustaining treatment does not identify patients with greater perceived need for hospice services. Other characteristics offer a better way to identify the patients who are most likely to benefit from hospice.
Pharmacogenomic considerations in the opioid management of pain
Authors: Paul J Jannetto, Nancy C Bratanow
Journal: Genome Medicine (2010)

Physicians continue to struggle with the clinical management of pain, in part because of the large interindividual variability in the efficacy, occurrence of side effects and undesired severe adverse drug reactions from the prescribed analgesics. Pharmacogenomics, the study of how an individual's genetic inheritance affects the body's response to medications, has an important role and can explain some of this interindividual variability. Genetic identification of known variant alleles that affect the pharmacokinetics or pharmacodynamics of medications used for pain management can enable physicians to select the appropriate analgesic drug and dosing regimen for an individual patient, instead of empirical selection and dosing escalation. In this article, clinically relevant pharmacogenomic targets for the management of opioid pain, including efflux transporters, proteins that metabolize drugs, enzymes that regulate the neurotransmitters that modulate pain, and opioid receptors, will be reviewed.
Involvement of functional autoantibodies against vascular receptors in systemic sclerosis
Authors: Gabriela Riemekasten, Aurélie Philippe, Melanie Näther, Torsten Slowinski, Dominik N Müller, Harald Heidecke, Marco Matucci-Cerinic, László Czirják, Ivo Lukitsch, Mike Becker, Angela Kill, Jacob M van Laar, Rusan Catar, Friedrich C Luft, Gerd R Burmester, Björn Hegner, Duska Dragun
Journal: Annals of the Rheumatic Diseases (2010)

Background Systemic sclerosis (SSc) features autoimmunity, vasculopathy and tissue fibrosis. The renin-angiotensin and endothelin systems have been implicated in vasculopathy and fibrosis. A role for autoantibody-mediated receptor stimulation is hypothesised, linking three major pathophysiological features consistent with SSc. Methods Serum samples from 478 patients with SSc (298 in the study cohort and 180 from two further independent cohorts), 372 healthy subjects and 311 control-disease subjects were tested for antibodies against angiotensin II type 1 receptor (AT 1 R) and endothelin-1 type A receptor (ET A R) by solid phase assay. Binding specificities were tested by immunoprecipitation. The biological effects of autoantibodies in microvascular endothelial cells in vitro were also determined, as well as the quantitative differences in autoantibody levels on specific organ involvements and their predictive value for SSc-related mortality. Results Anti-AT 1 R and anti-ET A R autoantibodies were detected in most patients with SSc. Autoantibodies specifically bound to respective receptors on endothelial cells. Higher levels of both autoantibodies were associated with more severe disease manifestations and predicted SSc-related mortality. Both autoantibodies exert biological effects as they induced extracellular signal-regulated kinase 1/2 phosphorylation and increased transforming growth factor β gene expression in endothelial cells which could be blocked with specific receptor antagonists. Conclusions Functional autoimmunity directed at AT 1 R and ET A R is common in patients with SSc. AT 1 R and ET A R autoantibodies could contribute to disease pathogenesis and may serve as biomarkers for risk assessment of disease progression.
Abnormalities of pulmonary function tests after marrow transplantation predict nonrelapse mortality.
Authors: S W Crawford, M Pepe, D Lin, F Benedetti, H J Deeg
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

To determine whether pulmonary function test (PFT) results after marrow transplantation were predictive of nonrelapse mortality, a review was made of prospective, nonrandomized PFT results for association with nonrelapse mortality by log-rank test and Cox proportional hazards modeling. The setting was a tertiary referral center. The patients were all marrow recipients who performed PFT between Days 60 and 120 after marrow transplantation between July 1, 1983 and December 31, 1990 (n = 906). At 3 mo after transplantation, the mean values for total lung capacity (TLC) and diffusing capacity decreased, and restrictive ventilatory defects (TLC < 80% of predicted) were noted in 34% of the cohort. Airflow rates (FEV1/FVC) were unchanged. A restrictive lung defect at 3 mo after transplant or a significant decline (> or = 15%) in TLC from baseline despite remaining within the normal range was associated with a twofold increased risk of nonrelapse mortality. Neither airflow obstruction nor impairment in diffusing capacity was associated with an increased risk. Abnormalities of the TLC at 3 mo after transplant were associated with death with respiratory failure, but not with an increased risk of chronic graft-versus-host disease (GVHD). There is an increase in the nonrelapse mortality rate associated with either the presence of a restrictive defect 3 mo after marrow transplantation or a significant decline in lung volume compared with baseline. This effect is most pronounced more than 1 yr after marrow transplant and appears to be a result of an increase in the rate of death with respiratory failure, not chronic GVHD.(ABSTRACT TRUNCATED AT 250 WORDS)
Prostaglandin E2 regulates B cell proliferation through a candidate tumor suppressor, <i>Ptger4 </i>
Authors: Jernej Murn, Olivier Alibert, Ning Wu, Simon Tendil, Xavier Gidrol
Journal: The Journal of Experimental Medicine (2008)

B cell receptor (BCR) signaling contributes to the pathogenesis of B cell malignancies, and most B cell lymphomas depend on BCR signals for survival. Identification of genes that restrain BCR-mediated proliferation is therefore an important goal toward improving the therapy of B cell lymphoma. Here, we identify Ptger4 as a negative feedback regulator of proliferation in response to BCR signals and show that its encoded EP4 receptor is a principal molecule conveying the growth-suppressive effect of prostaglandin E2 (PGE2). Stable knockdown of Ptger4 in B cell lymphoma markedly accelerated tumor spread in mice, whereas Ptger4 overexpression yielded significant protection. Mechanistically, we show that the intrinsic activity of Ptger4 and PGE2-EP4 signaling target a similar set of activating genes, and find Ptger4 to be significantly down-regulated in human B cell lymphoma. We postulate that Ptger4 functions in B cells as a candidate tumor suppressor whose activity is regulated by PGE2 in the microenvironment. These findings suggest that targeting EP4 receptor for prostaglandin may present a novel strategy for treatment of B cell malignancies.
A Protein Kinase A–Independent Pathway Controlling Aquaporin 2 Trafficking as a Possible Cause for the Syndrome of Inappropriate Antidiuresis Associated with Polycystic Kidney Disease 1 Haploinsufficiency
Authors: Grazia Tamma, Domenica Lasorsa, Christiane Trimpert, Marianna Ranieri, Annarita Di Mise, Maria Grazia Mola, Lisa Mastrofrancesco, Olivier Devuyst, Maria Svelto, Peter M.T. Deen, Giovanna Valenti
Journal: Journal of the American Society of Nephrology (2014)

Renal water reabsorption is controlled by arginine vasopressin (AVP), which binds to V2 receptors, resulting in protein kinase A (PKA) activation, phosphorylation of aquaporin 2 (AQP2) at serine 256, and translocation of AQP2 to the plasma membrane. However, AVP also causes dephosphorylation of AQP2 at S261. Recent studies showed that cyclin-dependent kinases (cdks) can phosphorylate AQP2 peptides at S261 in vitro. We investigated the possible role of cdks in the phosphorylation of AQP2 and identified a new PKA-independent pathway regulating AQP2 trafficking. In ex vivo kidney slices and MDCK-AQP2 cells, R-roscovitine, a specific inhibitor of cdks, increased pS256 levels and decreased pS261 levels. The changes in AQP2 phosphorylation status were paralleled by increases in cell surface expression of AQP2 and osmotic water permeability in the absence of forskolin stimulation. R-Roscovitine did not alter cAMP-dependent PKA activity but specifically reduced protein phosphatase 2A (PP2A) expression and activity in MDCK cells. Notably, we found reduced PP2A expression and activity and reduced pS261 levels in Pkd1(+/-) mice displaying a syndrome of inappropriate antidiuresis with high levels of pS256, despite unchanged AVP and cAMP. Similar to previous findings in Pkd1(+/-) mice, R-roscovitine treatment caused a significant decrease in intracellular calcium in MDCK cells. Our data indicate that reduced activity of PP2A, secondary to reduced intracellular Ca(2+) levels, promotes AQP2 trafficking independent of the AVP-PKA axis. This pathway may be relevant for explaining pathologic states characterized by inappropriate AVP secretion and positive water balance.
Association of BMD and FRAX Score With Risk of Fracture in Older Adults With Type 2 Diabetes
Authors: Ann V. Schwartz
Journal: JAMA (2011)

Type 2 diabetes mellitus (DM) is associated with higher bone mineral density (BMD) and paradoxically with increased fracture risk. It is not known if low BMD, central to fracture prediction in older adults, identifies fracture risk in patients with DM.
Arthritis of the hip joint in Paget's disease, and treatment by osteotomy.
Authors: J R Pearson
Journal: Annals of the Rheumatic Diseases (1968)

the right-hand side in a right-handed man, suggesting some correlation with use.In general, therefore, it may be that minor trauma, causing increase in vascular perme- ability, is a localizing factor, not only in relation to skin lesions, but possibly in relation to joint lesions also.DR. GOLDING: I do not think that the skin lesions were, in fact, more severe on the right than on the left side.
Hemopexin Induces Nephrin-Dependent Reorganization of the Actin Cytoskeleton in Podocytes
Authors: Rachel Lennon, Anurag Singh, Gavin I. Welsh, Richard J. Coward, Simon Satchell, Lan Ni, Peter W. Mathieson, Winston W. Bakker, Moin A. Saleem
Journal: Journal of the American Society of Nephrology (2008)

Hemopexin is an abundant plasma protein that effectively scavenges heme. When infused into rats, hemopexin induces reversible proteinuria, and activated hemopexin is increased in children with minimal change nephrotic syndrome. These observations suggest a role for hemopexin in glomerular disease; in this study, the effects of active hemopexin on human podocytes and glomerular endothelial cells, the two cell types that compose the glomerular filtration barrier, were investigated. Within 30 min of treatment with hemopexin, actin reorganized from stress fibers to cytoplasmic aggregates and membrane ruffles in wild-type podocytes. This did not occur in nephrin-deficient podocytes unless they were transfected with nephrin-expressing plasmids. Furthermore, hemopexin did not affect actin organization in cells that do not express nephrin, specifically human glomerular endothelial cells, fibroblasts, and HEK293 cells. The effects of hemopexin on wild-type podocytes reversed within 4 h and were inhibited by preincubation with human plasma. Treatment with hemopexin activated protein kinase B in both wild-type and nephrin-deficient podocytes but activated RhoA only in wild-type cells. In addition, hemopexin led to a selective increase in the passage of albumin across monolayers of glomerular endothelial cells and to a reduction in glycocalyx. In summary, active hemopexin causes nephrin-dependent remodeling of podocytes and affects permeability of the glomerular filtration barrier by degrading the glycocalyx.
Ghrelin Inhibits Proinflammatory Responses and Nuclear Factor-κB Activation in Human Endothelial Cells
Authors: Wei Gen Li, Dan Gavrila, Xuebo Liu, Lixing Wang, Skuli Gunnlaugsson, Lynn L. Stoll, Michael L. McCormick, Curt D. Sigmund, Chaosu Tang, Neal L. Weintraub
Journal: Circulation (2004)

Ghrelin is a novel growth hormone-releasing peptide that has been shown to improve cachexia in heart failure and cancer and to ameliorate the hemodynamic and metabolic disturbances in septic shock. Because cytokine-induced inflammation is critical in these pathological states and because the growth hormone secretagogue receptor has been identified in blood vessels, we examined whether ghrelin inhibits proinflammatory responses in human endothelial cells in vitro and after administration of endotoxin to rats in vivo.Human umbilical vein endothelial cells (HUVECs) were treated with or without tumor necrosis factor-alpha (TNF-alpha), and induction of proinflammatory cytokines and mononuclear cell adhesion were determined. Ghrelin (0.1 to 1000 ng/mL) inhibited both basal and TNF-alpha-induced cytokine release and mononuclear cell binding. Intravenous administration of ghrelin also inhibited endotoxin-induced proinflammatory cytokine production in rats in vivo. Ghrelin inhibited H2O2-induced cytokine release in HUVECs, suggesting that the peptide blocks redox-mediated cellular signaling. Moreover, ghrelin inhibited basal and TNF-alpha-induced activation of nuclear factor-kappaB. Des-acyl ghrelin had no effect on TNF-alpha-induced cytokine production in HUVECs, suggesting that the antiinflammatory effects of ghrelin require interaction with endothelial growth hormone secretagogue receptors.Ghrelin inhibits proinflammatory cytokine production, mononuclear cell binding, and nuclear factor-kappaB activation in human endothelial cells in vitro and endotoxin-induced cytokine production in vivo. These novel antiinflammatory actions of ghrelin suggest that the peptide could play a modulatory role in atherosclerosis, especially in obese patients, in whom ghrelin levels are reduced.
Psychologists and Detainee Interrogations: Key Decisions, Opportunities Lost, and Lessons Learned
Authors: Kenneth S. Pope
Journal: Annual Review of Clinical Psychology (2011)

After the 9-11 terrorist attacks, U.S. psychologists faced hard choices about what roles, if any, were appropriate for psychologists in the detainee interrogations conducted in settings such as the Bagram Airbase, the Abu Ghraib Prison, and the Guantanamo Bay Detention Camps. The American Psychological Association (APA) sparked intense controversy with its policies and public statements. This article reviews APA decisions, documents, and public statements in this area, in the context of major criticisms and responses to those criticisms. The review focuses on key issues: how the APA created and reported policies in the areas of ethics and national security; transparency; psychologists' professional identities; psychologists' qualifications; ethical-legal conflicts; policies opposing torture; interpretations of avoiding harm; and effective interrogations. It suggests lessons learned, missed opportunities, and questions in need of a fresh approach.
What are the breast support choices of Australian women during physical activity?
Authors: K-A Bowles, J R Steele, B Munro
Journal: British Journal of Sports Medicine (2008)

This study aimed to quantify the breast support wearing and purchasing habits of young women and to assess factors that affect their sports bra usage during physical activity.Study results were obtained from a self-administered mail survey, which was posted to participants after gaining their verbal consent via random telephone recruitment.413 women aged 20 to 35 years were recruited from New South Wales, Australia.From the returned (65%) surveys only 41% of respondents currently wore an encapsulating sports bra during physical activity, primarily due to a lack of awareness of the importance of good breast support during physical activity. Bra size was a predictor of sports bra usage, whereby participants with large breasts were more than twice as likely to wear a sports bra as their smaller-breasted counterparts.It was concluded that, although encapsulating sports bras have been shown to effectively reduce breast motion and associated exercise-induced breast discomfort, these bras were not the breast support option most commonly chosen by young women during physical activity. It is recommended that all women, irrespective of breast size, be educated on the importance of wearing a well-fitted and supportive bra during physical activity to decrease excessive strain on breast tissue structures and related breast discomfort.
Impact of Type 2 Diabetes Mellitus on Sympathetic Neural Mechanisms in Hypertension
Authors: Robert J. Huggett, Eleanor M. Scott, Stephen G. Gilbey, John B. Stoker, Alan F. Mackintosh, David A.S.G. Mary
Journal: Circulation (2003)

Essential hypertension (EHT) is a major cardiovascular risk factor, and the additional presence of type 2 diabetes mellitus (DM2) increases this risk. However, although the sympathetic nerve hyperactivity of EHT is known to play a role in cardiovascular risk, the level of sympathetic nerve activity is known neither in DM2 nor in hypertensive type 2 diabetic patients (EHT+DM2). Therefore, we planned to quantify the vasoconstrictor sympathetic nerve activity in patients with EHT+DM2 and with DM2 relative to that in matched groups with EHT and normal blood pressure (NT).In 68 closely matched subjects with EHT+DM2 (n=17), DM2 (n=17), EHT (n=17), and NT (n=17), we measured resting muscle sympathetic nerve activity as the mean frequency of multiunit bursts (MSNA) and of single units (s-MSNA) with defined vasoconstrictor properties. The s-MSNA in EHT+DM2 (97+/-3.8 impulses/100 beats) was greater (at least P<0.001) than in EHT (69+/-3.4 impulses/100 beats) and DM2 (78+/-4.1 impulses/100 beats), and all these were significantly greater (at least P<0.01) than in NT (53+/-3.3 impulses/100 beats) despite similar age and body mass index. The MSNA followed a similar trend. In addition, the level of insulin was also raised in EHT+DM2 (20.4+/-3.6 microU/mL) and DM2 (18.1+/-3.1 microU/mL; at least P<0.05) compared with HT or NT.Patients with EHT+DM2, EHT, or DM2 had central sympathetic hyperactivity, although plasma insulin levels were raised only in EHT+DM2 and DM2. The combination of EHT and DM2 resulted in the greatest sympathetic hyperactivity and level of plasma insulin, and this hyperactivity could constitute a mechanism for the increased risks of this condition.
Screening for colorectal cancer: flexible sigmoidoscopy and faecal occult blood immunochemical testing. Which test is superior?
Authors: G. Castiglione
Journal: Gut (2009)

This issue of Gut reports a very interesting article by Hol and colleagues1 (see page 62) which compares the results of a randomised controlled trial (RCT) of a 3-day guaiac-based faecal occult blood test (gFOBT), a 1-day immunochemical faecal occult blood test (FIT), and flexible sigmoidoscopy (SIG) for the screening of colorectal cancer (CRC). This is the first study to compare the three tests contemporarily by an RCT as far compliance and detection rates (DRs) of tests are concerned. For this reason the paper is positioned at a crucial point in the discussion on CRC screening.

Several RCTs have been successfully concluded demonstrating the efficacy of gFOBT screening in reducing CRC mortality (range, 13–33%).2 Considering the limited impact of the gFOBT on mortality reduction, FITs have been introduced and several studies3 have demonstrated that FITs are more accurate than the gFOBT.

Moreover, in the last two decades SIG has been proposed as a screening test for CRC based on the assumption that distal colonic significant neoplasia may be predictive of possible proximal neoplasia.4 5 6 In the existing literature SIG DRs proved to be consistently higher than FIT or gFOBT DRs as far as single rank of screening was considered.7 Participation in SIG screening is usually low, at about 30%,5 6 7 with the notable exception …