tbuckley/cabot-search huggingface dataset:
Reduced Caudate and Nucleus Accumbens Response to Rewards in Unmedicated Individuals With Major Depressive Disorder
Authors: Diego A. Pizzagalli, Avram J. Holmes, Daniel G. Dillon, Elena L. Goetz, Jeffrey L. Birk, Ryan Bogdan, Darin D. Dougherty, Dan V. Iosifescu, Scott L. Rauch, Maurizio Fava
Journal: American Journal of Psychiatry (2009)

Objective: Major depressive disorder is characterized by impaired reward processing, possibly due to dysfunction in the basal ganglia. However, few neuroimaging studies of depression have distinguished between anticipatory and consummatory phases of reward processing. Using functional MRI (fMRI) and a task that dissociates anticipatory and consummatory phases of reward processing, the authors tested the hypothesis that individuals with major depression would show reduced reward-related responses in basal ganglia structures. Method: A monetary incentive delay task was presented to 30 unmedicated individuals with major depressive disorder and 31 healthy comparison subjects during fMRI scanning. Whole-brain analyses focused on neural responses to reward-predicting cues and rewarding outcomes (i.e., monetary gains). Secondary analyses focused on the relationship between anhedonic symptoms and basal ganglia volumes. Results: Relative to comparison subjects, participants with major depression showed significantly weaker responses to gains in the left nucleus accumbens and the caudate bilaterally. Group differences in these regions were specific to rewarding outcomes and did not generalize to neutral or negative outcomes, although relatively reduced responses to monetary penalties in the major depression group emerged in other caudate regions. By contrast, evidence for group differences during reward anticipation was weaker, although participants with major depression showed reduced activation to reward cues in a small sector of the left posterior putamen. In the major depression group, anhedonic symptoms and depression severity were associated with reduced caudate volume bilaterally. Conclusions: These results suggest that basal ganglia dysfunction in major depression may affect the consummatory phase of reward processing. Additionally, morphometric results suggest that anhedonia in major depression is related to caudate volume.
People who believe body weight is genetic eat less healthily and take less exercise, study finds
Authors: Susan Mayor
Journal: BMJ (2015)

People who believe that their weight is genetically determined make less healthy food choices, take less exercise, and have poorer self rated health, particularly as they get older, than people who consider that they can influence their weight, concludes a study published in Health Education and Behaviour .1

The study’s lead author, Mike Parent, from Texas Tech University, Lubbock, Texas, said, “Although some popular press and non-scholarly sources have claimed that weight is largely unchangeable, the relationship between this belief and objective measures of health remains unclear.”

To explore this …
Blood-brain barrier traversal by African trypanosomes requires calcium signaling induced by parasite cysteine protease
Authors: O. V. Nikolskaia, A. P. C. de A. Lima, Y. V. Kim, J. D. Lonsdale-Eccles, T. Fukuma, J. Scharfstein, D. J. Grab
Journal: Journal of Clinical Investigation (2006)

In this study we investigated why bloodstream forms of Trypanosoma brucei gambiense cross human brain microvascular endothelial cells (BMECs), a human blood-brain barrier (BBB) model system, at much greater efficiency than do T. b. brucei. After noting that T. b. gambiense displayed higher levels of cathepsin L–like cysteine proteases, we investigated whether these enzymes contribute to parasite crossing. First, we found that T. b. gambiense crossing of human BMECs was abrogated by N-methylpiperazine-urea-Phe-homopheylalanine-vinylsulfone-benzene (K11777), an irreversible inhibitor of cathepsin L–like cysteine proteases. Affinity labeling and immunochemical studies characterized brucipain as the K11777-sensitive cysteine protease expressed at higher levels by T. b. gambiense. K11777-treated T. b. gambiense failed to elicit calcium fluxes in BMECs, suggesting that generation of activation signals for the BBB is critically dependant on brucipain activity. Strikingly, crossing of T. b. brucei across the BBB was enhanced upon incubation with brucipain-rich supernatants derived from T. b. gambiense. The effects of the conditioned medium, which correlated with ability to evoke calcium fluxes, were canceled by K11777, but not by the cathepsin B inhibitor CA074. Collectively, these in vitro studies implicate brucipain as a critical driver of T. b. gambiense transendothelial migration of the human BBB.
Model for the in vivo assembly of nascent Ld class I molecules and for the expression of unfolded Ld molecules at the cell surface.
Authors: J D Smith, N B Myers, J Gorka, T H Hansen
Journal: The Journal of Experimental Medicine (1993)

To characterize the process of class I assembly and maturation, we have studied the Ld molecule of the mouse. Previous studies have shown that a significant proportion of intracellular and surface Ld molecules can be detected in an alternative conformation designated Ldalt1. Nascent Ldalt molecules are non-peptide ligand associated and are weakly associated with beta 2-microglobulin (beta 2m). Unexpectedly, when monoclonal antibodies were added directly to the lysis buffer, significant amounts of Ldalt/beta 2m heterodimer were detected, suggesting that beta 2m association is not necessarily sufficient to induce Ld conformation. By contrast, addition of peptide to cell lysates rapidly induced the folding of beta 2m-associated Ldalt to conformed Ld. Furthermore, the time course and dynamics of this conversion correlated precisely with peptide binding to Ld. The precursor-product relationship of Ldalt and conformed Ld was also visualized in vivo by pulse-chase analysis of BALB/c splenocytes. To investigate the factors that regulate intracellular transport of class I molecules, expression of Ld was studied in the peptide transport-deficient cell line, RMA.S-Ld, and in beta 2m-/- splenocytes. In contrast to wild-type cell lines, both Ldalt and conformed Ld are poorly expressed at the cell surface of RMA.S-Ld and beta 2m-/- splenocytes. Therefore, surface expression of Ldalt is dependent upon the concomitant expression of conformed Ld molecules. To determine whether surface Ldalt molecules can result from melting of conformed Ld molecules, surface Ld molecules were loaded with several different known Ld peptide ligands. Complexes of Ld with different ligands were found to have dramatically disparate surface half-lives. Importantly, the Ld peptide complexes that turned over the most rapidly resulted in the most gain in surface Ldalt, implying that peptide dissociation can induce the accumulation of nonconformed Ld heavy chains at the cell surface.
Effect of European Clinical Trials Directive on academic drug trials in Denmark: retrospective study of applications to the Danish Medicines Agency 1993-2006
Authors: Louise Berendt, Cecilia Håkansson, Karin Friis Bach, Kim Dalhoff, Per Buch Andreasen, Lene Grejs Petersen, Elin Andersen, Henrik Enghusen Poulsen
Journal: BMJ (2007)

To determine the impact of the European Union's Clinical Trials Directive on the number of academic drug trials carried out in Denmark.Retrospective review of applications for drug trials to the Danish Medicines Agency, 1993-2006.Applications for drug trials for alternate years were classified as academic or commercial trials. A random subset of academic trials was reviewed for number of participants in and intended monitoring of the trials.Academic and commercial drug trials showed an identical steady decline from 1993 to 2006 and no noticeable change after 2004 when good clinical practice became mandatory for academic trials.The Clinical Trials Directive introduced in May 2004 to ensure good clinical practice for academic drug trials was not associated with a decline in research activity in Denmark; presumably because good clinical practice units had already been in place in Danish universities since 1999. With such an infrastructure academic researchers can do drug trials under the same regulations as drug companies.
3bn of NHS money will go to new pooled fund for health and social care
Authors: A. O'Dowd
Journal: BMJ (2013)

Almost £4bn (€4.7bn; $6.1bn) is to be spent on promoting more integrated working between healthcare and social care services for older and disabled people, as part of the government’s spending review, but the NHS budget in England will also rise overall.

Chancellor George Osborne unveiled his spending review on Wednesday 26 June.1 He said that the NHS would receive a real terms increase of 0.1% in 2015-16, taking the total to £110.4bn, plus £4.7bn capital spending, at the same time that most government departments would see a cut to their funding, including a 10% reduction in funds to local government.

Doctors’ leaders, while welcoming the decision to protect the NHS budget, said that the new pooled fund should not result in money being diverted away from general practice and warned that cuts to local government …
Role of angiotensin II in the development of peripheral vasoconstriction during cardiopulmonary bypass
Authors: K. M. TAYLOR, J. J. BRANNAN, W. H. BAIN, P. K. CAVES, I. J. MORTON
Journal: Cardiovascular Research (1979)

The possible relationship between angiotensin II — the end product of the reninangiotensin system, and the increase in peripheral vasoconstriction associated with cardiopulmonary bypass, has been investigated in 12 patients undergoing elective open-heart surgical procedures. Plasma angiotensin II (AII) levels were measured by radio-immunoassay at the start and the end of the period of cardiopulmonary bypass. Measurements of peripheral vascular resistance index were made at the times of AII sampling. Plasma AII levels rose during CPB from 78.0 to 231.3 pg·cm−3(normal values <35 pg·cm−3). Peripheral vascular resistance index also rose during perfusion from 20.87 to 27.83 units. The rise in plasma AII levels and in peripheral vascular resistance index were correlated for each of the 12 patients. A highly significant correlation was obtained (r=0.91; P <0.001). These results confirm the presence of parallel rises in plasma angiotensin II levels and in peripheral vasoconstriction during conventional non-pulsatile cardiopulmonary bypass, and suggest that increased plasma AII levels may be the principal causative factor in the increased vasoconstriction associated with open-heart surgical procedures.
Legal Ramifications of the Medical Definition of Back Disease
Authors: NORTlN M. HAULER
Journal: Annals of Internal Medicine (1978)

Back pain occurring without external force is extraordinarily prevalent in all segments of society. The practicing internist is often faced with the complaint, a need to define its cause, and a request to render an opinion as to whether the patient is disabled in the context of his employment. This opinion will have some weight in determining compensability under workmen's compensation law. This essay examines the inferences, as regards back pain, upon which compensation law is based. These inferences are then tested in light of our current understanding of the pathophysiology of back pain. A number of fallacies become apparent that may provide impetus for remedial legislation and clearly mandate further clinical investigation.
Cancer Survivorship and Cancer Rehabilitation: Revitalizing the Link
Authors: Catherine M. Alfano, Patricia A. Ganz, Julia H. Rowland, Erin E. Hahn
Journal: Journal of Clinical Oncology (2012)

Catherine M. Alfano, Office of Cancer Survivorship, National Cancer Institute/National Institutes of Health/Department of Health and Human Services, Bethesda, MD Patricia A. Ganz, School of Medicine, School of Public Health, and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA Julia H. Rowland, Office of Cancer Survivorship, National Cancer Institute/National Institutes of Health/Department of Health and Human Services, Bethesda, MD Erin E. Hahn, School of Public Health and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA
Troglitazone Acts on Cellular pH and DNA Synthesis through a Peroxisome Proliferator-Activated Receptor γ-Independent Mechanism in Breast Cancer-Derived Cell Lines
Authors: Francesco Turturro, Ellen Friday, Rocky Fowler, Diya Surie, Tomas Welbourne
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The purpose of this study was to assess whether troglitazone (TRO) would induce cellular acidosis by inhibiting Na+/H+ exchanger (NHE) 1 in breast carcinoma-derived cell lines and, if so, whether cellular acidosis would be associated with a reduction in proliferation. Experimental Design: Intracellular pH (pHi) and acid extrusion capacity after an exogenous acid load were assayed using (2, 7)-biscarboxyethyl-5(6)-carboxyfluorescein in MCF-7 and MDA-MB-231 cells treated with TRO. Radiolabeled thymidine incorporation was used to assess DNA synthesis. Peroxisome proliferator-activated receptor (PPAR) γ involvement was assessed using an antagonist and PPARγ−/− NIH3T3 cells. Results: TRO induced a prompt (&amp;lt;4 minute) and severe cellular acidosis in both MCF-7 (7.54 ± 0.23 to 6.77 ± 0.06; P &amp;lt; 0.001) and MDA-MB-231 cells (7.38 ± 0.18 to 6.89 ± 0.25; P &amp;lt; 0.05) after 12 minutes, without increasing acid production. Acid extrusion as assessed by the response to an exogenous acid load (NH4Cl pulse) was markedly blunted (MDA-MB-231, P &amp;lt; 0.01) or eliminated (MCF-7, P &amp;lt; 0.001). Chronic exposure to TRO resulted in NHE1 activity reduction (P &amp;lt; 0.05) and a dose-dependent decrease in DNA synthesis (&amp;lt;75% inhibition at 100 μmol/L; P &amp;lt; 0.001 and P &amp;lt; 0.01 for MCF-7 and MDA-MB-231, respectively) associated with a decreased number of viable cells. TRO-mediated inhibition of proliferation was not reversed by the presence of the PPARγ inhibitor GW9662 and was demonstrable in PPARγ−/− NIH3T3 cells, consistent with a PPARγ-independent mechanism. Conclusions: TRO induces marked cellular acidosis in MCF-7 and MDA-MD-231 cells. Sustained acidosis is consonant with decreased proliferation and growth that is not reversed by a PPARγ antagonist. Our results support a NHE-mediated action of TRO that exerts its effect independent of PPARγ.
Identification of persistent defects in insulin receptor structure and function capillary endothelial cells from diabetic rats.
Authors: C F Kwok, B J Goldstein, D Muller-Wieland, T S Lee, C R Kahn, G L King
Journal: Journal of Clinical Investigation (1989)

Insulin actions and receptors were studied in capillary endothelial cells cultured from diabetic BB rats and their nondiabetic colony mates. The endothelial cells from diabetic rats of 2 mo duration had persistent biological and biochemical defects in culture. Compared with normal rats, endothelial cells from diabetic rats grew 44% more slowly. Binding studies of insulin and insulin-like growth factor I (IGF-I) showed that cells from diabetic rats had 50% decrease of insulin receptor binding (nondiabetic: 4.6 +/- 0.7; diabetic: 2.6 +/- 0.4% per milligram protein, P less than 0.01), which was caused by a 50% decrease in the number of binding sites per milligram protein, whereas IGF-I binding was not changed. Insulin stimulation of 2-deoxy-glucose uptake and alpha-aminoisobutyric acid uptake were also severely impaired with a 80-90% decrease in maximal stimulation, in parallel with a 62% decrease in insulin-stimulated autophosphorylation (P less than 0.05). 125I-insulin cross-linking revealed an 140-kD alpha subunit of the insulin receptor similar to that in cells from nondiabetic rats, although bands at greater than 200 kD were also detected. The molecular weight of the insulin receptor beta subunit (by SDS-PAGE) was smaller in cells from diabetic than from normal rats (88-90 vs. 95 kD). Neuraminadase treatment of the partially purified insulin receptors decreased the molecular weight of the insulin receptors from nondiabetic rats to a greater degree than its diabetic counterpart. In contrast, Northern blot analysis of insulin receptor mRNAs using human cDNA probes revealed two species of 9.4 and 7.2 kb with no difference in mRNA abundance between cells from diabetic and nondiabetic rats. We conclude that the exposure of capillary endothelial cells to a diabetic milieu in vivo can cause specific and persistent changes in the insulin receptor and insulin action.
Effect of Chronic Renal Failure on Cardiac Contractile Function, Calcium Cycling, and Gene Expression of Proteins Important for Calcium Homeostasis in the Rat
Authors: David Kennedy, Eiad Omran, Sankaridrug M. Periyasamy, Jalaa Nadoor, Anumeet Priyadarshi, James C. Willey, Deepak Malhotra, Zijian Xie, Joseph I. Shapiro
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Patients with chronic renal failure frequently develop cardiac hypertrophy and diastolic dysfunction; however, the mechanisms by which this occurs are still unclear. Male Sprague-Dawley rats were subjected to 5/6 nephrectomy and studied for their isolated myocyte function, calcium cycling, and gene expression of proteins important in calcium homeostasis after 4 wk. Comparable rats subjected to suprarenal aortic banding for the same duration were used for comparison. Rats subjected to 5/6 nephrectomy and aortic banding developed comparable hypertension; however, rats subjected to 5/6 nephrectomy experienced a greater degree of cardiac hypertrophy and downregulation of cardiac sodium potassium ATPase (Na+/K+-ATPase) activity than rats subjected to aortic banding. Moreover, cells isolated from the 5/6 nephrectomy rat hearts displayed impaired contractile function and altered calcium cycling compared with cells isolated from control or aortic constriction rat hearts. The 5/6 nephrectomy rat heart cells displayed a prolonged time constant for calcium recovery following stimulation, which corresponded to decreases in homogenate sarcoplasmic reticulum calcium ATPase-2a (SERCA2a) activity, protein density, and mRNA for SERCA2a. In conclusion, chronic renal failure leads to alterations in cardiac gene expression, which produces alterations in cardiac calcium cycling and contractile function. These changes cannot be explained only by the observed increases in BP. E-mail: [email protected]
Androgen Receptor Overexpression in Prostate Cancer Linked to Purα Loss from a Novel Repressor Complex
Authors: Longgui G. Wang, Edward M. Johnson, Yayoi Kinoshita, James S. Babb, Michael T. Buckley, Leonard F. Liebes, Jonathan Melamed, Xiao-Mei Liu, Ralf Kurek, Liliana Ossowski, Anna C. Ferrari
Journal: Cancer Research (2008)

Abstract Increased androgen receptor (AR) expression and activity are pivotal for androgen-independent (AI) prostate cancer (PC) progression and resistance to androgen-deprivation therapy. We show that a novel transcriptional repressor complex that binds a specific sequence (repressor element) in the AR gene 5′-untranslated region contains Purα and hnRNP-K. Purα expression, its nuclear localization, and its AR promoter association, as determined by chromatin immunoprecipitation analysis, were found to be significantly diminished in AI-LNCaP cells and in hormone-refractory human PCs. Transfection of AI cells with a plasmid that restored Purα expression reduced AR at the transcription and protein levels. Purα knockdown in androgen-dependent cells yielded higher AR and reduced p21, a gene previously shown to be under negative control of AR. These changes were linked to increased proliferation in androgen-depleted conditions. Treatment of AI cells with histone deacetylase and DNA methylation inhibitors restored Purα protein and binding to the AR repressor element. This correlated with decreased AR mRNA and protein levels and inhibition of cell growth. Purα is therefore a key repressor of AR transcription and its loss from the transcriptional repressor complex is a determinant of AR overexpression and AI progression of PC. The success in restoring Purα and the repressor complex function by pharmacologic intervention opens a promising new therapeutic approach for advanced PC. [Cancer Res 2008;68(8):2678–88]
The Excitatory Amino Acid Receptors: Their Classes, Pharmacology, and Distinct Properties in the Function of the Central Nervous System
Authors: D T Monaghan, R J Bridges, C W Cotman
Journal: The Annual Review of Pharmacology and Toxicology (1989)

'The following abbreviations have been used in the text; I3-L-ODAP, I3-N-uxalyl-L-a,l3diaminu-prupiunic acid; ACPD, Trans-l-aminu-cydupentyl-I,3-dicarbuxylate; AMPA, a­ aminu-3-hydruxy-5-methyl-isoxazole-4-propionate; AP4, 2-amino-4-phosphonobutyrate; AP5, 2-amino-5-phuphonovalerate; ASP, aspartate; CNQX, 6-cyano-7-nitro-quinoxaline-2,3-dione; CPP, 3-(2-earboxypiperazin-4-yl)prupyl-l -phosphate; cyelo-Leu, eydo-Ieucine; DAA, D-a­ amino-adipate; DGG, y-D-glutamylglycine; DNQX, 6,7-dinitro-quinoxaline-2,3dione; EAA, excitatory amino acids; GABA, gamma-aminu-butyric acid; GDEE, glutamate diethyl ester; GLU, glutamate; GL Y, glycine; HA-966, 3-amino-l-hydroxypyrrolidone-2; lBO, ibotenate; IP, inositol phosphate; KA, kainate; KYN, kynurenate; MK-801, dibenzoeyclohepteneimine; NMDA, N-methyl-D-aspartate; PCP, phencyclidine; QA, quisqualate; SER, serine; SOP, serine­ O-phosphate; TCP, 1-[1-(2-thienyl)-eyclohexyIJpiperidine
Asthma exacerbations {middle dot} 3: Pathogenesis
Authors: P A B Wark
Journal: Thorax (2006)

Asthma exacerbations are an exaggerated lower airway response to an environmental exposure. Respiratory virus infection is the most common environmental exposure to cause a severe asthma exacerbation. Airway inflammation is a key part of the lower airway response in asthma exacerbation, and occurs together with airflow obstruction and increased airway responsiveness. The patterns of airway inflammation differ according to the trigger factor responsible for the exacerbation. The reasons for the exaggerated response of asthmatic airways are not completely understood, but recent studies have identified a deficient epithelial type 1 interferon response as an important susceptibility mechanism for viral infection.